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Sample records for repeated cocaine exposure

  1. Repeated restraint stress exposure during early withdrawal accelerates incubation of cue-induced cocaine craving.

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    Glynn, Ryan M; Rosenkranz, J Amiel; Wolf, Marina E; Caccamise, Aaron; Shroff, Freya; Smith, Alyssa B; Loweth, Jessica A

    2018-01-01

    A major challenge for treating cocaine addiction is the propensity for abstinent users to relapse. Two important triggers for relapse are cues associated with prior drug use and stressful life events. To study their interaction in promoting relapse during abstinence, we used the incubation model of craving and relapse in which cue-induced drug seeking progressively intensifies ('incubates') during withdrawal from extended-access cocaine self-administration. We tested rats for cue-induced cocaine seeking on withdrawal day (WD) 1. Rats were then subjected to repeated restraint stress or control conditions (seven sessions held between WD6 and WD14). All rats were tested again for cue-induced cocaine seeking on WD15, 1 day after the last stress or control session. Although controls showed a time-dependent increase in cue-induced cocaine seeking (incubation), rats exposed to repeated stress in early withdrawal exhibited a more robust increase in seeking behavior between WD1 and WD15. In separate stressed and control rats, equivalent cocaine seeking was observed on WD48. These results indicate that repeated stress in early withdrawal accelerates incubation of cocaine craving, although craving plateaus at the same level were observed in controls. However, 1 month after the WD48 test, rats subjected to repeated stress in early withdrawal showed enhanced cue-induced cocaine seeking following acute (24 hours) food deprivation stress. Together, these data indicate that chronic stress exposure enhances the initial rate of incubation of craving during early withdrawal, resulting in increased vulnerability to cue-induced relapse during this period, and may lead to a persistent increase in vulnerability to the relapse-promoting effects of stress. © 2016 Society for the Study of Addiction.

  2. Aberrant approach-avoidance conflict resolution following repeated cocaine pre-exposure.

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    Nguyen, David; Schumacher, Anett; Erb, Suzanne; Ito, Rutsuko

    2015-10-01

    Addiction is characterized by persistence to seek drug reinforcement despite negative consequences. Drug-induced aberrations in approach and avoidance processing likely facilitate the sustenance of addiction pathology. Currently, the effects of repeated drug exposure on the resolution of conflicting approach and avoidance motivational signals have yet to be thoroughly investigated. The present study sought to investigate the effects of cocaine pre-exposure on conflict resolution using novel approach-avoidance paradigms. We used a novel mixed-valence conditioning paradigm to condition cocaine-pre-exposed rats to associate visuo-tactile cues with either the delivery of sucrose reward or shock punishment in the arms in which the cues were presented. Following training, exploration of an arm containing a superimposition of the cues was assessed as a measure of conflict resolution behavior. We also used a mixed-valence runway paradigm wherein cocaine-pre-exposed rats traversed an alleyway toward a goal compartment to receive a pairing of sucrose reward and shock punishment. Latency to enter the goal compartment across trials was taken as a measure of motivational conflict. Our results reveal that cocaine pre-exposure attenuated learning for the aversive cue association in our conditioning paradigm and enhanced preference for mixed-valence stimuli in both paradigms. Repeated cocaine pre-exposure allows appetitive approach motivations to gain greater influence over behavioral output in the context of motivational conflict, due to aberrant positive and negative incentive motivational processing.

  3. Repeated cocaine exposure facilitates the expression of incentive motivation and induces habitual control in rats.

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    Kimberly H LeBlanc

    Full Text Available There is growing evidence that mere exposure to drugs can induce long-term alterations in the neural systems that mediate reward processing, motivation, and behavioral control, potentially causing the pathological pursuit of drugs that characterizes the addicted state. The incentive sensitization theory proposes that drug exposure potentiates the influence of reward-paired cues on behavior. It has also been suggested that drug exposure biases action selection towards the automatic execution of habits and away from more deliberate goal-directed control. The current study investigated whether rats given repeated exposure to peripherally administered cocaine would show alterations in incentive motivation (assayed using the Pavlovian-to-instrumental transfer (PIT paradigm or habit formation (assayed using sensitivity to reward devaluation. After instrumental and Pavlovian training for food pellet rewards, rats were given 6 daily injections of cocaine (15 mg/kg, IP or saline, followed by a 10-d period of rest. Consistent with the incentive sensitization theory, cocaine-treated rats showed stronger cue-evoked lever pressing than saline-treated rats during the PIT test. The same rats were then trained on a new instrumental action with a new food pellet reward before undergoing a reward devaluation testing. Although saline-treated rats exhibited sensitivity to reward devaluation, indicative of goal-directed performance, cocaine-treated rats were insensitive to this treatment, suggesting a reliance on habitual processes. These findings, when taken together, indicate that repeated exposure to cocaine can cause broad alterations in behavioral control, spanning both motivational and action selection processes, and could therefore help explain aberrations of decision-making that underlie drug addiction.

  4. Repeated cocaine exposure facilitates the expression of incentive motivation and induces habitual control in rats.

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    LeBlanc, Kimberly H; Maidment, Nigel T; Ostlund, Sean B

    2013-01-01

    There is growing evidence that mere exposure to drugs can induce long-term alterations in the neural systems that mediate reward processing, motivation, and behavioral control, potentially causing the pathological pursuit of drugs that characterizes the addicted state. The incentive sensitization theory proposes that drug exposure potentiates the influence of reward-paired cues on behavior. It has also been suggested that drug exposure biases action selection towards the automatic execution of habits and away from more deliberate goal-directed control. The current study investigated whether rats given repeated exposure to peripherally administered cocaine would show alterations in incentive motivation (assayed using the Pavlovian-to-instrumental transfer (PIT) paradigm) or habit formation (assayed using sensitivity to reward devaluation). After instrumental and Pavlovian training for food pellet rewards, rats were given 6 daily injections of cocaine (15 mg/kg, IP) or saline, followed by a 10-d period of rest. Consistent with the incentive sensitization theory, cocaine-treated rats showed stronger cue-evoked lever pressing than saline-treated rats during the PIT test. The same rats were then trained on a new instrumental action with a new food pellet reward before undergoing a reward devaluation testing. Although saline-treated rats exhibited sensitivity to reward devaluation, indicative of goal-directed performance, cocaine-treated rats were insensitive to this treatment, suggesting a reliance on habitual processes. These findings, when taken together, indicate that repeated exposure to cocaine can cause broad alterations in behavioral control, spanning both motivational and action selection processes, and could therefore help explain aberrations of decision-making that underlie drug addiction.

  5. Repeated stress exposure causes strain-dependent shifts in the behavioral economics of cocaine in rats

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    Groblewski, Peter A.; Zietz, Chad; Willuhn, Ingo; Phillips, Paul E. M.; Chavkin, Charles

    2015-01-01

    Cocaine-experienced Wistar and Wistar Kyoto (WKY) rats received four daily repeated forced swim stress sessions (R-FSS), each of which preceded 4-hour cocaine self-administration sessions. Twenty-four hours after the last swim stress, cocaine valuation was assessed during a single-session threshold

  6. Effects of acute versus repeated cocaine exposure on the expression of endocannabinoid signaling-related proteins in the mouse cerebellum

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    Ana ePalomino

    2014-03-01

    Full Text Available Growing awareness of cerebellar involvement in addiction is based on the cerebellum’s intermediary position between motor and reward, potentially acting as an interface between motivational and cognitive functions. Here, we examined the impact of acute and repeated cocaine exposure on the two main signaling systems in the mouse cerebellum: the endocannabinoid (eCB and glutamate systems. To this end, we investigated whether eCB signaling-related gene and protein expression (CB1 receptors and enzymes that produce (DAGLα/β and NAPE-PLD and degrade (MAGL and FAAH eCB were altered. In addition, we analyzed the gene expression of relevant components of the glutamate signaling system (glutamate synthesizing enzymes LGA and KGA, mGluR3/5 metabotropic receptors, and NR1/2A/2B/2C-NMDA and GluR1/2/3/4-AMPA ionotropic receptor subunits and the gene expression of tyrosine hydroxylase (TH, the rate-limiting enzyme in catecholamine biosynthesis, because noradrenergic terminals innervate the cerebellar cortex. Results indicated that acute cocaine exposure decreased DAGLα expression, suggesting a down-regulation of 2-AG production, as well as gene expression of TH, KGA, mGluR3 and all ionotropic receptor subunits analyzed in the cerebellum. The acquisition of conditioned locomotion and sensitization after repeated cocaine exposure were associated with an increased NAPE-PLD/FAAH ratio, suggesting enhanced anandamide production, and a decreased DAGLβ/MAGL ratio, suggesting decreased 2-AG generation. Repeated cocaine also increased LGA gene expression but had no effect on glutamate receptors. These findings indicate that acute cocaine modulates the expression of the eCB and glutamate systems. Repeated cocaine results in normalization of glutamate receptor expression, although sustained changes in eCB is observed. We suggest that cocaine-induced alterations to cerebellar eCB should be considered when analyzing the adaptations imposed by psychostimulants that

  7. Phasic Mesolimbic Dopamine Signaling Encodes the Facilitation of Incentive Motivation Produced by Repeated Cocaine Exposure

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    Ostlund, SB; LeBlanc, KH; Kosheleff, AR; Wassum, KM; Maidment, NT

    2014-01-01

    Drug addiction is marked by pathological drug seeking and intense drug craving, particularly in response to drug-related stimuli. Repeated psychostimulant administration is known to induce long-term alterations in mesolimbic dopamine (DA) signaling that are hypothesized to mediate this heightened sensitivity to environmental stimuli. However, there is little direct evidence that drug-induced alteration in mesolimbic DA function underlies this hypersensitivity to motivational cues. In the curr...

  8. Repeated in vivo exposure of cocaine induces long-lasting synaptic plasticity in hypocretin/orexin-producing neurons in the lateral hypothalamus in mice.

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    Rao, Yan; Mineur, Yann S; Gan, Geliang; Wang, Alex Hanxiang; Liu, Zhong-Wu; Wu, Xinyuan; Suyama, Shigetomo; de Lecea, Luis; Horvath, Tamas L; Picciotto, Marina R; Gao, Xiao-Bing

    2013-04-01

    Hypocretin (orexin), a neuropeptide synthesized exclusively in the perifornical/lateral hypothalamus, is critical for drug seeking and relapse, but it is not clear how the circuitry centred on hypocretin-producing neurons (hypocretin neurons) is modified by drugs of abuse and how changes in this circuit might alter behaviours related to drug addiction. In this study, we show that repeated, but not single, in vivo cocaine administration leads to a long-lasting, experience-dependent potentiation of glutamatergic synapses on hypocretin neurons in mice following a cocaine-conditioned place preference (CPP) protocol. The synaptic potentiation occurs postsynaptically and probably involves up-regulation of AMPA-type glutamate receptors on hypocretin neurons. Phosphorylation of cAMP response element-binding protein (CREB) is also significantly increased in hypocretin neurons in cocaine-treated animals, suggesting that CREB-mediated pathways may contribute to synaptic potentiation in these cells. Furthermore, the potentiation of synaptic efficacy in hypocretin neurons persists during cocaine withdrawal, but reverses to baseline levels after prolonged abstinence. Finally, the induction of long-term potentiation (LTP) triggered by a high-frequency stimulation is facilitated in hypocretin neurons in cocaine-treated mice, suggesting that long-lasting changes in synapses onto hypocretin neurons would probably be further potentiated by other stimuli (such as concurrent environmental cues) paired with the drug. In summary, we show here that hypocretin neurons undergo experience-dependent synaptic potentiation that is distinct from that reported in other reward systems, such as the ventral tegmental area, following exposure to cocaine. These findings support the idea that the hypocretin system is important for behavioural changes associated with cocaine administration in animals and humans.

  9. Prenatal and postnatal cocaine exposure predict teen cocaine use

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    Delaney-Black, Virginia; Chiodo, Lisa M.; Hannigan, John H.; Greenwald, Mark K.; Janisse, James; Patterson, Grace; Huestis, Marilyn A.; Partridge, Robert T.; Ager, Joel; Sokol, Robert J.

    2015-01-01

    Preclinical studies have identified alterations in cocaine and alcohol self-administration and behavioral responses to pharmacological challenges in adolescent offspring following prenatal exposure. To date, no published human studies have evaluated the relation between prenatal cocaine exposure and postnatal adolescent cocaine use. Human studies of prenatal cocaine-exposed children have also noted an increase in behaviors previously associated with substance use/abuse in teens and young adults, specifically childhood and teen externalizing behaviors, impulsivity, and attention problems. Despite these findings, human research has not addressed prior prenatal exposure as a potential predictor of teen drug use behavior. The purpose of this study was to evaluate the relations between prenatal cocaine exposure and teen cocaine use in a prospective longitudinal cohort (n = 316) that permitted extensive control for child, parent and community risk factors. Logistic regression analyses and Structural Equation Modeling revealed that both prenatal exposure and postnatal parent/caregiver cocaine use were uniquely related to teen use of cocaine at age 14 years. Teen cocaine use was also directly predicted by teen community violence exposure and caregiver negativity, and was indirectly related to teen community drug exposure. These data provide further evidence of the importance of prenatal exposure, family and community factors in the intergenerational transmission of teen/young adult substance abuse/use. PMID:20609384

  10. Prenatal and postnatal cocaine exposure predict teen cocaine use.

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    Delaney-Black, Virginia; Chiodo, Lisa M; Hannigan, John H; Greenwald, Mark K; Janisse, James; Patterson, Grace; Huestis, Marilyn A; Partridge, Robert T; Ager, Joel; Sokol, Robert J

    2011-01-01

    Preclinical studies have identified alterations in cocaine and alcohol self-administration and behavioral responses to pharmacological challenges in adolescent offspring following prenatal exposure. To date, no published human studies have evaluated the relation between prenatal cocaine exposure and postnatal adolescent cocaine use. Human studies of prenatal cocaine-exposed children have also noted an increase in behaviors previously associated with substance use/abuse in teens and young adults, specifically childhood and teen externalizing behaviors, impulsivity, and attention problems. Despite these findings, human research has not addressed prior prenatal exposure as a potential predictor of teen drug use behavior. The purpose of this study was to evaluate the relations between prenatal cocaine exposure and teen cocaine use in a prospective longitudinal cohort (n=316) that permitted extensive control for child, parent and community risk factors. Logistic regression analyses and Structural Equation Modeling revealed that both prenatal exposure and postnatal parent/caregiver cocaine use were uniquely related to teen use of cocaine at age 14 years. Teen cocaine use was also directly predicted by teen community violence exposure and caregiver negativity, and was indirectly related to teen community drug exposure. These data provide further evidence of the importance of prenatal exposure, family and community factors in the intergenerational transmission of teen/young adult substance abuse/use. Copyright © 2010 Elsevier Inc. All rights reserved.

  11. Prenatal Cocaine Exposure and Infant Cortisol Reactivity

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    Eiden, Rina D.; Veira, Yvette; Granger, Douglas A.

    2009-01-01

    This study examined the effects of prenatal cocaine exposure on infant hypothalamic-pituitary-adrenal axis activity and reactivity at 7 months of infant age. Participants were 168 caregiver-infant dyads (87 cocaine exposed, 81 not cocaine exposed; 47% boys). Maternal behavior, caregiving instability, and infant growth and behavior were assessed,…

  12. The effect of nicotine pre-exposure on demand for cocaine and sucrose in male rats.

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    Schwartz, Lindsay P; Kearns, David N; Silberberg, Alan

    2018-06-01

    The aim of the present study was to determine how nicotine pre-exposure affects the elasticity of demand for intravenous cocaine and for sucrose pellets in adult male rats. In Experiment 1, demand for cocaine was assessed in rats that had nicotine in their drinking water. Nicotine pre-exposure significantly decreased rats' willingness to defend cocaine consumption as the price (measured as the number of responses per cocaine infusion) increased compared with a control group with no nicotine pre-exposure. That is, nicotine increased the elasticity of demand for cocaine infusions. Experiment 2 repeated the first experiment, but with rats working for sucrose pellets instead of cocaine. Nicotine pre-exposure had no effect on the elasticity of demand for sucrose. This pattern of results suggests that nicotine pre-exposure can reduce the reinforcing effects of cocaine, but not sucrose, in adult male rats.

  13. Fetal cocaine exposure: analysis of vernix caseosa.

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    Moore, C; Dempsey, D; Deitermann, D; Lewis, D; Leikin, J

    1996-10-01

    Preliminary data regarding the use of vernix caseosa (VC) as an alternative to other biological specimens for the determination of fetal cocaine exposure are presented. Advantages of VC analysis include its presence on all newborn babies, historical record of drug exposure, and ease of collection and storage. Fifteen samples of vernix caseosa-five from babies known to be cocaine-exposed because of a positive benzoylecgonine result from the urine and umbilical cord blood and ten from nonexposed neonates-were analyzed for the presence of cocaine and metabolites. VC samples from three of the five neonates known to be cocaine-exposed were positive for cocaine or its metabolites, the other two had little or no remaining specimen. The remaining ten were negative.

  14. Impact of repeated intravenous cocaine administration on incentive motivation depends on mode of drug delivery.

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    LeBlanc, Kimberly H; Maidment, Nigel T; Ostlund, Sean B

    2014-11-01

    The incentive sensitization theory of addiction posits that repeated exposure to drugs of abuse, like cocaine, can lead to long-term adaptations in the neural circuits that support motivated behavior, providing an account of pathological drug-seeking behavior. Although pre-clinical findings provide strong support for this theory, much remains unknown about the conditions that support incentive sensitization. The current study examined whether the mode of cocaine administration is an important factor governing that drug's long-term impact on behavior. Separate groups of rats were allowed either to self-administer intravenous cocaine or were given an equivalent number and distribution of unsignaled cocaine or saline infusions. During the subsequent test of incentive motivation (Pavlovian-to-instrumental transfer), we found that rats with a history of cocaine self-administration showed strong cue-evoked food seeking, in contrast to rats given unsignaled cocaine or saline. This finding indicates that the manner in which cocaine is administered can determine its lasting behavioral effects, suggesting that subjective experiences during drug use play a critical role in the addiction process. Our findings may therefore have important implications for the study and treatment of compulsive drug seeking. © 2013 Society for the Study of Addiction.

  15. Cocaine Exposure Reorganizes Cell-Type and Input-Specific Connectivity in the Nucleus Accumbens

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    MacAskill, Andrew F.; Cassel, John M.; Carter, Adam G.

    2014-01-01

    Exposure to cocaine alters the structural and functional properties of medium spiny neurons (MSNs) in the Nucleus Accumbens (NAc). These changes suggest a rewiring of the NAc circuit, with an enhancement of excitatory synaptic connections onto MSNs. However, it is unknown how drug exposure alters the balance of long-range afferents onto different cell types in the NAc. Here we use whole-cell recordings, two-photon microscopy, optogenetics and pharmacogenetics to show how repeated cocaine alters connectivity in the mouse NAc medial shell. We first determine that cocaine selectively enhances amygdala innervation of D1-MSNs relative to D2-MSNs. We then show that amygdala activity is required for cocaine-induced changes to behavior and connectivity. Finally, we establish how heightened amygdala innervation can explain the structural and functional changes induced by cocaine. Our findings reveal how exposure to drugs of abuse fundamentally reorganizes cell-type and input-specific connectivity in the NAc. PMID:25108911

  16. Dopamine transporter down-regulation following repeated cocaine: implications for 3,4-methylenedioxymethamphetamine-induced acute effects and long-term neurotoxicity in mice.

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    Peraile, I; Torres, E; Mayado, A; Izco, M; Lopez-Jimenez, A; Lopez-Moreno, J A; Colado, M I; O'Shea, E

    2010-01-01

    3,4-Methylenedioxymethamphetamine (MDMA) and cocaine are two widely abused psychostimulant drugs targeting the dopamine transporter (DAT). DAT availability regulates dopamine neurotransmission and uptake of MDMA-derived neurotoxic metabolites. We aimed to determine the effect of cocaine pre-exposure on the acute and long-term effects of MDMA in mice. Mice received a course of cocaine (20 mg*kg(-1), x2 for 3 days) followed by MDMA (20 mg*kg(-1), x2, 3 h apart). Locomotor activity, extracellular dopamine levels and dopaminergic neurotoxicity were determined. Furthermore, following the course of cocaine, DAT density in striatal plasma membrane and endosome fractions was measured. Four days after the course of cocaine, challenge with MDMA attenuated the MDMA-induced striatal dopaminergic neurotoxicity. Co-administration of the protein kinase C (PKC) inhibitor NPC 15437 prevented cocaine protection. At the same time, after the course of cocaine, DAT density was reduced in the plasma membrane and increased in the endosome fraction, and this effect was prevented by NPC 15437. The course of cocaine potentiated the MDMA-induced increase in extracellular dopamine and locomotor activity, following challenge 4 days later, compared with those pretreated with saline. Repeated cocaine treatment followed by withdrawal protected against MDMA-induced dopaminergic neurotoxicity by internalizing DAT via a mechanism which may involve PKC. Furthermore, repeated cocaine followed by withdrawal induced behavioural and neurochemical sensitization to MDMA, measures which could be indicative of increased rewarding effects of MDMA.

  17. Adolescent cocaine exposure simplifies orbitofrontal cortical dendritic arbors

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    Lauren M DePoy

    2014-10-01

    Full Text Available Cocaine and amphetamine remodel dendritic spines within discrete cortico-limbic brain structures including the orbitofrontal cortex (oPFC. Whether dendrite structure is similarly affected, and whether pre-existing cellular characteristics influence behavioral vulnerabilities to drugs of abuse, remain unclear. Animal models provide an ideal venue to address these issues because neurobehavioral phenotypes can be defined both before, and following, drug exposure. We exposed mice to cocaine from postnatal days 31-35, corresponding to early adolescence, using a dosing protocol that causes impairments in an instrumental reversal task in adulthood. We then imaged and reconstructed excitatory neurons in deep-layer oPFC. Prior cocaine exposure shortened and simplified arbors, particularly in the basal region. Next, we imaged and reconstructed orbital neurons in a developmental-genetic model of cocaine vulnerability – the p190rhogap+/- mouse. p190RhoGAP is an actin cytoskeleton regulatory protein that stabilizes dendrites and dendritic spines, and p190rhogap+/- mice develop rapid and robust locomotor activation in response to cocaine. Despite this, oPFC dendritic arbors were intact in drug-naïve p190rhogap+/- mice. Together, these findings provide evidence that adolescent cocaine exposure has long-term effects on dendrite structure in the oPFC, and they suggest that cocaine-induced modifications in dendrite structure may contribute to the behavioral effects of cocaine more so than pre-existing structural abnormalities in this cell population.

  18. The Rewarding and Locomotor-Sensitizing Effects of Repeated Cocaine Administration are Distinct and Separable in Mice

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    Riday, Thorfinn T.; Kosofsky, Barry E.; Malanga, C.J.

    2011-01-01

    Repeated psychostimulant exposure progressively increases their potency to stimulate motor activity in rodents. This behavioral or locomotor sensitization is considered a model for some aspects of drug addiction in humans, particularly drug craving during abstinence. However, the role of increased motor behavior in drug reward remains incompletely understood. Intracranial self-stimulation (ICSS) was measured concurrently with locomotor activity to determine if acute intermittent cocaine administration had distinguishable effects on motor behavior and perception of brain stimulation-reward (BSR) in the same mice. Sensitization is associated with changes in neuronal activity and glutamatergic neurotransmission in brain reward circuitry. Expression of AMPA receptor subunits (GluR1 and GluR2) and CRE binding protein (CREB) was measured in the ventral tegmental area (VTA), dorsolateral striatum (STR) and nucleus accumbens (NAc) before and after a sensitizing regimen of cocaine, with and without ICSS. Repeated cocaine administration sensitized mice to its locomotor stimulating effects but not its ability to potentiate BSR. ICSS increased GluR1 in the VTA but not NAc or STR, demonstrating selective changes in protein expression with electrical stimulation of discrete brain structures. Repeated cocaine reduced GluR1, GluR2 and CREB expression in the NAc, and reductions of GluR1 and GluR2 but not CREB were further enhanced by ICSS. These data suggest that the effects of repeated cocaine exposure on reward and motor processes are dissociable in mice, and that reduction of excitatory neurotransmission in the NAc may predict altered motor function independently from changes in reward perception. PMID:22197517

  19. Sex differences in behavioral and PKA cascade responses to repeated cocaine administration.

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    Zhou, Luyi; Sun, Wei-Lun; Weierstall, Karen; Minerly, Ana Christina; Weiner, Jan; Jenab, Shirzad; Quinones-Jenab, Vanya

    2016-10-01

    Previous studies have shown sex different patterns in behavioral responses to cocaine. Here, we used between-subject experiment design to study whether sex differences exist in the development of behavioral sensitization and tolerance to repeated cocaine, as well as the role of protein kinase A (PKA) signaling cascade in this process. Ambulatory and rearing responses were recorded in male and female rats after 1 to 14 days of administration of saline or cocaine (15 mg/kg; ip). Correspondent PKA-associated signaling in the nucleus accumbens (NAc) and caudate-putamen (CPu) was measured at each time point. Our results showed that females exhibited higher cocaine-induced behavioral responses and developed behavioral sensitization and tolerance faster than males. Whereas females developed behavioral sensitization to cocaine after 2 days and tolerance after 14 days, male rats developed sensitization after 5 days. In addition, cocaine induced a sexual dimorphic pattern in the progression of neuronal adaptations on the PKA cascade signaling in region (NAc vs. CPu) and time (days of cocaine administration)-dependent manners. In general, more PKA signaling cascade changes were found in the NAc of males on day 5 and in the CPu of females with repeated cocaine injection. In addition, in females, behavioral activities positively correlated with FosB levels in the NAc and CPu and negatively correlated with Cdk5 and p35 in the CPu, while no correlation was observed in males. Our studies suggest that repeated cocaine administration induced different patterns of behavioral and molecular responses in the PKA cascade in male and female rats.

  20. D-cycloserine combined with cue exposure therapy fails to attenuate subjective and physiological craving in cocaine dependence.

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    Santa Ana, Elizabeth J; Prisciandaro, James J; Saladin, Michael E; McRae-Clark, Aimee L; Shaftman, Stephanie R; Nietert, Paul J; Brady, Kathleen T

    2015-04-01

    Based on preclinical studies showing that the partial N-methyl-D-aspartate (NMDA) agonist D-cycloserine (DCS) facilitates extinction of cocaine self-administration and cocaine-induced conditioned place preference, we evaluated whether 50 mg of DCS would reduce craving to cocaine cues when combined with cue exposure (CE) in cocaine dependent humans. In this double-blind placebo-controlled pilot study, 47 cocaine dependent participants were randomized to DCS or placebo (PBO), plus CE. Participants received DCS or PBO 30 minutes prior to two CE sessions, conducted one day apart. Craving and heart rate was assessed prior to CE sessions, during CE trials, and after CE trials. These measures were assessed again at a 1-week follow-up (session 3) after the second CE session. DCS failed to significantly attenuate cocaine cue reactivity based on subjective craving and physiological reactivity (heart rate) compared to PBO. The CE protocol, consisting of repeated exposure to drug cues combined with skills training, resulted in extinction to cocaine cues as suggested by decreased craving within and between sessions in both treatment conditions. All participants exhibited elevated heart rate with repeated exposures, demonstrating a potentiation in heart rate between sessions. 50 mg of DCS may not be effective for extinguishing reactivity to drug cues for individuals with cocaine dependence. Future studies examining the effect of DCS on facilitating extinction to drug cues should examine variations in cue exposure length, number of CE presentations, and timing of DCS dose administration prior to cue exposures, which may differentially impact drug cue reactivity. © American Academy of Addiction Psychiatry.

  1. Mephedrone interactions with cocaine: prior exposure to the 'bath salt' constituent enhances cocaine-induced locomotor activation in rats.

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    Gregg, Ryan A; Tallarida, Christopher S; Reitz, Allen B; Rawls, Scott M

    2013-12-01

    Concurrent use of mephedrone (4-methylmethcathinone; MEPH) and established drugs of abuse is now commonplace, but knowledge about interactions between these drugs is sparse. The present study was designed to test the hypothesis that prior MEPH exposure enhances the locomotor-stimulant effects of cocaine and methamphetamine (METH). For cocaine experiments, rats pretreated with saline, cocaine (15 mg/kg), or MEPH (15 mg/kg) for 5 days were injected with cocaine after 10 days of drug absence. For METH experiments, rats pretreated with saline, METH (2 mg/kg), or MEPH (15 mg/kg) were injected with METH after 10 days of drug absence. Cocaine challenge produced greater locomotor activity after pretreatment with cocaine or MEPH than after pretreatment with saline. METH challenge produced greater locomotor activity after METH pretreatment than after saline pretreatment; however, locomotor activity in rats pretreated with MEPH or saline and then challenged with METH was not significantly different. The locomotor response to MEPH (15 mg/kg) was not significantly affected by pretreatment with cocaine (15 mg/kg) or METH (0.5, 2 mg/kg). The present demonstration that cocaine-induced locomotor activation is enhanced by prior MEPH exposure suggests that MEPH cross-sensitizes to cocaine and increases cocaine efficacy. Interestingly, MEPH cross-sensitization was not bidirectional and did not extend to METH, suggesting that the phenomenon is sensitive to specific psychostimulants.

  2. Adolescent Initiation of Drug Use: Effects of Prenatal Cocaine Exposure

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    Richardson, Gale A.; Larkby, Cynthia; Goldschmidt, Lidush; Day, Nancy L.

    2013-01-01

    Objective: To investigate the direct effects of prenatal cocaine exposure (PCE) on adolescent drug use, while controlling for other predictors of adolescent use. Method: Data are from a longitudinal study of PCE in which women and their offspring were assessed throughout childhood. Adolescents were interviewed at 15 years about their age at…

  3. Behavioral sensitization after repeated formaldehyde exposure in rats.

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    Sorg, B A; Hochstatter, T

    1999-01-01

    Multiple chemical sensitivity (MCS) is a phenomenon whereby individuals report increased sensitivity to chemicals in the environment, and attribute their sensitivities to prior exposure to the same or often structurally unrelated chemicals. A leading hypothesis suggests that MCS is akin to behavioral sensitization observed in rodents after repeated exposure to drugs of abuse or environmental stressors. Sensitization occurring within limbic circuitry of the central nervous system (CNS) may explain the multisymptom complaints in individuals with MCS. The present studies represent the continuing development of an animal model for MCS, the basis of which is the CNS sensitization hypothesis. Three behaviors were assessed in rats repeatedly exposed to formaldehyde (Form) inhalation. In the first series of experiments, rats were given high-dose Form exposure (11 parts per million [ppm]; 1 h/day x 7 days) or low-dose Form exposure (1 ppm; either 1 h/day x 7 days or 1 h/day x 5 days/week x 4 weeks). Within a few days after discontinuing daily Form, cocaine-induced locomotor activity was elevated after high-dose Form or 20 days of low-dose Form inhalation. Approximately 1 month later, cocaine-induced locomotor activity remained significantly elevated in the 20-day Form-exposed rats. The second experiment assessed whether prior exposure to Form (20 days, as above) would alter the ability to condition to an odor (orange oil) paired with footshock. The results suggested a tendency to increase the conditioned fear response to the odor but not the context of the footshock box, and a decreased tendency to extinguish the conditioned fear response to odor. The third experiment examined whether CNS sensitization to daily cocaine or stress would alter subsequent avoidance responding to odor (Form). Daily cocaine significantly elevated approach responses to Form, while daily stress pretreatment produced a trend in the opposite direction, producing greater avoidance of Form. Preliminary

  4. Cocaine

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    ... Viral) HIV/AIDS Mental Health Military Opioid Overdose Reversal with Naloxone (Narcan, Evzio) Pain Prevention Recovery Substance ... cocaine impairs judgment, which can lead to risky sexual behavior with infected partners (see " Cocaine, HIV, and ...

  5. Cocaine

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    Cocaine is a white powder. It can be snorted up the nose or mixed with water and injected with a needle. Cocaine can also be made into small white rocks, ... Crack is smoked in a small glass pipe. Cocaine speeds up your whole body. You may feel ...

  6. Kalrn promoter usage and isoform expression respond to chronic cocaine exposure

    Directory of Open Access Journals (Sweden)

    Ma Xin-Ming

    2011-02-01

    Full Text Available Abstract Background The long-term effects of cocaine on behavior are accompanied by structural changes in excitatory glutamatergic synapses onto the medium spiny neurons of the striatum. The Kalrn gene encodes several functionally distinct isoforms; these multidomain guanine nucleotide exchange factors (GEFs contain additional domains known to interact with phosphatidylinositides as well as with a number of different proteins. Through their activation of Rho proteins and their interactions with other proteins, the different Kalirin isoforms affect cytoskeletal organization. Chronic exposure of adult male rodents to cocaine increases levels of Kalirin 7 in the striatum. When exposed chronically to cocaine, mice lacking Kalirin 7, the major adult isoform, fail to show an increase in dendritic spine density in the nucleus accumbens, show diminished place preference for cocaine, and exhibit increased locomotor activity in response to cocaine. Results The use of alternate promoters and 3'-terminal exons of the mouse Kalrn gene were investigated using real-time quantitative polymerase chain reaction. While the two most distal full-length Kalrn promoters are used equally in the prefrontal cortex, the more proximal of these promoters accounts for most of the transcripts expressed in the nucleus accumbens. The 3'-terminal exon unique to the Kalirin 7 isoform accounts for a greater percentage of the Kalrn transcripts in prefrontal cortex than in nucleus accumbens. Western blot analyses confirmed these differences. Chronic cocaine treatment increases usage of the promoter encoding the Δ-Kalirin isoforms but does not alter full-length Kalirin promoter usage. Usage of the 3'-terminal exon unique to Kalirin 7 increases following chronic cocaine exposure. Conclusions Kalrn promoter and 3'-terminal exon utilization are region-specific. In the nucleus accumbens, cocaine-mediated alterations in promoter usage and 3'-terminal exon usage favor expression of

  7. Prenatal Cocaine Exposure: A Comparison of 2-Year-Old Children in Parental and Nonparental Care

    Science.gov (United States)

    Brown, Josephine V.; Bakeman, Roger; Coles, Claire D.; Platzman, Kathleen A.; Lynch, Mary Ellen

    2004-01-01

    Effects of prenatal cocaine exposure and parental versus nonparental care on outcome at 2 years of age were examined. The sample included 83 cocaine-exposed and 63 nonexposed children and their caregivers; 49 and 34 of the cocaine-exposed children experienced parental and nonparental care, respectively. Prenatal drug exposure was not related…

  8. Repeated cocaine administration results in supersensitivity of striatal D-2 dopamine autoreceptors to pergolide

    International Nuclear Information System (INIS)

    Dwoskin, L.P.; Peris, J.; Yasuda, R.P.; Philpott, K.; Zahniser, N.R.

    1988-01-01

    Groups of rats administered cocaine-HCl (10 mg/kg, i.p.) or saline either acutely or once daily for 8 or 14 days were killed 24 hrs after the last dose. In striatal slices prelabelled with [ 3 H]DA, modulation of [ 3 H]-overflow by pergolide was used to measure D-2 autoreceptor activity. Compared to the contemporaneous control group pergolide produced a greater inhibition only in striatal slices from rats treated repeatedly with cocaine. In radioligand binding studies using striatal membranes from control rats, pergolide had a 500-fold greater affinity for the D-2, as opposed to the D-1, dopamine (DA) receptor subtype. These results indicate that repeated treatment with cocaine produces supersensitive striatal D-2 release-modulating autoreceptors consistent with a compensatory change to diminish the effect of elevated synaptic concentrations of DA produced by cocaine. In contrast, supersensitivity of D-2 receptors was not detected in [ 3 H]spiperone binding assays. 31 references, 2 figures, 1 table

  9. Cocaine

    Science.gov (United States)

    ... different competition is going on: the National Football League (NFL) vs. drug use. Read More » 92 Comments ... opioid abuse, cigarette and alcohol use among the nation’s youth. View Online Dirty Money and Cocaine Published: ...

  10. Cocaine

    Science.gov (United States)

    ... Alcohol Club Drugs Cocaine Fentanyl Hallucinogens Inhalants Heroin Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Over-the-Counter Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/ ...

  11. Impact of DCS-facilitated cue exposure therapy on brain activation to cocaine cues in cocaine dependence.

    Science.gov (United States)

    Prisciandaro, James J; Myrick, Hugh; Henderson, Scott; McRae-Clark, Aimee L; Santa Ana, Elizabeth J; Saladin, Michael E; Brady, Kathleen T

    2013-09-01

    The development of addiction is marked by a pathological associative learning process that imbues incentive salience to stimuli associated with drug use. Recent efforts to treat addiction have targeted this learning process using cue exposure therapy augmented with d-cycloserine (DCS), a glutamatergic agent hypothesized to enhance extinction learning. To better understand the impact of DCS-facilitated extinction on neural reactivity to drug cues, the present study reports fMRI findings from a randomized, double-blind, placebo-controlled trial of DCS-facilitated cue exposure for cocaine dependence. Twenty-five participants completed two MRI sessions (before and after intervention), with a cocaine-cue reactivity fMRI task. The intervention consisted of 50mg of DCS or placebo, combined with two sessions of cocaine cue exposure and skills training. Participants demonstrated cocaine cue activation in a variety of brain regions at baseline. From the pre- to post-study scan, participants experienced decreased activation to cues in a number of regions (e.g., accumbens, caudate, frontal poles). Unexpectedly, placebo participants experienced decreases in activation to cues in the left angular and middle temporal gyri and the lateral occipital cortex, while DCS participants did not. Three trials of DCS-facilitated cue exposure therapy for cocaine dependence have found that DCS either increases or does not significantly impact response to cocaine cues. The present study adds to this literature by demonstrating that DCS may prevent extinction to cocaine cues in temporal and occipital brain regions. Although consistent with past research, results from the present study should be considered preliminary until replicated in larger samples. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  12. Prenatal cocaine exposure alters alpha2 receptor expression in adolescent rats

    Directory of Open Access Journals (Sweden)

    Silvers Janelle M

    2006-04-01

    Full Text Available Abstract Background Prenatal cocaine exposure produces attentional deficits which to persist through early childhood. Given the role of norepinephrine (NE in attentional processes, we examined the forebrain NE systems from prenatal cocaine exposed rats. Cocaine was administered during pregnancy via the clinically relevant intravenous route of administration. Specifically, we measured α2-adrenergic receptor (α2-AR density in adolescent (35-days-old rats, using [3H]RX821002 (5 nM. Results Sex-specific alterations of α2-AR were found in the hippocampus and amygdala of the cocaine-exposed animals, as well as an upregulation of α2-AR in parietal cortex. Conclusion These data suggest that prenatal cocaine exposure results in a persistent alteration in forebrain NE systems as indicated by alterations in receptor density. These neurochemical changes may underlie behavioral abnormalities observed in offspring attentional processes following prenatal exposure to cocaine.

  13. Cocaine Self-Administration Produces Long-Lasting Alterations in Dopamine Transporter Responses to Cocaine

    Science.gov (United States)

    Siciliano, Cody A.; Fordahl, Steve C.

    2016-01-01

    Cocaine addiction is a debilitating neuropsychiatric disorder characterized by uncontrolled cocaine intake, which is thought to be driven, at least in part, by cocaine-induced deficits in dopamine system function. A decreased ability of cocaine to elevate dopamine levels has been repeatedly observed as a consequence of cocaine use in humans, and preclinical work has highlighted tolerance to cocaine's effects as a primary determinant in the development of aberrant cocaine taking behaviors. Here we determined that cocaine self-administration in rats produced tolerance to the dopamine transporter-inhibiting effects of cocaine in the nucleus accumbens core, which was normalized following a 14 or 60 d abstinence period; however, although these rats appeared to be similar to controls, a single self-administered infusion of cocaine at the end of abstinence, even after 60 d, fully reinstated tolerance to cocaine's effects. A single cocaine infusion in a naive rat had no effect on cocaine potency, demonstrating that cocaine self-administration leaves the dopamine transporter in a “primed” state, which allows for cocaine-induced plasticity to be reinstated by a subthreshold cocaine exposure. Further, reinstatement of cocaine tolerance was accompanied by decreased cocaine-induced locomotion and escalated cocaine intake despite extended abstinence from cocaine. These data demonstrate that cocaine leaves a long-lasting imprint on the dopamine system that is activated by re-exposure to cocaine. Further, these results provide a potential mechanism for severe cocaine binge episodes, which occur even after sustained abstinence from cocaine, and suggest that treatments aimed at transporter sites may be efficacious in promoting binge termination following relapse. SIGNIFICANCE STATEMENT Tolerance is a DSM-V criterion for substance abuse disorders. Abusers consistently show reduced subjective effects of cocaine concomitant with reduced effects of cocaine at its main site of action

  14. Influence of prenatal cocaine exposure on full-term infant neurobehavioral functioning.

    Science.gov (United States)

    Morrow, C E; Bandstra, E S; Anthony, J C; Ofir, A Y; Xue, L; Reyes, M L

    2001-01-01

    This study investigated infant neurobehavioral functioning during the newborn period in 334 full-term, African American neonates (187 cocaine exposed, 147 non-cocaine exposed) enrolled prospectively at birth, with documentation of drug exposure status through maternal interview and urine and meconium toxicology assays. Infants were assessed using the Brazelton Neonatal Behavioral Assessment Scale (BNBAS) during the newborn period (0-6 postnatal days). Findings from multivariate profile analyses support a consistent, modest effect of prenatal cocaine exposure on neurobehavioral functioning in full-term neonates. All of the BNBAS cluster scores, with the exception of abnormal reflexes, were similarly affected, sharing a common slope (D=-0.14; 95% CI=-0.27, -0.003; P=.046) representing a -0.14 point difference between cocaine-exposed and non-cocaine-exposed infants after controlling for prenatal exposure to alcohol, tobacco, and marijuana (ATM); maternal age, education, employment, primigravida status, and prenatal care visits; and infant sex and postnatal age in days. Fetal growth was also related to neurobehavioral functioning and, in part, mediated the relationship between cocaine exposure and the BNBAS cluster scores. Cocaine exposure during each trimester similarly influenced infant neurobehavioral profiles, with cocaine-associated deficits most pronounced in infants with exposure in all three trimesters. Results from qualitative and quantitative urine and meconium bioassay indicators further substantiated these results. Findings, while significant, represent modest effect sizes in full-term infants.

  15. Methylphenidate Attenuates Limbic Brain Inhibition after Cocaine-Cues Exposure in Cocaine Abusers

    OpenAIRE

    Volkow, Nora D.; Wang, Gene-Jack; Tomasi, Dardo; Telang, Frank; Fowler, Joanna S.; Pradhan, Kith; Jayne, Millard; Logan, Jean; Goldstein, Rita Z.; Alia-Klein, Nelly; Wong, Christopher

    2010-01-01

    Dopamine (phasic release) is implicated in conditioned responses. Imaging studies in cocaine abusers show decreases in striatal dopamine levels, which we hypothesize may enhance conditioned responses since tonic dopamine levels modulate phasic dopamine release. To test this we assessed the effects of increasing tonic dopamine levels (using oral methylphenidate) on brain activation induced by cocaine-cues in cocaine abusers. Brain metabolism (marker of brain function) was measured with PET and...

  16. Methylphenidate attenuates limbic brain inhibition after cocaine-cues exposure in cocaine abusers.

    Directory of Open Access Journals (Sweden)

    Nora D Volkow

    2010-07-01

    Full Text Available Dopamine (phasic release is implicated in conditioned responses. Imaging studies in cocaine abusers show decreases in striatal dopamine levels, which we hypothesize may enhance conditioned responses since tonic dopamine levels modulate phasic dopamine release. To test this we assessed the effects of increasing tonic dopamine levels (using oral methylphenidate on brain activation induced by cocaine-cues in cocaine abusers. Brain metabolism (marker of brain function was measured with PET and (18FDG in 24 active cocaine abusers tested four times; twice watching a Neutral video (nature scenes and twice watching a Cocaine-cues video; each video was preceded once by placebo and once by methylphenidate (20 mg. The Cocaine-cues video increased craving to the same extent with placebo (68% and with methylphenidate (64%. In contrast, SPM analysis of metabolic images revealed that differences between Neutral versus Cocaine-cues conditions were greater with placebo than methylphenidate; whereas with placebo the Cocaine-cues decreased metabolism (p<0.005 in left limbic regions (insula, orbitofrontal, accumbens and right parahippocampus, with methylphenidate it only decreased in auditory and visual regions, which also occurred with placebo. Decreases in metabolism in these regions were not associated with craving; in contrast the voxel-wise SPM analysis identified significant correlations with craving in anterior orbitofrontal cortex (p<0.005, amygdala, striatum and middle insula (p<0.05. This suggests that methylphenidate's attenuation of brain reactivity to Cocaine-cues is distinct from that involved in craving. Cocaine-cues decreased metabolism in limbic regions (reflects activity over 30 minutes, which contrasts with activations reported by fMRI studies (reflects activity over 2-5 minutes that may reflect long-lasting limbic inhibition following activation. Studies to evaluate the clinical significance of methylphenidate's blunting of cue-induced limbic

  17. Methylphenidate attenuates limbic brain inhibition after cocaine-cues exposure in cocaine abusers

    International Nuclear Information System (INIS)

    Volkow, N.D.; Wang, G.-J.; Tomasi, D.; Telang, F.; Fowler, J.S.; Pradhan, K.; Jayne, M.; Logan, J.; Goldstein, R.Z.; Alia-Klein, N.; Wong, C.T.

    2010-01-01

    Dopamine (phasic release) is implicated in conditioned responses. Imaging studies in cocaine abusers show decreases in striatal dopamine levels, which we hypothesize may enhance conditioned responses since tonic dopamine levels modulate phasic dopamine release. To test this we assessed the effects of increasing tonic dopamine levels (using oral methylphenidate) on brain activation induced by cocaine-cues in cocaine abusers. Brain metabolism (marker of brain function) was measured with PET and 18 FDG in 24 active cocaine abusers tested four times; twice watching a Neutral video (nature scenes) and twice watching a Cocaine-cues video; each video was preceded once by placebo and once by methylphenidate (20 mg). The Cocaine-cues video increased craving to the same extent with placebo (68%) and with methylphenidate (64%). In contrast, SPM analysis of metabolic images revealed that differences between Neutral versus Cocaine-cues conditions were greater with placebo than methylphenidate; whereas with placebo the Cocaine-cues decreased metabolism (p<0.005) in left limbic regions (insula, orbitofrontal, accumbens) and right parahippocampus, with methylphenidate it only decreased in auditory and visual regions, which also occurred with placebo. Decreases in metabolism in these regions were not associated with craving; in contrast the voxel-wise SPM analysis identified significant correlations with craving in anterior orbitofrontal cortex (p<0.005), amygdala, striatum and middle insula (p<0.05). This suggests that methylphenidate's attenuation of brain reactivity to Cocaine-cues is distinct from that involved in craving. Cocaine-cues decreased metabolism in limbic regions (reflects activity over 30 minutes), which contrasts with activations reported by fMRI studies (reflects activity over 2-5 minutes) that may reflect long-lasting limbic inhibition following activation. Studies to evaluate the clinical significance of methylphenidate's blunting of cue-induced limbic

  18. Reduced Metabolism in Brain 'Control Networks' Following Cocaine-Cues Exposure in Female Cocaine Abusers

    International Nuclear Information System (INIS)

    Volkow, N.D.; Tomasi, D.; Wang, G.-J.; Fowler, J.S.; Telang, F.; Goldstein, R.Z.; Alia-Klein, N.; Wong, C.T.

    2011-01-01

    Gender differences in vulnerability for cocaine addiction have been reported. Though the mechanisms are not understood, here we hypothesize that gender differences in reactivity to conditioned-cues, which contributes to relapse, are involved. To test this we compared brain metabolism (using PET and 18 FDG) between female (n = 10) and male (n = 16) active cocaine abusers when they watched a neutral video (nature scenes) versus a cocaine-cues video. Self-reports of craving increased with the cocaine-cue video but responses did not differ between genders. In contrast, changes in whole brain metabolism with cocaine-cues differed by gender (p<0.05); females significantly decreased metabolism (-8.6% ± 10) whereas males tended to increase it (+5.5% ± 18). SPM analysis (Cocaine-cues vs Neutral) in females revealed decreases in frontal, cingulate and parietal cortices, thalamus and midbrain (p<0.001) whereas males showed increases in right inferior frontal gyrus (BA 44/45) (only at p<0.005). The gender-cue interaction showed greater decrements with Cocaine-cues in females than males (p<0.001) in frontal (BA 8, 9, 10), anterior cingulate (BA 24, 32), posterior cingulate (BA 23, 31), inferior parietal (BA 40) and thalamus (dorsomedial nucleus). Females showed greater brain reactivity to cocaine-cues than males but no differences in craving, suggesting that there may be gender differences in response to cues that are not linked with craving but could affect subsequent drug use. Specifically deactivation of brain regions from 'control networks' (prefrontal, cingulate, inferior parietal, thalamus) in females could increase their vulnerability to relapse since it would interfere with executive function (cognitive inhibition). This highlights the importance of gender tailored interventions for cocaine addiction.

  19. Reduced metabolism in brain "control networks" following cocaine-cues exposure in female cocaine abusers.

    Directory of Open Access Journals (Sweden)

    Nora D Volkow

    2011-02-01

    Full Text Available Gender differences in vulnerability for cocaine addiction have been reported. Though the mechanisms are not understood, here we hypothesize that gender differences in reactivity to conditioned-cues, which contributes to relapse, are involved.To test this we compared brain metabolism (using PET and ¹⁸FDG between female (n = 10 and male (n = 16 active cocaine abusers when they watched a neutral video (nature scenes versus a cocaine-cues video.Self-reports of craving increased with the cocaine-cue video but responses did not differ between genders. In contrast, changes in whole brain metabolism with cocaine-cues differed by gender (p<0.05; females significantly decreased metabolism (-8.6%±10 whereas males tended to increase it (+5.5%±18. SPM analysis (Cocaine-cues vs Neutral in females revealed decreases in frontal, cingulate and parietal cortices, thalamus and midbrain (p<0.001 whereas males showed increases in right inferior frontal gyrus (BA 44/45 (only at p<0.005. The gender-cue interaction showed greater decrements with Cocaine-cues in females than males (p<0.001 in frontal (BA 8, 9, 10, anterior cingulate (BA 24, 32, posterior cingulate (BA 23, 31, inferior parietal (BA 40 and thalamus (dorsomedial nucleus.Females showed greater brain reactivity to cocaine-cues than males but no differences in craving, suggesting that there may be gender differences in response to cues that are not linked with craving but could affect subsequent drug use. Specifically deactivation of brain regions from "control networks" (prefrontal, cingulate, inferior parietal, thalamus in females could increase their vulnerability to relapse since it would interfere with executive function (cognitive inhibition. This highlights the importance of gender tailored interventions for cocaine addiction.

  20. Effects of prenatal cocaine exposure on social development in mice.

    Science.gov (United States)

    Kabir, Zeeba D; Kennedy, Bruce; Katzman, Aaron; Lahvis, Garet P; Kosofsky, Barry E

    2014-01-01

    Prenatal cocaine exposure (PCE) in humans and animals has been shown to impair social development. Molecules that mediate synaptic plasticity and learning in the medial prefrontal cortex (mPFC), specifically brain-derived neurotrophic factor (BDNF) and its downstream signaling molecule, early growth response protein 1 (egr1), have been shown to affect the regulation of social interactions (SI). In this study we determined the effects of PCE on SI and the corresponding ultrasonic vocalizations (USVs) in developing mice. Furthermore, we studied the PCE-induced changes in the constitutive expression of BDNF, egr1 and their transcriptional regulators in the mPFC as a possible molecular mechanism mediating the altered SI. In prenatal cocaine-exposed (PCOC) mice we identified increased SI and USV production at postnatal day (PD) 25, and increased SI but not USVs at PD35. By PD45 the expression of both social behaviors normalized in PCOC mice. At the molecular level, we found increased BDNF exon IV and egr1 mRNA in the mPFC of PCOC mice at PD30 that normalized by PD45. This was concurrent with increased EGR1 protein in the mPFC of PCOC mice at PD30, suggesting a role of egr1 in the enhanced SI observed in juvenile PCOC mice. Additionally, by measuring the association of acetylation of histone 3 at lysine residues 9 and 14 (acH3K9,14) and MeCP2 at the promoters of BDNF exons I and IV and egr1, our results provide evidence of promoter-specific alterations in the mPFC of PCOC juvenile mice, with increased association of acH3K9,14 only at the BDNF exon IV promoter. These results identify a potential PCE-induced molecular alteration as the underlying neurobiological mechanism mediating the altered social development in juvenile mice. © 2014 S. Karger AG, Basel.

  1. Subjective perception of cocaine reward in mice assessed by a single exposure place preference (sePP) paradigm

    DEFF Research Database (Denmark)

    Runegaard, Annika H.; Jensen, Kathrine Louise; Dencker, Ditte

    2017-01-01

    -related behavior. Comparison with existing methods In rodents, the rewarding effects of drugs have often been assessed in self-administration or place preference paradigms; both involving repeated drug exposure and weeks of training and testing. New method Our investigation describes a valid approach to assess....... The sePP protocol allows further dissection of the mechanism and influence of initial cocaine exposure on subsequent drug-related behaviors by including extinction and reinstatement. The lack of sePP in female mice may reflect a biologically relevant sex difference in the initial subjective perception...

  2. Individual differences in food cue responsivity are associated with acute and repeated cocaine-induced vocalizations, but not cue-induced vocalizations.

    Science.gov (United States)

    Tripi, Jordan A; Dent, Micheal L; Meyer, Paul J

    2017-02-01

    Individuals prone to attribute incentive salience to food-associated stimuli ("cues") are also more sensitive to cues during drug seeking and drug taking. This may be due in part to a difference in sensitivity to the affective or other stimulus properties of the drug. In rats, these properties are associated with 50-kHz ultrasonic vocalizations (USVs), in that they are elicited during putative positive affective and motivational states, including in response to drugs of abuse. We sought to determine whether individual differences in the tendency to attribute incentive salience to a food cue (as measured by approach) were associated with differences in cocaine-induced USVs. We also tested whether the food cue would elicit USVs and if this response was related to approach to the food cue. In experiment 1, rats underwent Pavlovian conditioned approach (PavCA) training where they learned to associate a cue (an illuminated lever) with the delivery of a food pellet into a food cup. Subjects were categorized based on their approach to the cue ("sign-trackers") or to the food cup ("goal-trackers"). Rats subsequently underwent nine testing days in which they were given saline or cocaine (10 mg/kg i.p) and placed into a locomotor chamber. In experiment 2, rats were first tested in the locomotor chambers for one saline-treated day followed by one cocaine-treated day and then trained in PavCA. USVs were recorded from a subset of individuals during the last day of PavCA to determine if the food cue would elicit USVs. Sign-trackers produced 5-24 times more cocaine-induced 50 kHz USVs compared to goal-trackers for all days of experiment 1, and this response sensitized with repeated cocaine, only in sign-trackers. Similarly in experiment 2, individuals that produced the most cocaine-induced USVs on a single exposure also showed the greatest tendency to sign-track during PavCA. Lastly, while sign-trackers produced more USVs during PavCA generally, the cue itself did not elicit

  3. Postnatal cocaine exposure: effects on behavior of rats in forced swim test.

    Science.gov (United States)

    Magalhães, Ana; Tavares, Maria Amélia; de Sousa, Liliana

    2002-06-01

    Exposure to cocaine in early periods of postnatal life has adverse effects on behavior, namely, it induces the display of anxiety and fear-like behaviors that are associated with stress and depression. This study examined the effects of early developmental cocaine exposure in several categories of behavior observed in forced swim test. Male and female Wistar rats were given 15 mg/kg of cocaine hydrochloride/body weight/day, subcutaneously, in two daily doses, from postnatal day (PND) 1 to PND27. Controls were saline injected in the same protocol. In PND26-PND27, rats were placed in a swimming pool during 5 min in two sessions. The categories of behavior studied in this work included horizontal and vertical rotation, vibrissae clean, head clean, fast and slow swim, struggling, floating, sliding, diving, head-diving, and wagging head. Results showed differences in the frequencies of several behavioral categories that allowed the discrimination of the behaviors that may constitute "behavioral despair" indicators, as well as which behaviors are most affected by cocaine exposure. Cocaine groups were less active and more immobile than controls. These results suggest that postnatal exposure to cocaine can produce depression-like effects and affect the ability of these animals to cope with stress situations.

  4. Limitations to the Generality of Cocaine Locomotor Sensitization

    OpenAIRE

    Marusich, Julie A.; Branch, Marc N.; Dallery, Jesse

    2008-01-01

    Repeated exposure to cocaine often leads to tolerance to effects on operant behavior, whereas sensitization often develops to effects on locomotor activity. The purpose of the present set of experiments was to examine if locomotor sensitization to cocaine would develop in the presence or absence of an operant contingency in rats. In Experiment 1, rats lever pressed on an FR schedule of reinforcement, and were administered chronic cocaine. Tolerance to effects of cocaine on lever pressing deve...

  5. Prenatal cocaine exposure decreases parvalbumin-immunoreactive neurons and GABA-to-projection neuron ratio in the medial prefrontal cortex.

    Science.gov (United States)

    McCarthy, Deirdre M; Bhide, Pradeep G

    2012-01-01

    Cocaine abuse during pregnancy produces harmful effects not only on the mother but also on the unborn child. The neurotransmitters dopamine and serotonin are known as the principal targets of the action of cocaine in the fetal and postnatal brain. However, recent evidence suggests that cocaine can impair cerebral cortical GABA neuron development and function. We sought to analyze the effects of prenatal cocaine exposure on the number and distribution of GABA and projection neurons (inhibitory interneurons and excitatory output neurons, respectively) in the mouse cerebral cortex. We found that the prenatal cocaine exposure decreased GABA neuron numbers and GABA-to-projection neuron ratio in the medial prefrontal cortex of 60-day-old mice. The neighboring prefrontal cortex did not show significant changes in either of these measures. However, there was a significant increase in projection neuron numbers in the prefrontal cortex but not in the medial prefrontal cortex. Thus, the effects of cocaine on GABA and projection neurons appear to be cortical region specific. The population of parvalbumin-immunoreactive GABA neurons was decreased in the medial prefrontal cortex following the prenatal cocaine exposure. The cocaine exposure also delayed the developmental decline in the volume of the medial prefrontal cortex. Thus, prenatal cocaine exposure produced persisting and region-specific effects on cortical cytoarchitecture and impaired the physiological balance between excitatory and inhibitory neurotransmission. These structural changes may underlie the electrophysiological and behavioral effects of prenatal cocaine exposure observed in animal models and human subjects. Copyright © 2012 S. Karger AG, Basel.

  6. Learning disabilities and intellectual functioning in school-aged children with prenatal cocaine exposure.

    Science.gov (United States)

    Morrow, Connie E; Culbertson, Jan L; Accornero, Veronica H; Xue, Lihua; Anthony, James C; Bandstra, Emmalee S

    2006-01-01

    Risk for developing a learning disability (LD) or impaired intellectual functioning by age 7 was assessed in full-term children with prenatal cocaine exposure drawn from a cohort of 476 children born full term and enrolled prospectively at birth. Intellectual functioning was assessed using the Wechsler Intelligence Scale for Children-Third Edition (Wechsler, 1991) short form, and academic functioning was assessed using the Wechsler Individual Achievement Test (WIAT; Wechsler, 1993) Screener by examiners blind to exposure status. LDs were categorized based on ability-achievement discrepancy scores, using the regression-based predicted achievement method described in the WIAT manual. The sample in this report included 409 children (212 cocaine-exposed, 197 non-cocaine-exposed) from the birth cohort with available data. Cumulative incidence proportions and relative risk values were estimated using STATA software (Statacorp, 2003). No differences were found in the estimate of relative risk for impaired intellectual functioning (IQ below 70) between children with and without prenatal cocaine exposure (estimated relative risk = .95; 95% confidence interval [CI] = 0.65, 1.39; p = .79). The cocaine-exposed children had 2.8 times greater risk of developing a LD by age 7 than non-cocaine-exposed children (95% CI = 1.05, 7.67; p = .038; IQ >/= 70 cutoff). Results remained stable with adjustment for multiple child and caregiver covariates, suggesting that children with prenatal cocaine exposure are at increased risk for developing a learning disability by age 7 when compared to their non-cocaine-exposed peers.

  7. Prenatal cocaine exposure and neonatal/infant outcomes.

    Science.gov (United States)

    Cambell, Shelly

    2003-01-01

    Illegal drug use throughout the nation is a problem of epidemic proportion. Of particular concern is drug use among pregnant women. In most cases, these women have little hope of achieving a better life for themselves or their children. Illegal drugs, cocaine in particular, can have devastating effects on the neonate. These effects can last well into childhood and can exhibit themselves in academic, social, and family situations. Challenges for the neonatal nurse include early identification of these infants and use of available resources. This article addresses prenatal cocaine use and support services for drug-dependent women, effects of cocaine during the neonatal period, possible neonatal and infant outcomes, and implications for nursing practice.

  8. Effects of prenatal cocaine exposure on special education in school-aged children.

    Science.gov (United States)

    Levine, Todd P; Liu, Jing; Das, Abhik; Lester, Barry; Lagasse, Linda; Shankaran, Seetha; Bada, Henrietta S; Bauer, Charles R; Higgins, Rosemary

    2008-07-01

    The objective of this study was to evaluate the effects of prenatal cocaine exposure on special education at age 7 with adjustment for covariates. As part of the prospective, longitudinal, multisite study of children with prenatal cocaine exposure (Maternal Lifestyle Study), school records were reviewed for 943 children at 7 years to determine involvement in special education outcomes: (1) individualized education plan; (2) special education conditions; (3) support services; (4) special education classes; and (5) speech and language services. Logistic regression was used to examine the effect of prenatal cocaine exposure on these outcomes with environmental, maternal, and infant medical variables as covariates, as well as with and without low child IQ. Complete data for each analysis model were available for 737 to 916 children. When controlling for covariates including low child IQ, prenatal cocaine exposure had a significant effect on individualized education plan. When low child IQ was not included in the model, prenatal cocaine exposure had a significant effect on support services. Male gender, low birth weight, white race, and low child IQ also predicted individualized education plan. Low birth weight and low child IQ were significant in all models. White race was also significant in speech and language services. Other covariate effects were model specific. When included in the models, low child IQ accounted for more of the variance and changed the significance of other covariates. Prenatal cocaine exposure increased the likelihood of receiving an individualized education plan and support services, with adjustment for covariates. Low birth weight and low child IQ increased the likelihood of all outcomes. The finding that white children were more likely to get an individualized education plan and speech and language services could indicate a greater advantage in getting educational resources for this population.

  9. Abnormal regulation for progesterone production in placenta with prenatal cocaine exposure in rats.

    Science.gov (United States)

    Wu, L; Yan, J; Qu, S C; Feng, Y Q; Jiang, X L

    2012-12-01

    Cocaine abuse in pregnant women is currently a significant public hygiene problem and is tightly associated with elevated risk for preterm delivery. Placental steroidogenesis especially progesterone production was essential for success and maintenance of pregnancy in humans and rodents. In the present study, we determined the impact of prenatal cocaine exposure on pathways of placental progesterone synthesis in rats. Pregnant rats were treated cocaine twice daily (15 mg/kg/day) during the third trimester, and the maternal and fetal plasma progesterone and pregnenolone concentrations were detected. We also examined both the protein and mRNA expression of some key enzymes and regulators for progesterone production in placenta. Results showed that, after maternal cocaine use during pregnancy, progesterone and pregnenolone concentrations in both maternal and fetal rats were significantly decreased. Although prenatal cocaine exposure had no effects on placental 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1) expression, protein and mRNA expression of the cholesterol side-chain cleavage enzyme (P450scc/CYP11a) in placenta was significantly inhibited. Moreover, protein and mRNA expressions of MLN64 that regulating cholesterol transport and activating protein 2γ (AP2γ/Tfap2c) that controlling P450scc/CYP11a gene expression in placenta were both decreased following maternal cocaine use in pregnancy. Collectively, this study suggested that prenatal cocaine exposure could insult the placental progesterone production in rats possibly associated with the high risk for preterm delivery. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. Brain ultrasonography findings in neonates with exposure to cocaine during pregnancy

    NARCIS (Netherlands)

    van Huis, M.; van Kempen, A.A.M.W.; Peelen, M.; Timmers, M.; Boer, K.; Smit, B.J.; van Rijn, R.R.

    2009-01-01

    BACKGROUND: Cocaine exposure during pregnancy has been reported to have detrimental effects on the fetus. OBJECTIVE: To describe the findings on cranial ultrasonography (CUS) as part of a neonatal screening programme for exposed neonates. MATERIALS AND METHODS: The study was a semiprospective

  11. Impaired sustained attention and altered reactivity to errors in an animal model of prenatal cocaine exposure.

    Science.gov (United States)

    Gendle, Mathew H; Strawderman, Myla S; Mactutus, Charles F; Booze, Rosemarie M; Levitsky, David A; Strupp, Barbara J

    2003-12-30

    Although correlations have been reported between maternal cocaine use and impaired attention in exposed children, interpretation of these findings is complicated by the many risk factors that differentiate cocaine-exposed children from SES-matched controls. For this reason, the present dose-response study (0, 0.5, 1.0, or 3.0 mg/kg cocaine HCl) was designed to explore the effect of prenatal cocaine exposure on visual attention in a rodent model, using an intravenous injection protocol that closely mimics the pharmacokinetic profile and physiological effects of human recreational cocaine use. In adulthood, animals were tested on an attention task in which the duration, location, and onset time of a brief visual cue varied randomly between trials. The 3.0 mg/kg exposed males committed significantly more omission errors than control males during the final 1/3 of each testing session, specifically on trials that followed an error, which implicates impaired sustained attention and increased reactivity to committing an error. During the final 1/3 of each testing session, the 0.5 and 1.0 mg/kg exposed females took longer to enter the testing alcove at trial onset, and failed to enter the alcove more frequently than control females. Because these effects were not seen in other tasks of similar duration and reinforcement density, these findings suggest an impairment of sustained attention. This inference is supported by the finding that the increase in omission errors in the final block of trials in each daily session (relative to earlier in the session) was significantly greater for the 1.0 mg/kg females than for controls, a trend also seen for the 0.5 mg/kg group. Unlike the cocaine-exposed males, who remain engaged in the task when attention is waning, the cocaine-exposed females appear to opt for another strategy; namely, refusing to participate when their ability to sustain attention is surpassed.

  12. Repeated intermittent administration of psychomotor stimulant drugs alters the acquisition of Pavlovian approach behavior in rats: differential effects of cocaine, d-amphetamine and 3,4- methylenedioxymethamphetamine ("Ecstasy").

    Science.gov (United States)

    Taylor, J R; Jentsch, J D

    2001-07-15

    Psychomotor stimulant drugs can produce long-lasting changes in neurochemistry and behavior after multiple doses. In particular, neuroadaptations within corticolimbic brain structures that mediate incentive learning and motivated behavior have been demonstrated after chronic exposure to cocaine, d-amphetamine, and 3,4-methylenedioxymethamphetamine (MDMA). As stimulus-reward learning is likely relevant to addictive behavior (i.e., augmented conditioned reward and stimulus control of behavior), we have investigated whether prior repeated administration of psychomotor stimulant drugs (of abuse, including cocaine, d-amphetamine, or MDMA, would affect the acquisition of Pavlovian approach behavior. Water-deprived rats were tested for the acquisition of Pavlovian approach behavior after 5 days treatment with cocaine (15-20 mg/kg once or twice daily), d-amphetamine (2.5 mg/kg once or twice daily), or MDMA (2.5 mg/kg twice daily) followed by a 7-day, drug-free period. Prior repeated treatment with cocaine or d-amphetamine produced a significant enhancement of acquisition of Pavlovian approach behavior, indicating accelerated stimulus-reward learning, whereas MDMA administration produced increased inappropriate responding, indicating impulsivity. Abnormal drug-induced approach behavior was found to persist throughout the testing period. These studies demonstrate that psychomotor stimulant-induced sensitization can produce long-term alterations in stimulus-reward learning and impulse control that may contribute to the compulsive drug taking that typifies addiction.

  13. Acute Cocaine Exposure elicits rises in calcium in Arousal Related Laterodorsal Tegmental Neurons

    DEFF Research Database (Denmark)

    Lambert, Mads; Ipsen, Theis; Kohlmeier, Kristi Anne

    2017-01-01

    Cocaine has strong reinforcing properties, which underlie its high addiction potential. Reinforcement of use of addictive drugs is associated with rises in dopamine (DA) in mesoaccumbal circuitry. Excitatory afferent input to mesoaccumbal circuitry sources from the laterodorsal tegmental nucleus...... (LDT). Chronic, systemic cocaine exposure has been shown to have cellular effects on LDT cells, but acute actions of local application have never been demonstrated. Using calcium imaging, we show that acute application of cocaine to mouse brain slices induces calcium spiking in cells of the LDT....... Spiking was attenuated by tetrodotoxin (TTX) and low calcium solutions, and abolished by prior exhaustion of intracellular calcium stores. Further, DA receptor antagonists reduced these transients, whereas DA induced rises with similar spiking kinetics. Amphetamine, which also results in elevated levels...

  14. Cocaine exposure shifts the balance of associative encoding from ventral to dorsolateral striatum

    Directory of Open Access Journals (Sweden)

    Yuji Takahashi

    2007-12-01

    Full Text Available Both dorsal and ventral striatum are implicated in the "habitization" of behavior that occurs in addiction. Here we examined the effect of cocaine exposure on associative encoding in these two regions. Neural activity was recorded during go/no-go discrimination learning and reversal. Activity in ventral striatum developed and reversed rapidly, tracking the valence of the predicted outcome, whereas activity in dorsolateral striatum developed and reversed more slowly, tracking discriminative responding. This difference is consistent with the putative roles of these two areas in promoting habit-like behavior. Dorsolateral striatum has been directly implicated in habit or stimulus response learning, whereas ventral striatum appears to be involved indirectly by allowing cues associated with reward to exert a general motivational influence on responding. Interestingly cocaine exposure did not uniformly enhance processing across both regions. Instead cocaine reduced the degree and flexibility of cue-evoked firing in ventral striatum while marginally enhanced cue-selective firing in dorsolateral striatum. Thus cocaine exposure causes regionally specific effects on neural processing in striatum; these effects may promote the habitization of behavior by shifting control from ventral to dorsolateral regions.

  15. Hippocampal cell fate regulation by chronic cocaine during periods of adolescent vulnerability: Consequences of cocaine exposure during adolescence on behavioral despair in adulthood.

    Science.gov (United States)

    García-Cabrerizo, R; Keller, B; García-Fuster, M J

    2015-09-24

    Given that adolescence represents a critical moment for shaping adult behavior and may predispose to disease vulnerability later in life, the aim of this study was to find a vulnerable period during adolescence in which hippocampal cell fate regulation was altered by cocaine exposure, and to evaluate the long-term consequences of a cocaine experience during adolescence in affecting hippocampal plasticity and behavioral despair in adulthood. Study I: Male rats were treated with cocaine (15mg/kg, i.p.) or saline for 7 consecutive days during adolescence (early post-natal day (PND) 33-39, mid PND 40-46, late PND 47-53). Hippocampal plasticity (i.e., cell fate regulation, cell genesis) was evaluated 24h after the last treatment dose during the course of adolescence (PND 40, PND 47, PND 54). Study II: The consequences of cocaine exposure during adolescence (PND 33-39 or PND 33-46; 7 or 14days) were measured in adulthood at the behavioral (i.e., forced swim test, PND 62-63) and molecular (hippocampal cell markers, PND 64) levels. Chronic cocaine during early adolescence dysregulated FADD forms only in the hippocampus (HC), as compared to other brain regions, and during mid adolescence, impaired cell proliferation (Ki-67) and increased PARP-1 cleavage (a cell death maker) in the HC. Interestingly, chronic cocaine exposure during adolescence did not alter the time adult rats spent immobile in the forced swim test. These results suggest that this paradigm of chronic cocaine administration during adolescence did not contribute to the later manifestation of behavioral despair (i.e., one pro-depressive symptom) as measured by the forced swim test in adulthood. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  16. No evidence that environmental enrichment during rearing protects against cocaine behavioral effects but as an intervention reduces an already established cocaine conditioned place preference.

    Science.gov (United States)

    Galaj, E; Shukur, A; Manuszak, M; Newman, K; Ranaldi, R

    2017-05-01

    Environmental enrichment (EE) produces differential effects on psychostimulant-related behaviors. Therefore, we investigated whether the timing of EE exposure - during rearing and before cocaine exposure versus in adulthood and after cocaine exposure might be a determining factor. In Experiment 1, rats reared with EE or not (non-EE) were conditioned with cocaine (5, 10 or 20mg/kg) in one compartment of a CPP apparatus and saline in the other, and later tested for cocaine CPP. In Experiment 2, locomotor activity in response to repeated injections of saline or cocaine was measured in rats raised with EE or non-EE. In Experiment 3 we measured the effects of EE or non-EE during rearing on food-based conditioned approach learning. In Experiment 4, rats were exposed to cocaine CPP conditioning then underwent 60days of EE or non-EE treatment after which they were tested for cocaine CPP. Our results show that rearing in EE did not reduce cocaine CPP or cocaine-induced locomotor activity (Experiments 1 and 2) but significantly facilitated conditioned approach learning (Experiment 3). On the other hand, EE treatment introduced after cocaine conditioning significantly reduced the expression of cocaine CPP (Experiment 4). These findings suggest that EE does not protect against cocaine's rewarding and stimulant effects but can reduce already established cocaine effects, suggesting that EE might be an effective treatment for cocaine addiction-related behaviors. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Learning Disabilities and Intellectual Functioning in School-Aged Children With Prenatal Cocaine Exposure

    OpenAIRE

    Morrow, Connie E.; Culbertson, Jan L.; Accornero, Veronica H.; Xue, Lihua; Anthony, James C.; Bandstra, Emmalee S.

    2006-01-01

    Risk for developing a learning disability (LD) or impaired intellectual functioning by age 7 was assessed in full-term children with prenatal cocaine exposure drawn from a cohort of 476 children born full term and enrolled prospectively at birth. Intellectual functioning was assessed using the Wechsler Intelligence Scale for Children–Third Edition (Wechsler,1991) shortform, and academic functioning was assessed using the Wechsler Individual Achievement Test (WIAT; Wechsler,1993) Screener by e...

  18. Toxicological characteristics of petroleum products repeated exposure

    Directory of Open Access Journals (Sweden)

    V.M. Rubin

    2015-03-01

    Full Text Available Abstract. The ability of petroleum products to initiate cumulative effects was assessed in experimental intragastric admission to male albino rats for one month. The analysis of skin-resorptive effects was performed using "test-tube" method on the skin of rats’ tails. It has been established that petroleum products can penetrate the intact skin and, with repeated admission, cause a general toxic effect. There were reductions bodyweights, the negative effect on the function of the kidneys and liver, changes of hematological parameters, as well as activation of the antioksidatnoy system. Repeated intragastric administration does not lead to the death of the animals testifying to the lack of accumulation capacity for petroleum products at the level of functional mortal effects, the cumulation coefficient being > 5.1. Negative impact on urinary function and hepatobiliary system, changes in hematological parameters and activation of the «lipid peroxidation – antioksidant defense» were observed.

  19. Prenatal coke: what's behind the smoke? Prenatal cocaine/alcohol exposure and school-age outcomes: the SCHOO-BE experience.

    Science.gov (United States)

    Delaney-Black, V; Covington, C; Templin, T; Ager, J; Martier, S; Compton, S; Sokol, R

    1998-06-21

    Despite media reports and educators' concerns, little substantive data have been published to document or refute the emerging reports that children prenatally exposed to cocaine have serious behavioral problems in school. Recent pilot data from this institution have indeed demonstrated teacher-reported problem behaviors following prenatal cocaine exposure after controlling for the effects of prenatal alcohol use and cigarette exposure. Imperative in the study of prenatal exposure and child outcome is an acknowledgement of the influence of other control factors such as postnatal environment, secondary exposures, and parenting issues. We report preliminary evaluation from a large ongoing historical prospective study of prenatal cocaine exposure on school-age outcomes. The primary aim of this NIDA-funded study is to determine if a relationship exists between prenatal cocaine/alcohol exposures and school behavior and, if so, to determine if the relationship is characterized by a dose-response relationship. A secondary aim evaluates the relationship between prenatal cocaine/alcohol exposures and school achievement. Both relationships will be assessed in a black, urban sample of first grade students using multivariate statistical techniques for confounding as well as mediating and moderating prenatal and postnatal variables. A third aim is to evaluate the relationship between a general standardized classroom behavioral measure and a tool designed to tap the effects thought to be specific to prenatal cocaine exposure. This interdisciplinary research team can address these aims because of the existence of a unique, prospectively collected perinatal Database, funded in part by NIAAA and NICHD. The database includes repeated measures of cocaine, alcohol, and other substances for over 3,500 births since 1986. Information from this database is combined with information from the database of one of the largest public school systems in the nation. The final sample will be

  20. Prenatal Coke: What's Behind the Smoke?: Prenatal Cocaine/Alcohol Exposure and School-Age Outcomes: The SCHOO-BE Experiencea.

    Science.gov (United States)

    Delaney-Black, Virginia; Covington, Chandice; Templin, Tom; Ager, Joel; Martier, Sue; Compton, Scott; Sokol, Robert

    1998-06-01

    Despite media reports and educators' concerns, little substantive data have been published to document or refute the emerging reports that children prenatally exposed to cocaine have serious behavioral problems in school. Recent pilot data from this institution have indeed demonstrated teacher-reported problem behaviors following prenatal cocaine exposure after controlling for the effects of prenatal alcohol use and cigarette exposure. Imperative in the study of prenatal exposure and child outcome is an acknowledgment of the influence of other control factors such as postnatal environment, secondary exposures, and parenting issues. We report preliminary evaluation from a large ongoing historical prospective study of prenatal cocaine exposure on school-age outcomes. The primary aim of this NIDA-funded study is to determine if a relationship exists between prenatal cocaine/alcohol exposures and school behavior and, if so, to determine if the relationship is characterized by a dose-response relationship. A secondary aim evaluates the relationship between prenatal cocaine/alcohol exposures and school achievement. Both relationships will be assessed in a black, urban sample of first grade students using multivariate statistical techniques for confounding as well as mediating and moderating prenatal and postnatal variables. A third aim is to evaluate the relationship between a general standardized classroom behavioral measure and a tool designed to tap the effects thought to be specific to prenatal cocaine exposure. This interdisciplinary research team can address these aims because of the existence of a unique, prospectively collected Perinatal Database, funded in part by NIAAA and NICHD. The database includes repeated measures of cocaine, alcohol, and other substances for over 3,500 births since 1986. Information from this database is combined with information from the database of one of the largest public school systems in the nation. The final sample will be composed

  1. Reduced Metabolsim in Brain 'Control Networks' Following Cocaine-Cues Exposure in Female Cocaine Abusers

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D.; Wang, G.; Volkow, N.D.; Tomasi, D.; Wang, G.-J.; Fowler, J.S.; Telang, F.; Goldstein, R.Z.; Alia-Klein, N.; Wong, C.T.

    2011-03-01

    Gender differences in vulnerability for cocaine addiction have been reported. Though the mechanisms are not understood, here we hypothesize that gender differences in reactivity to conditioned-cues, which contributes to relapse, are involved. To test this we compared brain metabolism (using PET and {sup 18}FDG) between female (n = 10) and male (n = 16) active cocaine abusers when they watched a neutral video (nature scenes) versus a cocaine-cues video. Self-reports of craving increased with the cocaine-cue video but responses did not differ between genders. In contrast, changes in whole brain metabolism with cocaine-cues differed by gender (p<0.05); females significantly decreased metabolism (-8.6% {+-} 10) whereas males tended to increase it (+5.5% {+-} 18). SPM analysis (Cocaine-cues vs Neutral) in females revealed decreases in frontal, cingulate and parietal cortices, thalamus and midbrain (p<0.001) whereas males showed increases in right inferior frontal gyrus (BA 44/45) (only at p<0.005). The gender-cue interaction showed greater decrements with Cocaine-cues in females than males (p<0.001) in frontal (BA 8, 9, 10), anterior cingulate (BA 24, 32), posterior cingulate (BA 23, 31), inferior parietal (BA 40) and thalamus (dorsomedial nucleus). Females showed greater brain reactivity to cocaine-cues than males but no differences in craving, suggesting that there may be gender differences in response to cues that are not linked with craving but could affect subsequent drug use. Specifically deactivation of brain regions from 'control networks' (prefrontal, cingulate, inferior parietal, thalamus) in females could increase their vulnerability to relapse since it would interfere with executive function (cognitive inhibition). This highlights the importance of gender tailored interventions for cocaine addiction.

  2. Cocaine-conditioned odor cues without chronic exposure: Implications for the development of addiction vulnerability

    Directory of Open Access Journals (Sweden)

    Steven B. Lowen

    2015-01-01

    Full Text Available Adolescents are highly vulnerable to addiction and are four times more likely to become addicted at first exposure than at any other age. The dopamine D1 receptor, which is typically overexpressed in the normal adolescent prefrontal cortex, is involved in drug cue responses and is associated with relapse in animal models. In human drug addicts, imaging methods have detected increased activation in response to drug cues in reward- and habit-associated brain regions. These same methods can be applied more quantitatively to rodent models. Here, changes in neuronal activation in response to cocaine-conditioned cues were observed using functional magnetic resonance imaging in juvenile rats that were made to over-express either D1 receptors or green fluorescent protein by viral-mediated transduction. Reduced activation was observed in the amygdala and dopamine cell body regions in the low cue-preferring/control juvenile rats in response to cocaine cues. In contrast, increased activation was observed in the dorsal striatum, nucleus accumbens, prefrontal cortex, and dopamine cell bodies in high cue-preferring/D1 juveniles. The increase in cue salience that is mediated by increased D1 receptor density, rather than excessive cocaine experience, appears to underlie the transition from aversion to reward in cue-induced neural response and may form the basis for habit-forming vulnerability.

  3. Cocaine-conditioned odor cues without chronic exposure: Implications for the development of addiction vulnerability.

    Science.gov (United States)

    Lowen, Steven B; Rohan, Michael L; Gillis, Timothy E; Thompson, Britta S; Wellons, Clara B W; Andersen, Susan L

    2015-01-01

    Adolescents are highly vulnerable to addiction and are four times more likely to become addicted at first exposure than at any other age. The dopamine D1 receptor, which is typically overexpressed in the normal adolescent prefrontal cortex, is involved in drug cue responses and is associated with relapse in animal models. In human drug addicts, imaging methods have detected increased activation in response to drug cues in reward- and habit-associated brain regions. These same methods can be applied more quantitatively to rodent models. Here, changes in neuronal activation in response to cocaine-conditioned cues were observed using functional magnetic resonance imaging in juvenile rats that were made to over-express either D1 receptors or green fluorescent protein by viral-mediated transduction. Reduced activation was observed in the amygdala and dopamine cell body regions in the low cue-preferring/control juvenile rats in response to cocaine cues. In contrast, increased activation was observed in the dorsal striatum, nucleus accumbens, prefrontal cortex, and dopamine cell bodies in high cue-preferring/D1 juveniles. The increase in cue salience that is mediated by increased D1 receptor density, rather than excessive cocaine experience, appears to underlie the transition from aversion to reward in cue-induced neural response and may form the basis for habit-forming vulnerability.

  4. Estimated Risk of Developing Selected DSM-IV Disorders among 5-Year-Old Children with Prenatal Cocaine Exposure

    Science.gov (United States)

    Morrow, Connie E.; Accornero, Veronica H.; Xue, Lihua; Manjunath, Sudha; Culbertson, Jan L.; Anthony, James C.; Bandstra, Emmalee S.

    2009-01-01

    We estimated childhood risk of developing selected DSM-IV Disorders, including Attention-Deficit Hyperactivity Disorder (ADHD), Oppositional Defiant Disorder (ODD), and Separation Anxiety Disorder (SAD), in children with prenatal cocaine exposure (PCE). Children were enrolled prospectively at birth (n = 476) with prenatal drug exposures documented…

  5. Psychopathology and special education enrollment in children with prenatal cocaine exposure.

    Science.gov (United States)

    Levine, Todd P; Lester, Barry; Lagasse, Linda; Shankaran, Seetha; Bada, Henrietta S; Bauer, Charles R; Whitaker, Toni M; Higgins, Rosemary; Hammond, Jane; Roberts, Mary B

    2012-06-01

    This study evaluated how enrollment in special education services in 11-year-old children relates to prenatal cocaine exposure (PCE), psychopathology, and other risk factors. Participants were 498 children enrolled in The Maternal Lifestyle Study, a prospective, longitudinal, multisite study examining outcomes of children with PCE. Logistic regression was used to examine the effect of PCE and psychopathology on enrollment in an individualized education plan (IEP; a designation specific to children with special education needs), with environmental, maternal, and infant medical variables as covariates. PCE, an interaction of PCE and oppositional defiant disorder, child attention-deficit hyperactivity disorder, parent-reported internalizing behaviors, and teacher-reported externalizing behaviors, predicted enrollment in an IEP. Other statistically significant variables in the model were male gender, low birth weight, being small for gestational age, white race, caregiver change, low socioeconomic status, low child intelligence quotient, caregiver depression, and prenatal marijuana exposure. PCE increased the likelihood of receiving an IEP with adjustment for covariates. Psychopathology also predicted this special education outcome, in combination with and independent of prenatal cocaine exposure.

  6. Bioanalysis for cocaine, opiates, methadone, and amphetamines exposure detection during pregnancy.

    Science.gov (United States)

    Concheiro, Marta; Lendoiro, Elena; de Castro, Ana; Gónzalez-Colmenero, Eva; Concheiro-Guisan, Ana; Peñas-Silva, Patricia; Macias-Cortiña, Manuel; Cruz-Landeira, Angelines; López-Rivadulla, Manuel

    2017-06-01

    Drug exposure during pregnancy constitutes a major legal issue and a public health concern. Drug and metabolite determination in biological matrices from mother and newborn is an objective indication of prenatal drug exposure. However, limited data are available regarding the interpretation of these analytical results in terms of window of detection and degree of exposure. We collected paired maternal hair, meconium, placenta, and umbilical cord from 727 mother-newborn dyads. We analyzed these specimens by liquid chromatography-tandem mass spectrometry for the determination of cocaine, opioids, methadone, and amphetamines, and compared the analytical results from the four different matrices. The cases were divided in non-exposure, low, and frequent exposure, based on maternal hair concentrations and segmental analysis by trimesters. For cocaine, 62 cases tested positive in hair, 9 in meconium, 6 in placenta and 7 in umbilical cord. In the case of opioids, 14 maternal hair cases were positive, 11 meconium and umbilical cord and 9 placenta samples. For methadone, 11 cases were positive in hair, 9 in meconium and 6 in placenta and umbilical cord. For amphetamines, 18 cases were positive according to maternal hair, but all meconium, placenta, and umbilical cord tested negative. Maternal hair was the most sensitive specimen to detect drug exposure during pregnancy. Meconium, placenta, and umbilical cord tested positive if hair concentrations showed frequent drug use during the whole pregnancy, especially during the third trimester. Meconium, placenta, and umbilical cord also tested positive for morphine and metabolites, if this drug was administered during labour and delivery. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  7. Adolescents with and without gestational cocaine exposure: Longitudinal analysis of inhibitory control, memory and receptive language.

    Science.gov (United States)

    Betancourt, Laura M; Yang, Wei; Brodsky, Nancy L; Gallagher, Paul R; Malmud, Elsa K; Giannetta, Joan M; Farah, Martha J; Hurt, Hallam

    2011-01-01

    Preclinical studies of gestational cocaine exposure (GCE) show evidence of changes in brain function at the anatomical, physiological, and behavioral levels, to include effects on developing dopaminergic systems. In contrast, human studies have produced less consistent results, with most showing small effects or no effects on developmental outcomes. Important changes in brain structure and function occur through adolescence, therefore it is possible that prenatal cocaine exposure has latent effects on neurocognitive (NC) outcome that do not manifest until adolescence or young adulthood. We examined NC function using a set of 5 tasks designed to tap 4 different systems: inhibitory control, working memory, receptive language, and incidental memory. For each NC task, data were collected longitudinally at ages 12, 14.5 and 17 years and examined using generalized estimating equations. One hundred and nine children completed at least two of the three evaluations. Covariates included in the final model were assessment number, gender, participant age at first assessment, caregiver depression, and two composites from the Home Observation for Measurement of the Environment (HOME), Environmental Stimulation and Parental Nurturance. We found no cocaine effects on inhibitory control, working memory, or receptive language (p=0.18). GCE effects were observed on incidental face memory task (p=0.055), and GCE by assessment number interaction effects were seen on the incidental word memory task (p=0.031). Participant performance on inhibitory control, working memory, and receptive language tasks improved over time. HOME Environmental Stimulation composite was associated with better receptive language functioning. With a larger sample size smaller differences between groups may have been detected. This report shows no evidence of latent effects of GCE on inhibitory control, working memory, or receptive language. GCE effects were observed on the incidental face memory task, and GCE by

  8. Increasing Positive Perceptions of Counseling: The Importance of Repeated Exposures

    Science.gov (United States)

    Kaplan, Scott A.; Vogel, David L.; Gentile, Douglas A.; Wade, Nathaniel G.

    2012-01-01

    This study assesses the effectiveness of repeated exposures to a video intervention based on the Elaboration Likelihood Model. The video was designed to increase help-seeking attitudes and perceptions of peer norms and to decrease the stigma associated with seeking counseling. Participants were 290 undergraduates who were randomly assigned to a…

  9. Executive function in children with prenatal cocaine exposure (12-15years).

    Science.gov (United States)

    Minnes, Sonia; Min, Meeyoung O; Short, Elizabeth J; Wu, Miaoping; Lang, Adelaide; Yoon, Susan; Singer, Lynn T

    Prenatal exposure to cocaine (PCE) may alter areas of the brain dense with monoamine receptors such as the prefrontal cortex and negatively affect cognitive processes implicated in executive function (EF). This study investigated the effects of PCE on EF at 12 and 15years. EF was examined in 189 PCE and 183 non-cocaine exposed (NCE) children who were primarily African American and of low socioeconomic status. Caregivers rated their child on the Behavior Rating Inventory of Executive Function (BRIEF) at ages 12 and 15. The BRIEF includes two summary scales and eight subscales: Behavioral Regulation Index (BRI) (Inhibit, Shift, and Emotion) and Metacognition Index (MI) (Monitor, Working Memory, Plan/Organize, Organization of Materials and Task Completion). Two additional measures were included at age 15 (BRIEF Self-Report and the CANTAB Stockings of Cambridge (SOC)). Girls with PCE were perceived by caregivers to have more behavioral regulation problems at age 12 (p<0.005) and more metacognitive problems at age 12 (p<0.003) than NCE females, but there was no association for males. PCE girls improved in behavioral regulation (p<0.05) and metacognition (p<0.04) from 12 to 15years compared to NCE girls based on caregiver report. By self-report PCE was associated with problems of inhibition (p<0.006). Girls with PCE performed more poorly on number of moves to complete the SOC, requiring planning and problem solving, than NCE girls. Prenatally cocaine exposed girls were perceived by caregivers as having problems of behavioral regulation, and by self-report, inhibitory control problems. Girls with PCE also performed more poorly on a task of planning and problem solving at age 15 which corresponded to caregiver report at age 12. Early assessment and remediation of these weaknesses in girls may improve school performance and behavior associated with poor EF. Copyright © 2016. Published by Elsevier Inc.

  10. Absence of bacterial resistance following repeat exposure to photodynamic therapy

    Science.gov (United States)

    Pedigo, Lisa A.; Gibbs, Aaron J.; Scott, Robert J.; Street, Cale N.

    2009-06-01

    The prevalence of antibiotic resistant bacteria necessitates exploration of alternative approaches to treat hospital and community acquired infections. The aim of this study was to determine whether bacterial pathogens develop resistance to antimicrobial photodynamic therapy (aPDT) during repeated sub-lethal challenge. Antibiotic sensitive and resistant strains of S. aureus and antibiotic sensitive E. coli were subjected to repeat PDT treatments using a methylene blue photosensitizer formulation and 670 nm illumination from a non-thermal diode laser. Parameters were adjusted such that kills were antibiotic resistance strains. Furthermore, repeated sub-lethal exposure does not induce resistance to subsequent PDT treatments. The absence of resistance formation represents a significant advantage of PDT over traditional antibiotics.

  11. Repeated exposure of adult rats to transient oxidative stress induces various long-lasting alterations in cognitive and behavioral functions.

    Directory of Open Access Journals (Sweden)

    Yoshio Iguchi

    Full Text Available Exposure of neonates to oxidative stress may increase the risk of psychiatric disorders such as schizophrenia in adulthood. However, the effects of moderate oxidative stress on the adult brain are not completely understood. To address this issue, we systemically administrated 2-cyclohexen-1-one (CHX to adult rats to transiently reduce glutathione levels. Repeated administration of CHX did not affect the acquisition or motivation of an appetitive instrumental behavior (lever pressing rewarded by a food outcome under a progressive ratio schedule. In addition, response discrimination and reversal learning were not affected. However, acute CHX administration blunted the sensitivity of the instrumental performance to outcome devaluation, and this effect was prolonged in rats with a history of repeated CHX exposure, representing pro-depression-like phenotypes. On the other hand, repeated CHX administration reduced immobility in forced swimming tests and blunted acute cocaine-induced behaviors, implicating antidepressant-like effects. Multivariate analyses segregated a characteristic group of behavioral variables influenced by repeated CHX administration. Taken together, these findings suggest that repeated administration of CHX to adult rats did not cause a specific mental disorder, but it induced long-term alterations in behavioral and cognitive functions, possibly related to specific neural correlates.

  12. Effects of repeated skin exposure to low nickel concentrations

    DEFF Research Database (Denmark)

    Nielsen, N H; Menné, T; Kristiansen, J

    1999-01-01

    and nickel allergy, either on normal or on SLS-treated forearm skin. The present study strongly suggests that the changes observed were specific to nickel exposure. Standardized methods to assess trace to moderate nickel exposure on the hands, and the associated effects in nickel-sensitized subjects......We studied the effects of repeated daily exposure to low nickel concentrations on the hands of patients with hand eczema and nickel allergy. The concentrations used were chosen to represent the range of trace to moderate occupational nickel exposure. The study was double-blinded and placebo...... controlled. Patients immersed a finger for 10 min daily into a 10-p.p.m. nickel concentration in water for the first week, and during the second week into a 100-p.p.m. nickel concentration. This regimen significantly increased (P = 0.05) local vesicle formation and blood flow (P = 0.03) as compared...

  13. Cocaine Self-Administration Produces Long-Lasting Alterations in Dopamine Transporter Responses to Cocaine

    OpenAIRE

    Siciliano, Cody A.; Fordahl, Steve C.; Jones, Sara R.

    2016-01-01

    Cocaine addiction is a debilitating neuropsychiatric disorder characterized by uncontrolled cocaine intake, which is thought to be driven, at least in part, by cocaine-induced deficits in dopamine system function. A decreased ability of cocaine to elevate dopamine levels has been repeatedly observed as a consequence of cocaine use in humans, and preclinical work has highlighted tolerance to cocaine's effects as a primary determinant in the development of aberrant cocaine taking behaviors. Her...

  14. Calcium-permeable AMPA receptors in the VTA and nucleus accumbens after cocaine exposure: When, how and why?

    Directory of Open Access Journals (Sweden)

    Marina E Wolf

    2012-06-01

    Full Text Available In animal models of drug addiction, cocaine exposure has been shown to increase levels of calcium-permeable AMPA receptors (CP-AMPARs in two brain regions that are critical for motivation and reward - the ventral tegmental area (VTA and the nucleus accumbens (NAc. This review compares CP-AMPAR plasticity in the two brain regions and addresses its functional significance. In VTA dopamine neurons, cocaine exposure results in synaptic insertion of high conductance CP-AMPARs in exchange for lower conductance calcium-impermeable AMPARs (CI-AMPARs. This plasticity is rapid (hours, GluA2-dependent, and can be observed with a single cocaine injection. In addition to strengthening synapses and altering Ca2+ signaling, CP-AMPAR insertion affects subsequent induction of plasticity at VTA synapses. However, CP-AMPAR insertion is unlikely to mediate the increased dopamine cell activity that occurs during early withdrawal from cocaine exposure. Within the VTA, the group I metabotropic glutamate receptor mGluR1 exerts a negative influence on CP-AMPAR accumulation. Acutely, mGluR1 stimulation elicits a form of LTD resulting from CP-AMPAR removal and CI-AMPAR insertion. In medium spiny neurons (MSNs of the NAc, extended access cocaine self-administration is required to increase CP-AMPAR levels. This is first detected after approximately a month of withdrawal and then persists. Once present in NAc synapses, CP-AMPARs mediate the expression of incubation of cue-induced cocaine craving. The mechanism of their accumulation may be GluA1-dependent, which differs from that observed in the VTA. However, similar to VTA, mGluR1 stimulation removes CP-AMPARs from MSN synapses. Loss of mGluR1 tone during cocaine withdrawal may contribute to CP-AMPAR accumulation in the NAc. Thus, results in both brain regions point to the possibility of using positive modulators of mGluR1 as a treatment for cocaine addiction.

  15. Single prolonged stress effects on sensitization to cocaine and cocaine self-administration in rats.

    Science.gov (United States)

    Eagle, Andrew L; Singh, Robby; Kohler, Robert J; Friedman, Amy L; Liebowitz, Chelsea P; Galloway, Matthew P; Enman, Nicole M; Jutkiewicz, Emily M; Perrine, Shane A

    2015-05-01

    Posttraumatic stress disorder (PTSD) is often comorbid with substance use disorders (SUD). Single prolonged stress (SPS) is a well-validated rat model of PTSD that provides a framework to investigate drug-induced behaviors as a preclinical model of the comorbidity. We hypothesized that cocaine sensitization and self-administration would be increased following exposure to SPS. Male Sprague-Dawley rats were exposed to SPS or control treatment. After SPS, cocaine (0, 10 or 20 mg/kg, i.p.) was administered for 5 consecutive days and locomotor activity was measured. Another cohort was assessed for cocaine self-administration (0.1 or 0.32 mg/kg/i.v.) after SPS. Rats were tested for acquisition, extinction and cue-induced reinstatement behaviors. Control animals showed a dose-dependent increase in cocaine-induced locomotor activity after acute cocaine whereas SPS rats did not. Using a sub-threshold sensitization paradigm, control rats did not exhibit enhanced locomotor activity at Day 5 and therefore did not develop behavioral sensitization, as expected. However, compared to control rats on Day 5 the locomotor response to 20mg/kg repeated cocaine was greatly enhanced in SPS-treated rats, which exhibited enhanced cocaine locomotor sensitization. The effect of SPS on locomotor activity was unique in that SPS did not modify cocaine self-administration behaviors under a simple schedule of reinforcement. These data show that SPS differentially affects cocaine-mediated behaviors causing no effect to cocaine self-administration, under a simple schedule of reinforcement, but significantly augmenting cocaine locomotor sensitization. These results suggest that SPS shares common neurocircuitry with stimulant-induced plasticity, but dissociable from that underlying psychostimulant-induced reinforcement. Copyright © 2015. Published by Elsevier B.V.

  16. Proteasome phosphorylation regulates cocaine-induced sensitization.

    Science.gov (United States)

    Gonzales, Frankie R; Howell, Kristin K; Dozier, Lara E; Anagnostaras, Stephan G; Patrick, Gentry N

    2018-04-01

    Repeated exposure to cocaine produces structural and functional modifications at synapses from neurons in several brain regions including the nucleus accumbens. These changes are thought to underlie cocaine-induced sensitization. The ubiquitin proteasome system plays a crucial role in the remodeling of synapses and has recently been implicated in addiction-related behavior. The ATPase Rpt6 subunit of the 26S proteasome is phosphorylated by Ca 2+ /calmodulin-dependent protein kinases II alpha at ser120 which is thought to regulate proteasome activity and distribution in neurons. Here, we demonstrate that Rpt6 phosphorylation is involved in cocaine-induced locomotor sensitization. Cocaine concomitantly increases proteasome activity and Rpt6 S120 phosphorylation in cultured neurons and in various brain regions of wild type mice including the nucleus accumbens and prefrontal cortex. In contrast, cocaine does not increase proteasome activity in Rpt6 phospho-mimetic (ser120Asp) mice. Strikingly, we found a complete absence of cocaine-induced locomotor sensitization in the Rpt6 ser120Asp mice. Together, these findings suggest a critical role for Rpt6 phosphorylation and proteasome function in the regulation cocaine-induced behavioral plasticity. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Repeated 7-Day Treatment with the 5-HT2C Agonist Lorcaserin or the 5-HT2A Antagonist Pimavanserin Alone or in Combination Fails to Reduce Cocaine vs Food Choice in Male Rhesus Monkeys.

    Science.gov (United States)

    Banks, Matthew L; Negus, S Stevens

    2017-04-01

    Cocaine use disorder is a global public health problem for which there are no Food and Drug Administration-approved pharmacotherapies. Emerging preclinical evidence has implicated both serotonin (5-HT) 2C and 2A receptors as potential mechanisms for mediating serotonergic attenuation of cocaine abuse-related neurochemical and behavioral effects. Therefore, the present study aim was to determine whether repeated 7-day treatment with the 5-HT 2C agonist lorcaserin (0.1-1.0 mg/kg per day, intramuscular; 0.032-0.1 mg/kg/h, intravenous) or the 5-HT 2A inverse agonist/antagonist pimavanserin (0.32-10 mg/kg per day, intramuscular) attenuated cocaine reinforcement under a concurrent 'choice' schedule of cocaine and food availability in rhesus monkeys. During saline treatment, cocaine maintained a dose-dependent increase in cocaine vs food choice. Repeated pimavanserin (3.2 mg/kg per day) treatments significantly increased small unit cocaine dose choice. Larger lorcaserin (1.0 mg/kg per day and 0.1 mg/kg/h) and pimavanserin (10 mg/kg per day) doses primarily decreased rates of operant behavior. Coadministration of ineffective lorcaserin (0.1 mg/kg per day) and pimavanserin (0.32 mg/kg per day) doses also failed to significantly alter cocaine choice. These results suggest that neither 5-HT 2C receptor activation nor 5-HT 2A receptor blockade are sufficient to produce a therapeutic-like decrease in cocaine choice and a complementary increase in food choice. Overall, these results do not support the clinical utility of 5-HT 2C agonists and 5-HT 2A inverse agonists/antagonists alone or in combination as candidate anti-cocaine use disorder pharmacotherapies.

  18. Firefighting and mental health: Experiences of repeated exposure to trauma.

    Science.gov (United States)

    Jahnke, Sara A; Poston, Walker S Carlos; Haddock, Christopher K; Murphy, Beth

    2016-02-15

    Firefighters must be ready to respond to a broad range of emergencies every duty day. In the course of many of these emergencies, firefighters witness events which have the potential to induce emotional trauma, such as badly injured people, deceased children, and individuals who are highly distraught. Previous research suggests that repeated exposure to these traumas (RET) may have negative impacts on the emotional and mental health of fire service personnel. Research on the mental health of firefighters has been limited to small surveys reporting the prevalence of specific mental health problems such as depression and post-traumatic stress disorder among firefighters. Despite the likelihood that RET leads to negative outcomes in firefighters, data is lacking on how exposure impacts fire service personnel. The current study examines the experiences of firefighters related to RET. Using formative research methods, we examined the beliefs and experiences of firefighters and administrators from across the United States regarding the impact of RET on firefighter health. Study findings highlight the cumulative psychological toll of repeated exposure to traumatic events including desensitization, flashbacks, and irritability. Results of the current study suggest that RET is a significant concern for emergency responders that warrants additional research and attention. It is likely that the long term consequences of RET are closely intertwined with other mental health outcomes and general well-being of this important occupational group.

  19. Prenatal cocaine exposure and its impact on cognitive functions of offspring: a pathophysiological insight.

    Science.gov (United States)

    Gkioka, Eleana; Korou, Laskarina Maria; Daskalopoulou, Afrodite; Misitzi, Angelica; Batsidis, Eleni; Bakoyiannis, Ioannis; Pergialiotis, Vasilios

    2016-07-01

    It is estimated that approximately 0.5%-3% of fetuses are prenatally exposed to cocaine (COC). The neurodevelopmental implications of this exposure are numerous and include motor skill impairments, alterations of social function, predisposition to anxiety, and memory function and attention deficits; these implications are commonly observed in experimental studies and ultimately affect both learning and IQ. According to previous studies, the clinical manifestations of prenatal COC exposure seem to persist at least until adolescence. The pathophysiological cellular processes that underlie these impairments include dysfunctional myelination, disrupted dendritic architecture, and synaptic alterations. On a molecular level, various neurotransmitters such as serotonin, dopamine, catecholamines, and γ-aminobutyric acid seem to participate in this process. Finally, prenatal COC abuse has been also associated with functional changes in the hormones of the hypothalamic-pituitary-adrenal axis that mediate neuroendocrine responses. The purpose of this review is to summarize the neurodevelopmental consequences of prenatal COC abuse, to describe the pathophysiological pathways that underlie these consequences, and to provide implications for future research in the field.

  20. Association Between Gambling and Exposure to Guns Among Cocaine-Using Women.

    Science.gov (United States)

    Vaddiparti, Krishna; Striley, Catherine W; Cottler, Linda B

    2016-09-01

    The purpose of this study is to assess the association between gambling severity and exposure to guns among substance-using women recruited in the community. Data for these analyses come from the baseline phase of two community-based HIV prevention interventions conducted among alcohol and drug-using women in St. Louis, MO. Gun exposure was assessed using the Violence Exposure Questionnaire (VEQ), and DSM-IV pathological gambling (PG) symptoms and other psychiatric symptoms were assessed using the Computerized Diagnostic Interview Schedule; The Composite International Diagnostic Interview Substance Abuse Module assessed DSM-IV substance dependence, including cocaine dependence and alcohol dependence. Women in the study were predominantly African American (80%), mean age was 35.70 years ±8.8. Women exposed to guns were significantly more likely than women not exposed to guns to have gambled with all consequences: without meeting PG criteria (21% vs. 15%); to meet 1 to 4 PG criteria (22% vs. 12%), and to report 5 or more PG criteria (10% vs. 5%). These differences were significant at p  gambled without PG symptoms (OR = 1.77; 95% CI = 1.10-2.85) were nearly twice more likely to have exposure to guns than women who did not gamble. The risk for gun exposure increased with severity of gambling. Women who gambled and reported one to four PG criteria were twice as likely to have had an exposure to guns (OR 2.04; 95% CI = 1.45-3.06) and this risk increased to nearly threefold among women who met five or more criteria of PG (OR 2.65; 95% CI = 1.32-5.32). In addition, endorsing five or more criteria for major depressive disorder (OR 1.44; 95% CI = 1.00-2.06) and three or more criteria for antisocial personality adult criteria (OR 3.78; 95% CI = 2.03-7.02) were strong predictors for gun exposure among these women. The findings indicate that substance-using women with gambling behavior are at an enhanced risk to have exposure to guns.

  1. Myocardial ischaemia following cocaine and adrenaline exposure in a child during an ophthalmological procedure.

    LENUS (Irish Health Repository)

    McGovern, E

    2015-03-01

    We report a 23-month old girl who presented with bilateral epiphora who underwent bilateral lacrimal probing and syringing, during which a cocaine adrenaline solution was used. Two hours after the procedure she developed acute pulmonary oedema secondary to myocardial ischaemia. The patient was treated with intravenous glyceryltrinitrate and milrinone infusions; cardiac enzymes and left ventricular function normalised over the subsequent 72 hours. Topical administration of cocaine and adrenaline solution may have dangerous systemic cardiac effects and should always be used judiciously.

  2. The effects of repeated low-dose sarin exposure

    International Nuclear Information System (INIS)

    Shih, T.-M.; Hulet, S.W.; McDonough, J.H.

    2006-01-01

    This project assessed the effects of repeated low-dose exposure of guinea pigs to the organophosphorus nerve agent sarin. Animals were injected once a day, 5 days per week (Monday-Friday), for 2 weeks with fractions (0.3x, 0.4x, 0.5x, or 0.6x) of the established LD 5 dose of sarin (42 μg/kg, s.c.). The animals were assessed for changes in body weight, red blood cell (RBC) acetylcholinesterase (AChE) levels, neurobehavioral reactions to a functional observational battery (FOB), cortical electroencephalographic (EEG) power spectrum, and intrinsic acetylcholine (ACh) neurotransmitter (NT) regulation over the 2 weeks of sarin exposure and for up to 12 days postinjection. No guinea pig receiving 0.3, 0.4 or 0.5 x LD 5 of sarin showed signs of cortical EEG seizures despite decreases in RBC AChE levels to as low as 10% of baseline, while seizures were evident in animals receiving 0.6 x LD 5 of sarin as early as the second day; subsequent injections led to incapacitation and death. Animals receiving 0.5 x LD 5 sarin showed obvious signs of cholinergic toxicity; overall, 2 of 13 animals receiving 0.5 x LD 5 sarin died before all 10 injections were given, and there was a significant increase in the angle of gait in the animals that lived. By the 10th day of injection, the animals receiving saline were significantly easier to remove from their cages and handle and significantly less responsive to an approaching pencil and touch on the rump in comparison with the first day of testing. In contrast, the animals receiving 0.4 x LD 5 sarin failed to show any significant reductions in their responses to an approaching pencil and a touch on the rump as compared with the first day. The 0.5 x LD 5 sarin animals also failed to show any significant changes to the approach and touch responses and did not adjust to handling or removal from the cage from the first day of injections to the last day of handling. Thus, the guinea pigs receiving the 0.4 and 0.5 x LD 5 doses of sarin failed to

  3. Exposure to chronic mild stress prevents kappa opioid-mediated reinstatement of cocaine and nicotine place preference

    Directory of Open Access Journals (Sweden)

    Ream eAl-Hasani

    2013-08-01

    Full Text Available Stress increases the risk of drug abuse, causes relapse to drug seeking, and potentiates the rewarding properties of both nicotine and cocaine. Understanding the mechanisms by which stress regulates the rewarding properties of drugs of abuse provides valuable insight into potential treatments for drug abuse. Prior reports have demonstrated that stress causes dynorphin release, activating kappa-opioid receptors (KOR in monoamine circuits resulting in both potentiation and reinstatement of cocaine and nicotine conditioned place preference. Here we report that kappa-opioid dependent reinstatement of cocaine and nicotine place preference is reduced when the mice are exposed to a randomized chronic mild stress regime prior to training in a conditioned place preference-reinstatement paradigm. The chronic mild stress schedule involves seven different stressors (removal of nesting for 24hr, 5min forced swim stress at 15°C, 8hr food and water deprivation, damp bedding overnight, white noise, cage tilt and disrupted home cage lighting rotated over a three-week period. This response is KOR-selective, because chronic mild stress does not protect against cocaine or nicotine drug-primed reinstatement. This protection from reinstatement is also observed following sub-chronic social defeat stress, where each mouse is placed in an aggressor mouse home cage for a period of 20 min over five days. In contrast, a single acute stressor resulted in a potentiation of KOR-induced reinstatement, similarly to previously reported. Prior studies have shown that stress alters sensitivity to opioids and prior stress can influence the pharmacodynamics of the opioid receptor system. Together, these findings suggest that exposure to different forms of stress may cause a dysregulation of kappa opioid circuitry and that changes resulting from mild stress can have protective and adaptive effects against drug relapse.

  4. Single cocaine exposure does not alter striatal pre-synaptic dopamine function in mice: an [18 F]-FDOPA PET study.

    Science.gov (United States)

    Bonsall, David R; Kokkinou, Michelle; Veronese, Mattia; Coello, Christopher; Wells, Lisa A; Howes, Oliver D

    2017-12-01

    Cocaine is a recreational drug of abuse that binds to the dopamine transporter, preventing reuptake of dopamine into pre-synaptic terminals. The increased presence of synaptic dopamine results in stimulation of both pre- and post-synaptic dopamine receptors, considered an important mechanism by which cocaine elicits its reinforcing properties. However, the effects of acute cocaine administration on pre-synaptic dopamine function remain unclear. Non-invasive imaging techniques such as positron emission tomography have revealed impaired pre-synaptic dopamine function in chronic cocaine users. Similar impairments have been seen in animal studies, with microdialysis experiments indicating decreased basal dopamine release. Here we use micro positron emission tomography imaging techniques in mice to measure dopamine synthesis capacity and determine the effect of acute cocaine administration of pre-synaptic dopamine function. We show that a dose of 20 mg/kg cocaine is sufficient to elicit hyperlocomotor activity, peaking 15-20 min post treatment (p dopamine synthesis capacity in the striatum was not significantly altered by acute cocaine treatment (KiCer: 0.0097 per min vs. 0.0112 per min in vehicle controls, p > 0.05). Furthermore, expression levels of two key enzymes related to dopamine synthesis, tyrosine hydroxylase and aromatic l-amino acid decarboxylase, within the striatum of scanned mice were not significantly affected by acute cocaine pre-treatment (p > 0.05). Our findings suggest that while the regulation of dopamine synthesis and release in the striatum have been shown to change with chronic cocaine use, leading to a reduced basal tone, these adaptations to pre-synaptic dopaminergic neurons are not initiated following a single exposure to the drug. © 2017 International Society for Neurochemistry.

  5. Repeated Exposure to Conditioned Fear Stress Increases Anxiety and Delays Sleep Recovery Following Exposure to an Acute Traumatic Stressor

    OpenAIRE

    Greenwood, Benjamin N.; Thompson, Robert S.; Opp, Mark R.; Fleshner, Monika

    2014-01-01

    Repeated stressor exposure can sensitize physiological responses to novel stressors and facilitate the development of stress-related psychiatric disorders including anxiety. Disruptions in diurnal rhythms of sleep–wake behavior accompany stress-related psychiatric disorders and could contribute to their development. Complex stressors that include fear-eliciting stimuli can be a component of repeated stress experienced by human beings, but whether exposure to repeated fear can prime the develo...

  6. The Effects of Repeated Exposure to Graphic Fear Appeals on Cigarette Packages: A Field Experiment

    NARCIS (Netherlands)

    Dijkstra, A.; Bos, C.

    2015-01-01

    Experimental studies on the effects of graphic fear appeals on cigarette packages typically expose smokers in a single session to a fear appeal, although in practice the exposure is always repeated. The present study applied an improved study design with repeated exposure to fear appeals on

  7. The Effects of Repeated Exposure to Graphic Fear Appeals on Cigarette Packages : A Field Experiment

    NARCIS (Netherlands)

    Dijkstra, Arie; Colin, Bos,

    2015-01-01

    Experimental studies on the effects of graphic fear appeals on cigarette packages typically expose smokers in a single session to a fear appeal, although in practice the exposure is always repeated. The present study applied an improved study design with repeated exposure to fear appeals on

  8. Dealing with consumer differences in liking during repeated exposure to food; typical dynamics in rating behavior

    NARCIS (Netherlands)

    Horst, ter G.J.; Renken, R.; Nanneti, L.; Dalenberg, J.R.; Wijk, de R.A.

    2014-01-01

    Consumers show high interindividual variability in food liking during repeated exposure. To investigate consumer liking during repeated exposure, data is often interpreted on a product level by averaging results over all consumers. However, a single product may elicit inconsistent behaviors in

  9. Dealing with Consumer Differences in Liking during Repeated Exposure to Food; Typical Dynamics in Rating Behavior

    NARCIS (Netherlands)

    Dalenberg, Jelle R.; Nanetti, Luca; Renken, Remco J.; de Wijk, Rene A.; ter Horst, Gert J.

    2014-01-01

    Consumers show high interindividual variability in food liking during repeated exposure. To investigate consumer liking during repeated exposure, data is often interpreted on a product level by averaging results over all consumers. However, a single product may elicit inconsistent behaviors in

  10. Attenuated response to repeated daily ozone exposures in asthmatic subjects

    Energy Technology Data Exchange (ETDEWEB)

    Gong, H. Jr.; Linn, W.S. [Rancho Low Amigos Medical Center, Downey, CA (United States); McManus, M.S. [Univ. of California, Los Angeles, CA (United States)

    1997-01-01

    The development of attenuated response ({open_quotes}tolerance{close_quotes}) to daily ozone (O{sub 3}) exposures in the laboratory is well established in healthy adult volunteers. However, the capability of asthmatics to develop tolerance during multiday ozone exposures in unclear. We exposed 10 adult volunteers with mild asthma to 0.4 ppm O{sub 3} in filtered air for 3 h/d on 5 consecutive d. Two similar filtered-air exposures during the preceding week served as controls. Follow-up O{sub 3} exposures were performed 4 and 7 d after the most recent consecutive exposure. All exposures were performed in an environmental chamber at 31 {degrees}C and 35% relative humidity. The subjects performed moderate exercise (mean ventilation rate of 32 l/min) for 15 min of each half-hour. Responses were measured with spirometry and symptom evaluations before and after each exposure, and a bronchial reactivity test (methacholine challenge) was conducted after each exposure. All response measurements showed clinically and statistically significant day-to-day variation. Symptom and forced-expiratory-volume-in-1-s responses were similarly large on the 1st and 2nd O{sub 3} exposure days, after which they diminished progressively, approaching filtered air response levels by the 5th consecutive O{sub 3} day. This tolerance was partially lost 4 and 7 d later. Bronchial reactivity peaked after the first O{sub 3} exposure and remained somewhat elevated after all subsequent O{sub 3} exposures, relative to its control level following filtered-air exposures. Individual responses varied widely; more severe initial responses to O{sub 3} predicted less rapid attenuation. We concluded that asthmatics can develop tolerance to frequent high-level O{sub 3} exposures in much the same manner as normal subjects, although the process may be slower and less fully effective in asthmatics. 27 refs., 3 figs., 4 tabs.

  11. Regulation of BAZ1A and nucleosome positioning in the nucleus accumbens in response to cocaine.

    Science.gov (United States)

    Sun, HaoSheng; Damez-Werno, Diane M; Scobie, Kimberly N; Shao, Ning-Yi; Dias, Caroline; Rabkin, Jacqui; Wright, Katherine N; Mouzon, Ezekiell; Kabbaj, Mohamed; Neve, Rachael; Turecki, Gustavo; Shen, Li; Nestler, Eric J

    2017-06-14

    Chromatin regulation, in particular ATP-dependent chromatin remodelers, have previously been shown to be important in the regulation of reward-related behaviors in animal models of mental illnesses. Here we demonstrate that BAZ1A, an accessory subunit of the ISWI family of chromatin remodeling complexes, is downregulated in the nucleus accumbens (NAc) of mice exposed repeatedly to cocaine and of cocaine-addicted humans. Viral-mediated overexpression of BAZ1A in mouse NAc reduces cocaine reward as assessed by conditioned place preference (CPP), but increases cocaine-induced locomotor activation. Furthermore, we investigate nucleosome repositioning genome-wide by conducting chromatin immunoprecipitation (ChIP)-sequencing for total H3 in NAc of control mice and after repeated cocaine administration, and find extensive nucleosome occupancy and shift changes across the genome in response to cocaine exposure. These findings implicate BAZ1A in molecular and behavioral plasticity to cocaine and offer new insight into the pathophysiology of cocaine addiction. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  12. Level of intrauterine cocaine exposure and neuropsychological test scores in preadolescence: subtle effects on auditory attention and narrative memory.

    Science.gov (United States)

    Beeghly, Marjorie; Rose-Jacobs, Ruth; Martin, Brett M; Cabral, Howard J; Heeren, Timothy C; Frank, Deborah A

    2014-01-01

    Neuropsychological processes such as attention and memory contribute to children's higher-level cognitive and language functioning and predict academic achievement. The goal of this analysis was to evaluate whether level of intrauterine cocaine exposure (IUCE) alters multiple aspects of preadolescents' neuropsychological functioning assessed using a single age-referenced instrument, the NEPSY: A Developmental Neuropsychological Assessment (NEPSY) (Korkman et al., 1998), after controlling for relevant covariates. Participants included 137 term 9.5-year-old children from low-income urban backgrounds (51% male, 90% African American/Caribbean) from an ongoing prospective longitudinal study. Level of IUCE was assessed in the newborn period using infant meconium and maternal report. 52% of the children had IUCE (65% with lighter IUCE, and 35% with heavier IUCE), and 48% were unexposed. Infants with Fetal Alcohol Syndrome, HIV seropositivity, or intrauterine exposure to illicit substances other than cocaine and marijuana were excluded. At the 9.5-year follow-up visit, trained examiners masked to IUCE and background variables evaluated children's neuropsychological functioning using the NEPSY. The association between level of IUCE and NEPSY outcomes was evaluated in a series of linear regressions controlling for intrauterine exposure to other substances and relevant child, caregiver, and demographic variables. Results indicated that level of IUCE was associated with lower scores on the Auditory Attention and Narrative Memory tasks, both of which require auditory information processing and sustained attention for successful performance. However, results did not follow the expected ordinal, dose-dependent pattern. Children's neuropsychological test scores were also altered by a variety of other biological and psychosocial factors. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Level of Intrauterine Cocaine Exposure and Neuropsychological Test Scores in Preadolescence: Subtle Effects on Auditory Attention and Narrative Memory

    Science.gov (United States)

    Beeghly, Marjorie; Rose-Jacobs, Ruth; Martin, Brett M.; Cabral, Howard J.; Heeren, Timothy C.; Frank, Deborah A.

    2014-01-01

    Neuropsychological processes such as attention and memory contribute to children's higher-level cognitive and language functioning and predict academic achievement. The goal of this analysis was to evaluate whether level of intrauterine cocaine exposure (IUCE) alters multiple aspects of preadolescents' neuropsychological functioning assessed using a single age-referenced instrument, the NEPSY: A Developmental Neuropsychological Assessment (NEPSY) [71], after controlling for relevant covariates. Participants included 137 term 9.5-year-old children from low-income urban backgrounds (51% male, 90% African American/Caribbean) from an ongoing prospective longitudinal study. Level of IUCE was assessed in the newborn period using infant meconium and maternal report. 52% of the children had IUCE (65% with lighter IUCE, and 35% with heavier IUCE), and 48% were unexposed. Infants with Fetal Alcohol Syndrome, HIV seropositivity, or intrauterine exposure to illicit substances other than cocaine and marijuana were excluded. At the 9.5-year follow-up visit, trained examiners masked to IUCE and background variables evaluated children's neuropsychological functioning using the NEPSY. The association between level of IUCE and NEPSY outcomes was evaluated in a series of linear regressions controlling for intrauterine exposure to other substances and relevant child, caregiver, and demographic variables. Results indicated that level of IUCE was associated with lower scores on the Auditory Attention and Narrative Memory tasks, both of which require auditory information processing and sustained attention for successful performance. However, results did not follow the expected ordinal, dose-dependent pattern. Children's neuropsychological test scores were also altered by a variety of other biological and psychosocial factors. PMID:24978115

  14. Crack-ing the case: a patient with persistent delirium due to body packing with cocaine.

    LENUS (Irish Health Repository)

    2012-04-01

    A 36-year-old male presented acutely with encephalopathy, following his return to Ireland from a visit to West Africa. Clinical findings included confusion, agitation and tonic-clonic seizures. Difficulties in weaning sedation prompted repeat urine toxicology screening at day 8, which was positive for cocaine. Work-up for a source of continued cocaine exposure led to the discovery of cocaine-containing packages in the gastrointestinal tract. An index of suspicion should be maintained in patients presenting with drug toxicity following cross-border travel.

  15. Rapid induction of dopamine sensitization in the nucleus accumbens shell induced by a single injection of cocaine.

    Science.gov (United States)

    Singer, Bryan F; Bryan, Myranda A; Popov, Pavlo; Robinson, Terry E; Aragona, Brandon J

    2017-05-01

    Repeated intermittent exposure to cocaine results in the neurochemical sensitization of dopamine (DA) transmission within the nucleus accumbens (NAc). Indeed, the excitability of DA neurons in the ventral tegmental area (VTA) is enhanced within hours of initial psychostimulant exposure. However, it is not known if this is accompanied by a comparably rapid change in the ability of cocaine to increase extracellular DA concentrations in the ventral striatum. To address this question we used fast-scan cyclic voltammetry (FSCV) in awake-behaving rats to measure DA responses in the NAc shell following an initial intravenous cocaine injection, and then again 2-h later. Both injections quickly elevated DA levels in the NAc shell, but the second cocaine infusion produced a greater effect than the first, indicating sensitization. This suggests that a single injection of cocaine induces sensitization-related plasticity very rapidly within the mesolimbic DA system. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Effects of Cannabinoid Exposure during Adolescence on the Conditioned Rewarding Effects of WIN 55212-2 and Cocaine in Mice: Influence of the Novelty-Seeking Trait

    Directory of Open Access Journals (Sweden)

    M. Rodríguez-Arias

    2016-01-01

    Full Text Available Adolescent exposure to cannabinoids enhances the behavioural effects of cocaine, and high novelty-seeking trait predicts greater sensitivity to the conditioned place preference (CPP induced by this drug. Our aim was to evaluate the influence of novelty-seeking on the effects of adolescent cannabinoid exposure. Adolescent male mice were classified as high or low novelty seekers (HNS and LNS in the hole-board test. First, we evaluated the CPP induced by the cannabinoid agonist WIN 55212-2 (0.05 and 0.075 mg/kg, i.p. in HNS and LNS mice. Then, HNS and LNS mice were pretreated i.p. with vehicle, WIN 55212-2 (0.1 mg/kg, or cannabinoid antagonist rimonabant (1 mg/kg and were subsequently conditioned with WIN 55212-2 (0.05 mg/kg, i.p. or cocaine (1 or 6 mg/kg, i.p.. Only HNS mice conditioned with the 0.075 mg/kg dose acquired CPP with WIN 55212-2. Adolescent exposure to this cannabinoid agonist increased the rewarding effects of 1 mg/kg of cocaine in both HNS and LNS mice, and in HNS mice it also increased the reinstating effect of a low dose of cocaine. Our results endorse a role for individual differences such as a higher propensity for sensation-seeking in the development of addiction.

  17. Cocaine withdrawal

    Science.gov (United States)

    ... RE, Rakel DP, eds. Textbook of Family Medicine . 9th ed. Philadelphia, PA: Elsevier Saunders; 2016:chap 50. National Institute on Drug Abuse. What is cocaine? Updated May 2016. www.drugabuse.gov/publications/research-reports/cocaine/ ...

  18. Repeated exposure to conditioned fear stress increases anxiety and delays sleep recovery following exposure to an acute traumatic stressor

    Directory of Open Access Journals (Sweden)

    Benjamin N Greenwood

    2014-10-01

    Full Text Available Repeated stressor exposure can sensitize physiological responses to novel stressors and facilitate the development of stress-related psychiatric disorders including anxiety. Disruptions in diurnal rhythms of sleep-wake behavior accompany stress-related psychiatric disorders and could contribute to their development. Complex stressors that include fear-eliciting stimuli can be a component of repeated stress experienced by humans, but whether exposure to repeated fear can prime the development of anxiety and sleep disturbances is unknown. In the current study, adult male F344 rats were exposed to either control conditions or repeated contextual fear conditioning for 22 days followed by exposure to either no, mild (10, or severe (100 acute uncontrollable tail shock stress. Exposure to acute stress produced anxiety-like behavior as measured by a reduction in juvenile social exploration and exaggerated shock-elicited freezing in a novel context. Prior exposure to repeated fear enhanced anxiety-like behavior as measured by shock-elicited freezing, but did not alter social exploratory behavior. The potentiation of anxiety produced by prior repeated fear was temporary; exaggerated fear was present 1 day but not 4 days following acute stress. Interestingly, exposure to acute stress reduced REM and NREM sleep during the hours immediately following acute stress. This initial reduction in sleep was followed by robust REM rebound and diurnal rhythm flattening of sleep / wake behavior. Prior repeated fear extended the acute stress-induced REM and NREM sleep loss, impaired REM rebound, and prolonged the flattening of the diurnal rhythm of NREM sleep following acute stressor exposure. These data suggest that impaired recovery of sleep / wake behavior following acute stress could contribute to the mechanisms by which a history of prior repeated stress increases vulnerability to subsequent novel stressors and stress-related disorders.

  19. Repeated inhalation exposure of Beagle dogs to aerosols of 239PuO2. XII

    International Nuclear Information System (INIS)

    Diel, J.H.; Hahn, F.F.; Muggenburg, B.A.

    1988-01-01

    Beagle dogs were exposed once or semi-annually for 10 yr by inhalation to aerosols of 239 PuO 2 to study the relative doses and effects of these two types of exposures. All exposures have been completed. Dogs exposed at high levels died predominantly of radiation pneumonitis and pulmonary fibrosis. Dogs exposed at lower levels, either once or repeatedly, are dying of a variety of causes including lung cancer. Dogs have survived up to 11 yr after their first exposure. Preliminary results suggest that single and repeated exposures cause similar health effects for equal accumulated radiation doses. (author)

  20. Neonates' responses to repeated exposure to a still face.

    Science.gov (United States)

    Nagy, Emese; Pilling, Karen; Watt, Rachel; Pal, Attila; Orvos, Hajnalka

    2017-01-01

    The main aims of the study were to examine whether human neonates' responses to communication disturbance modelled by the still-face paradigm were stable and whether their responses were affected by their previous experience with the still-face paradigm. The still face procedure, as a laboratory model of interpersonal stress, was administered repeatedly, twice, to 84 neonates (0 to 4 day olds), with a delay of an average of 1.25 day. Frame-by-frame analysis of the frequency and duration of gaze, distressed face, crying, sleeping and sucking behaviours showed that the procedure was stressful to them both times, that is, the still face effect was stable after repeated administration and newborns consistently responded to such nonverbal violation of communication. They averted their gaze, showed distress and cried more during the still-face phase in both the first and the second administration. They also showed a carry-over effect in that they continued to avert their gaze and displayed increased distress and crying in the first reunion period, but their gaze behaviour changed with experience, in the second administration. While in the first administration the babies continued averting their gaze even after the stressful still-face phase was over, this carry-over effect disappeared in the second administration, and the babies significantly increased their gaze following the still-face phase. After excluding explanations of fatigue, habituation and random effects, a self-other regulatory model is discussed as a possible explanation for this pattern.

  1. Neonates’ responses to repeated exposure to a still face

    Science.gov (United States)

    Pilling, Karen; Watt, Rachel; Pal, Attila; Orvos, Hajnalka

    2017-01-01

    Aim The main aims of the study were to examine whether human neonates’ responses to communication disturbance modelled by the still-face paradigm were stable and whether their responses were affected by their previous experience with the still-face paradigm. Methods The still face procedure, as a laboratory model of interpersonal stress, was administered repeatedly, twice, to 84 neonates (0 to 4 day olds), with a delay of an average of 1.25 day. Results Frame-by-frame analysis of the frequency and duration of gaze, distressed face, crying, sleeping and sucking behaviours showed that the procedure was stressful to them both times, that is, the still face effect was stable after repeated administration and newborns consistently responded to such nonverbal violation of communication. They averted their gaze, showed distress and cried more during the still-face phase in both the first and the second administration. They also showed a carry-over effect in that they continued to avert their gaze and displayed increased distress and crying in the first reunion period, but their gaze behaviour changed with experience, in the second administration. While in the first administration the babies continued averting their gaze even after the stressful still-face phase was over, this carry-over effect disappeared in the second administration, and the babies significantly increased their gaze following the still-face phase. Conclusion After excluding explanations of fatigue, habituation and random effects, a self-other regulatory model is discussed as a possible explanation for this pattern. PMID:28771555

  2. Tumorigenic responses from single or repeated inhalation exposures to relatively insoluble aerosols of Ce-144

    International Nuclear Information System (INIS)

    Boecker, B.B.; Hahn, F.F.; Mauderly, J.L.; McClellan, R.O.

    1980-01-01

    Human occupational or environmental inhalation exposures may involve repeated or chronic exposures, but most laboratory studies of inhaled radionuclides have involved single exposures. This study was designed to compare the biological effects of repeated inhalation exposures of dogs to a relatively insoluble form of 144 Ce with existing data for singly-exposed dogs that had the same cumulative dose to the lungs two years after exposure. To date, the biological effects observed in these repeatedly-exposed dogs have been substantially different from those seen in singly-exposed dogs, particularly during the first 5 years after the initial exposure. Although pulmonary hemangiosarcoma was the prominent biological effect seen in singly-exposed dogs between 2 and 4 years after exposure, no lung tumors were seen during the 5 years after the first of the repeated exposures. This response plus other clinical observations are discussed in relation to the patterns of dose rate and cumulative dose for the different exposure conditions. (H.K.)

  3. The Effects of Repeated Low-Dose Sarin Exposure

    Science.gov (United States)

    2005-08-01

    support the idea that there is a triphasic NT model for onset and progression of seizures and subsequent brain damage upon acute exposure to OP ChE...An ACh microbore column (1x530 mm ID, 10 µm UniJet, BAS #MF-8904) coupled with AChE/choline oxidase immobilized enzyme reactor (BAS # MF-8903) was...peroxidase to the electrode for the reduction of hydrogen peroxide that was generated from the immobilized enzyme reactor . The detector was set at (-)1.0

  4. Cocaine adulteration.

    Science.gov (United States)

    Kudlacek, Oliver; Hofmaier, Tina; Luf, Anton; Mayer, Felix P; Stockner, Thomas; Nagy, Constanze; Holy, Marion; Freissmuth, Michael; Schmid, Rainer; Sitte, Harald H

    2017-10-01

    Cocaine is a naturally occurring and illicitly used psychostimulant drug. Cocaine acts at monoaminergic neurotransmitter transporters to block uptake of the monoamines, dopamine, serotonin and norepinephrine. The resulting increase of monoamines in the extracellular space underlies the positively reinforcing effects that cocaine users seek. In turn, this increase in monoamines underlies the development of addiction, and can also result in a number of severe side effects. Currently, cocaine is one of the most common illicit drugs available on the European market. However, cocaine is increasingly sold in impure forms. This trend is driven by cocaine dealers seeking to increase their profit margin by mixing ("cutting") cocaine with numerous other compounds ("adulterants"). Importantly, these undeclared compounds put cocaine consumers at risk, because consumers are not aware of the additional potential threats to their health. This review describes adulterants that have been identified in cocaine sold on the street market. Their typical pharmacological profile and possible reasons why these compounds can be used as cutting agents will be discussed. Since a subset of these adulterants has been found to exert effects similar to cocaine itself, we will discuss levamisole, the most frequently used cocaine cutting agent today, and its metabolite aminorex. Copyright © 2017. Published by Elsevier B.V.

  5. Repeated cue exposure effects on subjective and physiological indices of chocolate craving

    NARCIS (Netherlands)

    van Gucht, D.; Vansteenwegen, D.; Beckers, T.; Hermans, D.; Baeyens, F.; Van den Bergh, O.

    2008-01-01

    The aim of this study is to investigate the effects of repeated unreinforced exposure to chocolate cues in persons reporting chocolate craving. Participants in the experimental group (n ¼ 40) received 10 consecutive brief exposures to chocolate cues in each of two sessions, separated by 1-3 days.

  6. Repeated social defeat and the rewarding effects of cocaine in adult and adolescent mice: dopamine transcription factors, proBDNF signaling pathways, and the TrkB receptor in the mesolimbic system.

    Science.gov (United States)

    Montagud-Romero, Sandra; Nuñez, Cristina; Blanco-Gandia, M Carmen; Martínez-Laorden, Elena; Aguilar, María A; Navarro-Zaragoza, Javier; Almela, Pilar; Milanés, Maria-Victoria; Laorden, María-Luisa; Miñarro, José; Rodríguez-Arias, Marta

    2017-07-01

    Repeated social defeat (RSD) increases the rewarding effects of cocaine in adolescent and adult rodents. The aim of the present study was to compare the long-term effects of RSD on the conditioned rewarding effects of cocaine and levels of the transcription factors Pitx3 and Nurr1 in the ventral tegmental area (VTA), the dopamine transporter (DAT), the D2 dopamine receptor (D2DR) and precursor of brain-derived neurotrophic factor (proBDNF) signaling pathways, and the tropomyosin-related kinase B (TrkB) receptor in the nucleus accumbens (NAc) in adult and adolescent mice. Male adolescent and young adult OF1 mice were exposed to four episodes of social defeat and were conditioned 3 weeks later with 1 mg/kg of cocaine. In a second set of mice, the expressions of the abovementioned dopaminergic and proBDNF and TrkB receptor were measured in VTA and NAc, respectively. Adolescent mice experienced social defeats less intensely than their adult counterparts and produced lower levels of corticosterone. However, both adult and adolescent defeated mice developed conditioned place preference for the compartment associated with this low dose of cocaine. Furthermore, only adolescent defeated mice displayed diminished levels of the transcription factors Pitx3 in the VTA, without changes in the expression of DAT and D2DR in the NAc. In addition, stressed adult mice showed a decreased expression of proBDNF and the TrkB receptor, while stressed adolescent mice exhibited increased expression of latter without changes in the former. Our findings suggest that dopaminergic pathways and proBDNF signaling and TrkB receptors play different roles in social defeat-stressed mice exposed to cocaine.

  7. Repeated cue exposure effects on subjective and physiological indices of chocolate craving

    OpenAIRE

    Van Gucht, Dinska; Vansteenwegen, Debora; Beckers, Tom; Hermans, Dirk; Baeyens, Frank; Van den Bergh, Omer

    2008-01-01

    The aim of this study is to investigate the effects of repeated unreinforced exposure to chocolate cues in persons reporting chocolate craving. Participants in the experimental group (n=40) received 10 consecutive brief exposures to chocolate cues in each of two sessions, separated by 1-3 days. Control participants (n=18) received two exposures at the start and end of each session. Chocolate craving was measured (alternately) through subjective report and the amount of saliva secretion to cho...

  8. The Role of Repeated Exposure to Multimodal Input in Incidental Acquisition of Foreign Language Vocabulary.

    Science.gov (United States)

    Bisson, Marie-Josée; van Heuven, Walter J B; Conklin, Kathy; Tunney, Richard J

    2014-12-01

    Prior research has reported incidental vocabulary acquisition with complete beginners in a foreign language (FL), within 8 exposures to auditory and written FL word forms presented with a picture depicting their meaning. However, important questions remain about whether acquisition occurs with fewer exposures to FL words in a multimodal situation and whether there is a repeated exposure effect. Here we report a study where the number of exposures to FL words in an incidental learning phase varied between 2, 4, 6, and 8 exposures. Following the incidental learning phase, participants completed an explicit learning task where they learned to recognize written translation equivalents of auditory FL word forms, half of which had occurred in the incidental learning phase. The results showed that participants performed better on the words they had previously been exposed to, and that this incidental learning effect occurred from as little as 2 exposures to the multimodal stimuli. In addition, repeated exposure to the stimuli was found to have a larger impact on learning during the first few exposures and decrease thereafter, suggesting that the effects of repeated exposure on vocabulary acquisition are not necessarily constant.

  9. Analysis of real-time mixture cytotoxicity data following repeated exposure using BK/TD models

    International Nuclear Information System (INIS)

    Teng, S.; Tebby, C.; Barcellini-Couget, S.; De Sousa, G.; Brochot, C.; Rahmani, R.; Pery, A.R.R.

    2016-01-01

    Cosmetic products generally consist of multiple ingredients. Thus, cosmetic risk assessment has to deal with mixture toxicity on a long-term scale which means it has to be assessed in the context of repeated exposure. Given that animal testing has been banned for cosmetics risk assessment, in vitro assays allowing long-term repeated exposure and adapted for in vitro – in vivo extrapolation need to be developed. However, most in vitro tests only assess short-term effects and consider static endpoints which hinder extrapolation to realistic human exposure scenarios where concentration in target organs is varies over time. Thanks to impedance metrics, real-time cell viability monitoring for repeated exposure has become possible. We recently constructed biokinetic/toxicodynamic models (BK/TD) to analyze such data (Teng et al., 2015) for three hepatotoxic cosmetic ingredients: coumarin, isoeugenol and benzophenone-2. In the present study, we aim to apply these models to analyze the dynamics of mixture impedance data using the concepts of concentration addition and independent action. Metabolic interactions between the mixture components were investigated, characterized and implemented in the models, as they impacted the actual cellular exposure. Indeed, cellular metabolism following mixture exposure induced a quick disappearance of the compounds from the exposure system. We showed that isoeugenol substantially decreased the metabolism of benzophenone-2, reducing the disappearance of this compound and enhancing its in vitro toxicity. Apart from this metabolic interaction, no mixtures showed any interaction, and all binary mixtures were successfully modeled by at least one model based on exposure to the individual compounds. - Highlights: • We could predict cell response over repeated exposure to mixtures of cosmetics. • Compounds acted independently on the cells. • Metabolic interactions impacted exposure concentrations to the compounds.

  10. Analysis of real-time mixture cytotoxicity data following repeated exposure using BK/TD models

    Energy Technology Data Exchange (ETDEWEB)

    Teng, S.; Tebby, C. [Models for Toxicology and Ecotoxicology Unit, INERIS, Parc Technologique Alata, BP 2, 60550 Verneuil-en-Halatte (France); Barcellini-Couget, S. [ODESIA Neosciences, Sophia Antipolis, 400 route des chappes, 06903 Sophia Antipolis (France); De Sousa, G. [INRA, ToxAlim, 400 route des Chappes, BP, 167 06903 Sophia Antipolis, Cedex (France); Brochot, C. [Models for Toxicology and Ecotoxicology Unit, INERIS, Parc Technologique Alata, BP 2, 60550 Verneuil-en-Halatte (France); Rahmani, R. [INRA, ToxAlim, 400 route des Chappes, BP, 167 06903 Sophia Antipolis, Cedex (France); Pery, A.R.R., E-mail: alexandre.pery@agroparistech.fr [AgroParisTech, UMR 1402 INRA-AgroParisTech Ecosys, 78850 Thiverval Grignon (France); INRA, UMR 1402 INRA-AgroParisTech Ecosys, 78850 Thiverval Grignon (France)

    2016-08-15

    Cosmetic products generally consist of multiple ingredients. Thus, cosmetic risk assessment has to deal with mixture toxicity on a long-term scale which means it has to be assessed in the context of repeated exposure. Given that animal testing has been banned for cosmetics risk assessment, in vitro assays allowing long-term repeated exposure and adapted for in vitro – in vivo extrapolation need to be developed. However, most in vitro tests only assess short-term effects and consider static endpoints which hinder extrapolation to realistic human exposure scenarios where concentration in target organs is varies over time. Thanks to impedance metrics, real-time cell viability monitoring for repeated exposure has become possible. We recently constructed biokinetic/toxicodynamic models (BK/TD) to analyze such data (Teng et al., 2015) for three hepatotoxic cosmetic ingredients: coumarin, isoeugenol and benzophenone-2. In the present study, we aim to apply these models to analyze the dynamics of mixture impedance data using the concepts of concentration addition and independent action. Metabolic interactions between the mixture components were investigated, characterized and implemented in the models, as they impacted the actual cellular exposure. Indeed, cellular metabolism following mixture exposure induced a quick disappearance of the compounds from the exposure system. We showed that isoeugenol substantially decreased the metabolism of benzophenone-2, reducing the disappearance of this compound and enhancing its in vitro toxicity. Apart from this metabolic interaction, no mixtures showed any interaction, and all binary mixtures were successfully modeled by at least one model based on exposure to the individual compounds. - Highlights: • We could predict cell response over repeated exposure to mixtures of cosmetics. • Compounds acted independently on the cells. • Metabolic interactions impacted exposure concentrations to the compounds.

  11. Effects of repeated exposure to white noise on central cholinergic activity in the rat.

    Science.gov (United States)

    Lai, H

    1988-03-01

    Acute (45 min) exposure to noise has been shown to decrease sodium-dependent high-affinity choline uptake activity in the frontal cortex and hippocampus of the rat. In the present experiment, the effects of repeated noise exposure on choline uptake in these two brain regions were studied. Rats were exposed to 100-dB white noise in ten 45-min sessions. Tolerance developed to the effects of noise on choline uptake. In addition, the effects were found to be classically conditionable to cues in the exposure environment. These data may have important implications in understanding the health hazard of noise exposure in both the public and occupational environments.

  12. IL-6 and IL-10 levels in the umbilical cord blood of newborns with a history of crack/cocaine exposure in utero: a comparative study

    Directory of Open Access Journals (Sweden)

    Victor Mardini

    2016-03-01

    Full Text Available Introduction Prenatal cocaine exposure (PCE is associated with neurobehavioral problems during childhood and adolescence. Early activation of the inflammatory response may contribute to such changes. Our aim was to compare inflammatory markers (IL-6 and IL-10 both in umbilical cord blood and in maternal peripheral blood at delivery between newborns with history of crack/cocaine exposure in utero and non-exposed newborns. Methods In this cross-sectional study, 57 newborns with a history of crack/cocaine exposure in utero (EN and 99 non-exposed newborns (NEN were compared for IL-6 and IL-10 levels. Sociodemographic and perinatal data, maternal psychopathology, consumption of nicotine and other substances were systematically collected in cases and controls. Results After adjusting for potential confounders, mean IL-6 was significantly higher in EN than in NEN (10,208.54, 95% confidence interval [95%CI] 1,328.54-19,088.55 vs. 2,323.03, 95%CI 1,484.64-3,161.21; p = 0.007; generalized linear model [GLM]. Mean IL-10 was also significantly higher in EN than in NEN (432.22, 95%CI 51.44-812.88 vs. 75.52, 95%CI 5.64-145.39, p = 0.014; GLM. Adjusted postpartum measures of IL-6 were significantly higher in mothers with a history of crack/cocaine use (25,160.05, 95%CI 10,958.15-39,361.99 vs. 8,902.14, 95%CI 5,774.97-12,029.32; p = 0.007; GLM, with no significant differences for IL-10. There was no correlation between maternal and neonatal cytokine levels (Spearman test, p ≥ 0.28 for all measures. Conclusions IL-6 and IL-10 might be early biomarkers of PCE in newborns. These findings could help to elucidate neurobiological pathways underlying neurodevelopmental changes and broaden the range of possibilities for early intervention.

  13. Primary blast survival and injury risk assessment for repeated blast exposures.

    Science.gov (United States)

    Panzer, Matthew B; Bass, Cameron R Dale; Rafaels, Karin A; Shridharani, Jay; Capehart, Bruce P

    2012-02-01

    The widespread use of explosives by modern insurgents and terrorists has increased the potential frequency of blast exposure in soldiers and civilians. This growing threat highlights the importance of understanding and evaluating blast injury risk and the increase of injury risk from exposure to repeated blast effects. Data from more than 3,250 large animal experiments were collected from studies focusing on the effects of blast exposure. The current study uses 2,349 experiments from the data collection for analysis of the primary blast injury and survival risk for both long- and short-duration blasts, including the effects from repeated exposures. A piecewise linear logistic regression was performed on the data to develop survival and injury risk assessment curves. New injury risk assessment curves uniting long- and short-duration blasts were developed for incident and reflected pressure measures and were used to evaluate the risk of injury based on blast over pressure, positive-phase duration, and the number of repeated exposures. The risk assessments were derived for three levels of injury severity: nonauditory, pulmonary, and fatality. The analysis showed a marked initial decrease in injury tolerance with each subsequent blast exposure. This effect decreases with increasing number of blast exposures. The new injury risk functions showed good agreement with the existing experimental data and provided a simplified model for primary blast injury risk. This model can be used to predict blast injury or fatality risk for single exposure and repeated exposure cases and has application in modern combat scenarios or in setting occupational health limits. .Copyright © 2012 by Lippincott Williams & Wilkins

  14. N-acetylcysteine amide (AD4) reduces cocaine-induced reinstatement.

    Science.gov (United States)

    Jastrzębska, Joanna; Frankowska, Malgorzata; Filip, Malgorzata; Atlas, Daphne

    2016-09-01

    Chronic exposure to drugs of abuse changes glutamatergic transmission in human addicts and animal models. N-acetylcysteine (NAC) is a cysteine prodrug that indirectly activates cysteine-glutamate antiporters. In the extrasynaptic space, NAC restores basal glutamate levels during drug abstinence and normalizes increased glutamatergic tone in rats during reinstatement to drugs of abuse. In initial clinical trials, repeated NAC administration seems to be promising for reduced craving in cocaine addicts. In this study, NAC-amide, called AD4 or NACA, was examined in intravenous cocaine self-administration and extinction/reinstatement procedures in rats. We investigated the behavioral effects of AD4 in the olfactory bulbectomized (OBX) rats, considered an animal model of depression. Finally, we tested rats injected with AD4 or NAC during 10-daily extinction training sessions to examine subsequent cocaine seeking. AD4 (25-75 mg kg(-1)) given acutely did not alter the rewarding effects of cocaine in OBX rats and sham-operated controls. However, at 6.25-50 mg kg(-1), AD4 decreased dose-dependently cocaine seeking and relapse triggered by cocaine priming or drug-associated conditioned cues in both phenotypes. Furthermore, repeated treatment with AD4 (25 mg kg(-1)) or NAC (100 mg kg(-1)) during daily extinction trials reduced reinstatement of drug-seeking behavior in sham-operated controls. In the OBX rats only, AD4 effectively blocked cocaine-seeking behavior. Our results demonstrate that AD4 is effective at blocking cocaine-seeking behavior, highlighting its potential clinical use toward cocaine use disorder.

  15. Cocaine Promotes Coincidence Detection and Lowers Induction Threshold during Hebbian Associative Synaptic Potentiation in Prefrontal Cortex.

    Science.gov (United States)

    Ruan, Hongyu; Yao, Wei-Dong

    2017-01-25

    Addictive drugs usurp neural plasticity mechanisms that normally serve reward-related learning and memory, primarily by evoking changes in glutamatergic synaptic strength in the mesocorticolimbic dopamine circuitry. Here, we show that repeated cocaine exposure in vivo does not alter synaptic strength in the mouse prefrontal cortex during an early period of withdrawal, but instead modifies a Hebbian quantitative synaptic learning rule by broadening the temporal window and lowers the induction threshold for spike-timing-dependent LTP (t-LTP). After repeated, but not single, daily cocaine injections, t-LTP in layer V pyramidal neurons is induced at +30 ms, a normally ineffective timing interval for t-LTP induction in saline-exposed mice. This cocaine-induced, extended-timing t-LTP lasts for ∼1 week after terminating cocaine and is accompanied by an increased susceptibility to potentiation by fewer pre-post spike pairs, indicating a reduced t-LTP induction threshold. Basal synaptic strength and the maximal attainable t-LTP magnitude remain unchanged after cocaine exposure. We further show that the cocaine facilitation of t-LTP induction is caused by sensitized D1-cAMP/protein kinase A dopamine signaling in pyramidal neurons, which then pathologically recruits voltage-gated l-type Ca 2+ channels that synergize with GluN2A-containing NMDA receptors to drive t-LTP at extended timing. Our results illustrate a mechanism by which cocaine, acting on a key neuromodulation pathway, modifies the coincidence detection window during Hebbian plasticity to facilitate associative synaptic potentiation in prefrontal excitatory circuits. By modifying rules that govern activity-dependent synaptic plasticity, addictive drugs can derail the experience-driven neural circuit remodeling process important for executive control of reward and addiction. It is believed that addictive drugs often render an addict's brain reward system hypersensitive, leaving the individual more susceptible to

  16. A re-examination of the mere exposure effect: The influence of repeated exposure on recognition, familiarity, and liking.

    Science.gov (United States)

    Montoya, R Matthew; Horton, Robert S; Vevea, Jack L; Citkowicz, Martyna; Lauber, Elissa A

    2017-05-01

    To evaluate the veracity of models of the mere exposure effect and to understand the processes that moderate the effect, we conducted a meta-analysis of the influence of repeated exposure on liking, familiarity, recognition, among other evaluations. We estimated parameters from 268 curve estimates drawn from 81 articles and revealed that the mere exposure effect was characterized by a positive slope and negative quadratic effect consistent with an inverted-U shaped curve. In fact, such curves were associated with (a) all visual, but not auditory stimuli; (b) exposure durations shorter than 10 s and longer than 1 min; (c) both homogeneous and heterogeneous presentation types; and (d) ratings that were taken after all stimuli were presented. We conclude that existing models for the mere exposure effect do not adequately account for the findings, and we provide a framework to help guide future research. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  17. Consumer acceptance of salt-reduced 'soy sauce' foods over rapidly repeated exposure

    NARCIS (Netherlands)

    Kremer, S.; Shimojo, R.; Holthuysen, N.T.E.; Köster, E.P.; Mojet, J.

    2013-01-01

    The stability of the liking for salt reduced products was tested in a rapidly repeated exposure study using soup and bread (with ham). Salt was partially replaced by naturally brewed soy sauce. First, 44 consumers performed 5 two-alternative forced choice tests to establish the exchange rate (ER) at

  18. Developmental differences in stress responding after repeated underwater trauma exposures in rats.

    Science.gov (United States)

    Altman, Daniel E; Simmons, Laurence P; Vuong, Chau T; Taylor, Rachel M; Sousa, Jason C; Marcsisin, Sean R; Zottig, Victor E; Moore, Nicole L T

    2018-05-01

    Adolescence is a distinct developmental period characterized by behavioral and physiological maturation. Rapid ongoing changes during neurodevelopment in particular present potential opportunities for stress to have lasting effects on longitudinal outcomes of behavioral and neuroendocrine function. While adult stress effects on outcomes during adulthood have been characterized, little is known about the lasting effects of adolescent repeated stressor exposure on outcomes during adolescence. We have previously reported different stress responses in adolescent rats relative to adult rats, including a blunted fear response outcome in adulthood in rats stressed during adolescence. The present study characterized the ontogeny of behavioral and neuroendocrine responses to eight underwater trauma (UWT) exposures in rats over a two week poststress time period during adolescence (P34) or adulthood (P83) relative to age-matched control groups that underwent eight swimming episodes without UWT. Repeated UWT exposures starting in adolescence, but not adulthood, resulted in adverse behavioral responses on the elevated plus maze 1 day post-stress. Corticosterone responses did not differ between UWT-exposed and controls for either age group at 1 day or at 7 days poststress, although there was an effect of age on corticosterone levels. We conclude that repeated UWT stress events have a lasting, negative behavioral effect on adolescent rats that is not observed in adult rats after the two-week exposure window. These results suggest that neurophysiological mechanisms underlying recovery from a repeated stressor are immature in adolescence relative to adulthood in rats.

  19. College in the Media: The Relationship between Repeated Exposure and College Expectations

    Science.gov (United States)

    Nuñez, Roland

    2018-01-01

    Media consumption can influence viewer perceptions and attitudes. Recent research on media's effect on college students has failed to address gender differences. Using Mere Repeated Exposure Theory (traditionally used in marketing research), this study aims to answer three research questions regarding college media consumption and college…

  20. Sweet and sour preferences in young children and adults: role of repeated exposure

    NARCIS (Netherlands)

    Liem, D.G.; Graaf, de C.

    2004-01-01

    The authors investigated the influence of repeated exposure to orangeades with added sucrose and different concentrations of citric acid, on the taste preferences of 6- to-11-year-old children and young adults. During an intervention study of 8 days, 59 children (9.2±0.9 years) and 46 young adults

  1. Information technology-based approaches to reducing repeat drug exposure in patients with known drug allergies.

    Science.gov (United States)

    Cresswell, Kathrin M; Sheikh, Aziz

    2008-05-01

    There is increasing interest internationally in ways of reducing the high disease burden resulting from errors in medicine management. Repeat exposure to drugs to which patients have a known allergy has been a repeatedly identified error, often with disastrous consequences. Drug allergies are immunologically mediated reactions that are characterized by specificity and recurrence on reexposure. These repeat reactions should therefore be preventable. We argue that there is insufficient attention being paid to studying and implementing system-based approaches to reducing the risk of such accidental reexposure. Drawing on recent and ongoing research, we discuss a number of information technology-based interventions that can be used to reduce the risk of recurrent exposure. Proven to be effective in this respect are interventions that provide real-time clinical decision support; also promising are interventions aiming to enhance patient recognition, such as bar coding, radiofrequency identification, and biometric technologies.

  2. Substance use - cocaine

    Science.gov (United States)

    Substance abuse - cocaine; Drug abuse - cocaine; Drug use - cocaine ... thinking clearly Mood and emotional problems, such as aggressive or violent behavior Restlessness and tremors Sleep problems ...

  3. A single exposure to cocaine during development elicits regionally-selective changes in basal basic Fibroblast Growth Factor (FGF-2) gene expression and alters the trophic response to a second injection.

    Science.gov (United States)

    Giannotti, Giuseppe; Caffino, Lucia; Malpighi, Chiara; Melfi, Simona; Racagni, Giorgio; Fumagalli, Fabio

    2015-02-01

    During adolescence, the brain is maturing and more sensitive to drugs of abuse that can influence its developmental trajectory. Recently, attention has been focused on basic fibroblast growth factor (FGF-2) given that its administration early in life enhances the acquisition of cocaine self-administration and sensitization at adulthood (Turner et al. (Pharmacol Biochem Behav 92:100-4, 2009), Clinton et al. (Pharmacol Biochem Behav103:6-17, 2012)). Additionally, we found that abstinence from adolescent cocaine exposure long lastingly dysregulates FGF-2 transcription (Giannotti et al. (Psychopharmacology (Berl) 225:553-60, 2013 ). The objectives of the study are to evaluate if (1) a single injection of cocaine (20 mg/kg) at postnatal day 35 alters FGF-2 messenger RNA (mRNA) levels and (2) the first injection influences the trophic response to a second injection (10 mg/kg) provided 24 h or 7 days later. We found regional differences in the FGF-2 expression pattern as either the first or the second injection of cocaine by themselves upregulated FGF-2 mRNA in the medial prefrontal cortex and nucleus accumbens while downregulating it in the hippocampus. The first injection influences the trophic response of the second. Of note, 24 h after the first injection, accumbal and hippocampal FGF-2 changes produced by cocaine in saline-pretreated rats were prevented in cocaine-pretreated rats. Conversely, in the medial prefrontal cortex and hippocampus 7 days after the first injection, the cocaine-induced FGF-2 changes were modified by the subsequent exposure to the psychostimulant. These findings show that a single cocaine injection is sufficient to produce enduring changes in the adolescent brain and indicate that early cocaine priming alters the mechanisms regulating the trophic response in a brain region-specific fashion.

  4. Cocaine-conditioned odor cues without chronic exposure: Implications for the development of addiction vulnerability

    OpenAIRE

    Lowen, Steven B.; Rohan, Michael L.; Gillis, Timothy E.; Thompson, Britta S.; Wellons, Clara B.W.; Andersen, Susan L.

    2015-01-01

    Adolescents are highly vulnerable to addiction and are four times more likely to become addicted at first exposure than at any other age. The dopamine D1 receptor, which is typically overexpressed in the normal adolescent prefrontal cortex, is involved in drug cue responses and is associated with relapse in animal models. In human drug addicts, imaging methods have detected increased activation in response to drug cues in reward- and habit-associated brain regions. These same methods can be a...

  5. Analysis of real-time mixture cytotoxicity data following repeated exposure using BK/TD models.

    Science.gov (United States)

    Teng, S; Tebby, C; Barcellini-Couget, S; De Sousa, G; Brochot, C; Rahmani, R; Pery, A R R

    2016-08-15

    Cosmetic products generally consist of multiple ingredients. Thus, cosmetic risk assessment has to deal with mixture toxicity on a long-term scale which means it has to be assessed in the context of repeated exposure. Given that animal testing has been banned for cosmetics risk assessment, in vitro assays allowing long-term repeated exposure and adapted for in vitro - in vivo extrapolation need to be developed. However, most in vitro tests only assess short-term effects and consider static endpoints which hinder extrapolation to realistic human exposure scenarios where concentration in target organs is varies over time. Thanks to impedance metrics, real-time cell viability monitoring for repeated exposure has become possible. We recently constructed biokinetic/toxicodynamic models (BK/TD) to analyze such data (Teng et al., 2015) for three hepatotoxic cosmetic ingredients: coumarin, isoeugenol and benzophenone-2. In the present study, we aim to apply these models to analyze the dynamics of mixture impedance data using the concepts of concentration addition and independent action. Metabolic interactions between the mixture components were investigated, characterized and implemented in the models, as they impacted the actual cellular exposure. Indeed, cellular metabolism following mixture exposure induced a quick disappearance of the compounds from the exposure system. We showed that isoeugenol substantially decreased the metabolism of benzophenone-2, reducing the disappearance of this compound and enhancing its in vitro toxicity. Apart from this metabolic interaction, no mixtures showed any interaction, and all binary mixtures were successfully modeled by at least one model based on exposure to the individual compounds. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. N-acetyl cysteine mitigates the acute effects of cocaine-induced toxicity in astroglia-like cells.

    Directory of Open Access Journals (Sweden)

    Ramesh B Badisa

    Full Text Available Cocaine has a short half-life of only about an hour but its effects, predominantly on the central nervous system (CNS, are fairly long-lasting. Of all cells within the CNS, astrocytes may be the first to display cocaine toxicity owing to their relative abundance in the brain. Cocaine entry could trigger several early response changes that adversely affect their survival, and inhibiting these changes could conversely increase their rate of survival. In order to identify these changes and the minimal concentrations of cocaine that can elicit them in vitro, rat C6 astroglia-like cells were treated with cocaine (2-4 mM for 1h and assayed for alterations in gross cell morphology, cytoplasmic vacuolation, viability, reactive oxygen species (ROS generation, glutathione (GSH levels, cell membrane integrity, F-actin cytoskeleton, and histone methylation. We report here that all of the above identified features are significantly altered by cocaine, and may collectively represent the key pathology underlying acute toxicity-mediated death of astroglia-like cells. Pretreatment of the cells with the clinically available antioxidant N-acetyl cysteine (NAC, 5 mM for 30 min inhibited these changes during subsequent application of cocaine and mitigated cocaine-induced toxicity. Despite repeated cocaine exposure, NAC pretreated cells remained highly viable and post NAC treatment also increased viability of cocaine treated cells to a smaller yet significant level. We show further that this alleviation by NAC is mediated through an increase in GSH levels in the cells. These findings, coupled with the fact that astrocytes maintain neuronal integrity, suggest that compounds which target and mitigate these early toxic changes in astrocytes could have a potentially broad therapeutic role in cocaine-induced CNS damage.

  7. Repeated nicotine exposure enhances reward-related learning in the rat.

    Science.gov (United States)

    Olausson, Peter; Jentsch, J David; Taylor, Jane R

    2003-07-01

    Repeated exposure to addictive drugs causes neuroadaptive changes in cortico-limbic-striatal circuits that may underlie alterations in incentive-motivational processes and reward-related learning. Such drug-induced alterations may be relevant to drug addiction because enhanced incentive motivation and increased control over behavior by drug-associated stimuli may contribute to aspects of compulsive drug-seeking and drug-taking behaviors. This study investigated the consequences of repeated nicotine treatment on the acquisition and performance of Pavlovian discriminative approach behavior, a measure of reward-related learning, in male rats. Water-restricted rats were trained to associate a compound conditioned stimulus (tone+light) with the availability of water (the unconditioned stimulus) in 15 consecutive daily sessions. In separate experiments, rats were repeatedly treated with nicotine (0.35 mg/kg, s.c.) either (1) prior to the onset of training, (2) after each daily training session was completed (ie postsession injections), or (3) received nicotine both before the onset of training as well as after each daily training session. In this study, all nicotine treatment schedules increased Pavlovian discriminative approach behavior and, thus, prior repeated exposure to nicotine, repeated postsession nicotine injections, or both, facilitated reward-related learning.

  8. Biological effects of repeated exposure of beagle dogs to relatively insoluble aerosols of 144Ce. IV

    International Nuclear Information System (INIS)

    Boecker, B.B.; Hahn, F.F.; Hanika-Rebar, C.; McClellan, R.O.; Mauderly, J.L.; Pickrell, J.A.

    1977-01-01

    This experiment is being conducted to study the behavior and long-term biological effects in Beagle dogs of 144 Ce inhaled in fused aluminosilicate particles in repeated inhalation exposures for comparison with similar data from dogs that were exposed only once to a similar aerosol. Four groups of nine dogs each were exposed once every eight weeks for two years (13 exposures) to achieve specified exposure goals. The 144 Ce-exposed dogs received increasing or relatively constant beta radiation dose rates in contrast to the steadily decreasing dose rate seen after a single inhalation exposure. Exposures in the first and second groups were planned to yield a cumulative absorbed dose to lung of approximately equal to 35,000 rads and those in the third group approximately equal to 17,000 rads within two years after the first exposure. Singly exposed dogs that had died with pulmonary tumors when this experiment was initiated had cumulative doses to death of 29,000 to 61,000 rads. All 13 exposures have been completed. One dog in the 4.5-μCi 144 Ce/kg body weight group died at 771 days after first exposure with emaciation, adrenal cortical degeneration and bone marrow aplasia. One control dog died accidentally during anesthesia. During the past year, two additional dogs have died. One dog in the repeated 2.5-μCi 144 Ce/kg body weight group died at 1256 days after the first exposure with radiation pneumonitis and pulmonary fibrosis and a control dog died at 1052 days with autoimmune hemolytic anemia. The remaining 32 dogs appear to be in good physical condition except for a persistent lymphopenia at approximately equal to 4 years after the first exposure. They are being maintained for life span observations

  9. Repeated isoflurane exposure and neuroapoptosis in the midgestation fetal sheep brain.

    Science.gov (United States)

    Olutoye, Olutoyin A; Sheikh, Fariha; Zamora, Irving J; Yu, Ling; Akinkuotu, Adesola C; Adesina, Adekunle M; Olutoye, Oluyinka O

    2016-04-01

    Advances in surgery and technology have resulted in increased in-utero procedures. However, the effect of anesthesia on the fetal brain is not fully known. The inhalational anesthetic agent, isoflurane, other gamma amino butyric acid agonists (benzodiazepines, barbiturates, propofol, other inhalation anesthetics), and N-methyl D aspartate antagonists, eg, ketamine, have been shown to induce neuroapoptosis. The ovine model has been used extensively to study maternal-fetal physiologic interactions and to investigate different surgical interventions on the fetus. The purpose of this study was to determine effects of different doses and duration of isoflurane on neuroapoptosis in midgestation fetal sheep. We hypothesized that repeated anesthetic exposure and high concentrations of isoflurane would result in increased neuroapoptosis. Time-dated, pregnant sheep at 70 days gestation (term 145 days) received either isoflurane 2% × 1 hour, 4% × 3 hours, or 2% × 1 hour every other day for 3 exposures (repeated exposure group). Euthanasia occurred following anesthetic exposure and fetal brains were processed. Neuroapoptosis was detected by immunohistochemistry using anticaspase-3 antibodies. Fetuses unexposed to anesthesia served as controls. Another midgestation group with repeated 2% isoflurane exposure was examined at day 130 (long-term group) and neuronal cell density compared to age-matched controls. Representative sections of the brain were analyzed using Aperio Digital imaging (Leica Microsystems Inc, Buffalo Grove, IL). Data, reported by number of neurons per cubic millimeter of brain tissue are presented as means and SEM. Data were analyzed using the Mann-Whitney U and Kruskal-Wallis tests as appropriate. A total of 34 fetuses were studied. There was no significant difference in neuroapoptosis observed in fetuses exposed to 2% isoflurane for 1 hour or 4% isoflurane for 3 hours. Increased neuroapoptosis was observed in the frontal cortex following repeated 2

  10. Cocaine (Coke, Crack) Facts

    Science.gov (United States)

    ... That People Abuse » Cocaine (Coke, Crack) Facts Cocaine (Coke, Crack) Facts Listen Cocaine is a white ... 69 KB) "My life was built around getting cocaine and getting high." ©istock.com/ Marjot Stacey is ...

  11. Impact of repeated exposure on toxicity of perchloroethylene in Swiss Webster mice

    International Nuclear Information System (INIS)

    Philip, Binu K.; Mumtaz, Moiz M.; Latendresse, John R.; Mehendale, Harihara M.

    2007-01-01

    The aim was to study the subchronic toxicity of perchloroethylene (Perc) by measuring injury and repair in liver and kidney in relation to disposition of Perc and its major metabolites. Male SW mice (25-29 g) were given three dose levels of Perc (150, 500, and 1000 mg/kg day) via aqueous gavage for 30 days. Tissue injury was measured during the dosing regimen (0, 1, 7, 14, and 30 days) and over a time course of 24-96 h after the last dose (30 days). Perc produced significant liver injury (ALT) after single day exposure to all three doses. Liver injury was mild to moderate and regressed following repeated exposure for 30 days. Subchronic Perc exposure induced neither kidney injury nor dysfunction during the entire time course as evidenced by normal renal histology and BUN. TCA was the major metabolite detected in blood, liver, and kidney. Traces of DCA were also detected in blood at initial time points after single day exposure. With single day exposure, metabolism of Perc to TCA was saturated with all three doses. AUC/dose ratio for TCA was significantly decreased with a concomitant increase in AUC/dose of Perc levels in liver and kidney after 30 days as compared to 1 day exposures, indicating inhibition of metabolism upon repeated exposure to Perc. Hepatic CYP2E1 expression and activity were unchanged indicating that CYP2E1 is not the critical enzyme inhibited. Hepatic CYP4A expression, measured as a marker of peroxisome proliferation was increased transiently only on day 7 with the high dose, but was unchanged at later time points. Liver tissue repair peaked at 7 days, with all three doses and was sustained after medium and high dose exposure for 14 days. These data indicate that subchronic Perc exposure via aqueous gavage does not induce nephrotoxicity and sustained hepatotoxicity suggesting adaptive hepatic repair mechanisms. Enzymes other than CYP2E1, involved in the metabolism of Perc may play a critical role in the metabolism of Perc upon subchronic exposure

  12. Effects of repeated exposure to either vegetables or fruits on infant's vegetable and fruit acceptance at the beginning of weaning

    NARCIS (Netherlands)

    Barends, C.; Vries, de J.; Mojet, J.; Graaf, de C.

    2013-01-01

    This study investigated the effects of repeated exposure to either vegetables or fruits on an infant's vegetable and fruit acceptance during the first 18 days of weaning. We hypothesized that repeated exposure to a type of vegetable or fruit, would increase its intake. Furthermore, we expected that

  13. Cocaine use and the breastfeeding mother.

    Science.gov (United States)

    Jones, Wendy

    2015-01-01

    Cocaine is the second most commonly used illicit drug. Use in pregnancy and breastfeeding may have severe consequences for the baby due to its pharmacokinetic properties. Midwives need to be aware of the prolonged action of cocaine and be alert to the possibility of cocaine toxicity if a baby is excessively irritable and tachycardic. Euphoric highs are brief but breast milk and urine remain positive for long periods. Infant urine following exposure to cocaine via breast milk may remain positive for up to 60 hours. Mothers who snort cocaine should pump and dump breast milk for 24-48 hours. Passive inhalation of crack cocaine smoke may also result in infants with positive toxicology screens. Cocaine powder should never be applied to the nipples of breastfeeding mothers.

  14. A model of human nasal epithelial cells adapted for direct and repeated exposure to airborne pollutants.

    Science.gov (United States)

    Bardet, Gaëlle; Achard, Sophie; Loret, Thomas; Desauziers, Valérie; Momas, Isabelle; Seta, Nathalie

    2014-08-17

    Airway epithelium lining the nasal cavity plays a pivotal role in respiratory tract defense and protection mechanisms. Air pollution induces alterations linked to airway diseases such as asthma. Only very few in vitro studies to date have succeeded in reproducing physiological conditions relevant to cellular type and chronic atmospheric pollution exposure. We therefore, set up an in vitro model of human Airway Epithelial Cells of Nasal origin (hAECN) close to real human cell functionality, specifically adapted to study the biological effects of exposure to indoor gaseous pollution at the environmental level. hAECN were exposed under air-liquid interface, one, two, or three-times at 24 h intervals for 1 h, to air or formaldehyde (200 μg/m(3)), an indoor air gaseous pollutant. All experiments were ended at day 4, when both cellular viability and cytokine production were assessed. Optimal adherence and confluence of cells were obtained 96 h after cell seeding onto collagen IV-precoated insert. Direct and repeated exposure to formaldehyde did not produce any cellular damage or IL-6 production change, although weak lower IL-8 production was observed only after the third exposure. Our model is significantly better than previous ones due to cell type and the repeated exposure protocol. Copyright © 2014. Published by Elsevier Ireland Ltd.

  15. Eye lens radiation exposure and repeated head CT scans: A problem to keep in mind

    International Nuclear Information System (INIS)

    Michel, Morgane; Jacob, Sophie; Roger, Gilles; Pelosse, Béatrice; Laurier, Dominique; Le Pointe, Hubert Ducou; Bernier, Marie-Odile

    2012-01-01

    Objectives: The deterministic character of radiation-induced cataract is being called into question, raising the possibility of a risk in patients, especially children, exposed to ionizing radiation in case of repeated head CT-scans. This study aims to estimate the eye lens doses of a pediatric population exposed to repeated head CTs and to assess the feasibility of an epidemiological study. Methods: Children treated for a cholesteatoma, who had had at least one CT-scan of the middle ear before their tenth birthday, were included. Radiation exposure has been assessed from medical records and telephone interviews. Results: Out of the 39 subjects contacted, 32 accepted to participate. A total of 76 CT-scans were retrieved from medical records. At the time of the interview (mean age: 16 years), the mean number of CT per child was 3. Cumulative mean effective and eye lens doses were 1.7 mSv and 168 mGy, respectively. Conclusion: A relatively high lens radiation dose was observed in children exposed to repeated CT-scans. Due to that exposure and despite the difficulties met when trying to reach patients’ families, a large scale epidemiological study should be performed in order to assess the risk of radiation-induced cataracts associated with repeated head CT.

  16. Perturbations in different forms of cost/benefit decision making induced by repeated amphetamine exposure.

    Science.gov (United States)

    Floresco, Stan B; Whelan, Jennifer M

    2009-08-01

    Psychostimulant abuse has been linked to impairments in cost-benefit decision making. We assessed the effects of repeated amphetamine (AMPH) treatment in rodents on two distinct forms of decision making. Separate groups of rats were trained for 26 days on either a probabilistic (risk) or effort-discounting task, each consisting of four discrete blocks of ten choice trials. One lever always delivered a smaller reward (one or two pellets), whereas another lever delivered a four-pellet reward. For risk-discounting, the probability of receiving the larger reward decreased across trial blocks (100-12.5%), whereas on the effort task, four pellets could be obtained after a ratio of presses that increased across blocks (2-20). After training, rats received 15 saline or AMPH injections (escalating from 1 to 5 mg/kg) and were then retested during acute and long-term withdrawal. Repeated AMPH administration increased risky choice 2-3 weeks after drug exposure, whereas these treatments did not alter effort-based decision making in a separate group of animals. However, prior AMPH exposure sensitized the effects of acute AMPH on both forms of decision making, whereby lower doses were effective at inducing "risky" and "lazy" patterns of choice. Repeated AMPH exposure leads to relatively long-lasting increases in risky choice, as well as sensitization to the effects of acute AMPH on different forms of cost/benefit decision making. These findings suggest that maladaptive decision-making processes exhibited by psychostimulant abusers may be caused in part by repeated drug exposure.

  17. Effects of single and repeated exposure to biocidal active substances on the barrier function of the skin in vitro.

    Science.gov (United States)

    Buist, Harrie E; van de Sandt, Johannes J M; van Burgsteden, Johan A; de Heer, Cees

    2005-10-01

    The dermal route of exposure is important in worker exposure to biocidal products. Many biocidal active substances which are used on a daily basis may decrease the barrier function of the skin to a larger extent than current risk assessment practice addresses, due to possible skin effects of repeated exposure. The influence of repeated and single exposure to representative biocidal active substances on the skin barrier was investigated in vitro. The biocidal active substances selected were alkyldimethylbenzylammonium chloride (ADBAC), boric acid, deltamethrin, dimethyldidecylammonium chloride (DDAC), formaldehyde, permethrin, piperonyl butoxide, sodium bromide, and tebuconazole. Of these nine compounds, only the quaternary ammonium chlorides ADBAC and DDAC had a clear and consistent influence on skin permeability of the marker compounds tritiated water and [(14)C]propoxur. For these compounds, repeated exposure increased skin permeability more than single exposure. At high concentrations the difference between single and repeated exposure was quantitatively significant: repeated exposure to 300 mg/L ADBAC increased skin permeability two to threefold in comparison to single exposure. Therefore, single and repeated exposure to specific biocidal products may significantly increase skin permeability, especially when used undiluted.

  18. Enhancing consumer liking of low salt tomato soup over repeated exposure by herb and spice seasonings.

    Science.gov (United States)

    Ghawi, Sameer Khalil; Rowland, Ian; Methven, Lisa

    2014-10-01

    There is strong evidence for the link between high dietary sodium and increased risk of cardiovascular disease which drives the need to reduce salt content in foods. In this study, herb and spice blends were used to enhance consumer acceptability of a low salt tomato soup (0.26% w/w). Subjects (n = 148) scored their liking of tomato soup samples over 5 consecutive days. The first and last days were pre-and post-exposure visits where all participants rated three tomato soup samples; standard, low salt and low salt with added herbs and spices. The middle 3 days were the repeated exposure phase where participants were divided into three balanced groups; consuming the standard soup, the low salt soup, or the low salt soup with added herbs and spices. Reducing salt in the tomato soup led to a significant decline in consumer acceptability, and incorporating herbs and spices did not lead to an immediate enhancement in liking. However, inclusion of herbs and spices enhanced the perception of the salty taste of the low salt soup to the same level as the standard. Repeated exposure to the herbs and spice-modified soup led to a significant increase in the overall liking and liking of flavour, texture and aftertaste of the soup, whereas no changes in liking were observed for the standard and low salt tomato soups over repeated exposure. Moreover, a positive trend in increasing the post-exposure liking of the herbs and spices soup was observed. The findings suggest that the use of herbs and spices is a useful approach to reduce salt content in foods; however, herbs and spices should be chosen carefully to complement the food as large contrasts in flavour can polarise consumer liking. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  19. Repeated exposures to roadside particulate matter extracts suppresses pulmonary defense mechanisms, resulting in lipid and protein oxidative damage

    International Nuclear Information System (INIS)

    Pardo, Michal; Porat, Ziv; Rudich, Assaf; Schauer, James J.; Rudich, Yinon

    2016-01-01

    Exposure to particulate matter (PM) pollution in cities and urban canyons can be harmful to the exposed population. However, the underlying mechanisms that lead to health effects are not yet elucidated. It is postulated that exposure to repeated, small, environmentally relevant concentrations can affect lung homeostasis. This study examines the impact of repeated exposures to urban PM on mouse lungs with focus on inflammatory and oxidative stress parameters. Aqueous extracts from collected urban PM were administered to mice by 5 repeated intra-tracheal instillations (IT). Multiple exposures, led to an increase in cytokine levels in both bronchoalveolar lavage fluid and in the blood serum, indicating a systemic reaction. Lung mRNA levels of antioxidant/phase II detoxifying enzymes decreased by exposure to the PM extract, but not when metals were removed by chelation. Finally, disruption of lung tissue oxidant-inflammatory/defense balance was evidenced by increased levels of lipid and protein oxidation. Unlike response to a single IT exposure to the same dose and source of extract, multiple exposures result in lung oxidative damage and a systemic inflammatory reaction. These could be attributed to compromised capacity to activate the protective Nrf2 tissue defense system. It is suggested that water-soluble metals present in urban PM, potentially from break and tire wear, may constitute major drivers of the pulmonary and systemic responses to multiple exposure to urban PM. - Highlights: • Repeated exposure to urban PM cause systemic inflammation and oxidative damage to lung tissue lipids and proteins. • Repeated exposure to these PM extracts decreased transcription of Nrf2 protective genes. • Single as opposed to repeated exposure, induced confined lung response accompanied by activated defense mechanisms. • Metals, potentially from break and tire wear, drive the pulmonary response with exposure to urban PM. - Repeated exposures to urban PM water extracts

  20. CRFR1 in the ventromedial caudate putamen modulates acute stress-enhanced expression of cocaine locomotor sensitization.

    Science.gov (United States)

    Liu, Shuli; Wang, Zhiyan; Li, Yijing; Sun, Xiaowei; Ge, Feifei; Yang, Mingda; Wang, Xinjuan; Wang, Na; Wang, Junkai; Cui, Cailian

    2017-07-15

    Repeated exposure to psychostimulants induces a long-lasting enhancement of locomotor activity called behavioral sensitization, which is often reinforced by stress after drug withdrawal. The mechanisms underlying these phenomena remain elusive. Here we explored the effects of acute stress 3 or 14 days after the cessation of chronic cocaine treatment on the expression of locomotor sensitization induced by a cocaine challenge in rats and the key brain region and molecular mechanism underlying the phenomenon. A single session of forced swimming, as an acute stress (administered 2 days after the cessation of cocaine), significantly enhanced the expression of cocaine locomotor sensitization 14 days after the final cocaine injection (challenge at 12 days after acute stress) but not 3 days after the cessation of cocaine (challenge at 1 day after acute stress). The result indicated that acute stress enhanced the expression of cocaine locomotor sensitization after incubation for 12 days rather than 1 day after the last cocaine injection. Moreover, the enhancement in locomotor sensitization was paralleled by a selective increase in the number of the c-Fos + cells, the level of CRFR1 mRNA in the ventromedial caudate putamen (vmCPu). Furthermore, the enhancement was significantly attenuated by CRFR1 antagonist NBI-27914 into the vmCPu, implying that the up-regulation of CRFR1 in the vmCPu seems to be critical in the acute stress-enhanced expression of cocaine locomotor sensitization. The findings demonstrate that the long-term effect of acute stress on the expression of cocaine locomotor sensitization is partially mediated by CRFR1 in the vmCPu. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  1. Repeated low-dose exposures to sarin, soman, or VX affect acoustic startle in guinea pigs.

    Science.gov (United States)

    Smith, C D; Lee, R B; Moran, A V; Sipos, M L

    2016-01-01

    Chemical warfare nerve agents (CWNAs) are known to cause behavioral abnormalities in cases of human exposures and in animal models. The behavioral consequences of single exposures to CWNAs that cause observable toxic signs are particularly well characterized in animals; however, less is known regarding repeated smaller exposures that may or may not cause observable toxic signs. In the current study, guinea pigs were exposed to fractions (0.1, 0.2, or 0.4) of a medial lethal dose (LD50) of sarin, soman, or VX for two weeks. On each exposure day, and for a post-exposure period, acoustic startle response (ASR) was measured in each animal. Although relatively few studies use guinea pigs to measure behavior, this species is ideal for CWNA-related experiments because their levels of carboxylesterases closely mimic those of humans, unlike rats or mice. Results showed that the 0.4 LD50 doses of soman and VX transiently increased peak startle amplitude by the second week of injections, with amplitude returning to baseline by the second week post-exposure. Sarin also increased peak startle amplitude independent of week. Latencies to peak startle and PPI were affected by agent exposure but not consistently among the three agents. Most of the changes in startle responses returned to baseline following the cessation of exposures. These data suggest that doses of CWNAs not known to produce observable toxic signs in guinea pigs can affect behavior in the ASR paradigm. Further, these deficits are transient and usually return to baseline shortly after the end of a two-week exposure period. Published by Elsevier Inc.

  2. Consequences of repeated ethanol exposure during early or late adolescence on conditioned taste aversions in rats

    Directory of Open Access Journals (Sweden)

    Jessica Saalfield

    2015-12-01

    Full Text Available Alcohol use is prevalent during adolescence, yet little is known about possible long-lasting consequences. Recent evidence suggests that adolescents are less sensitive than adults to ethanol's aversive effects, an insensitivity that may be retained into adulthood after repeated adolescent ethanol exposure. This study assessed whether intermittent ethanol exposure during early or late adolescence (early-AIE or late-AIE, respectively would affect ethanol conditioned taste aversions 2 days (CTA1 and >3 weeks (CTA2 post-exposure using supersaccharin and saline as conditioning stimuli (CS, respectively. Pair-housed male Sprague-Dawley rats received 4 g/kg i.g. ethanol (25% or water every 48 h from postnatal day (P 25–45 (early AIE or P45-65 (late AIE, or were left non-manipulated (NM. During conditioning, 30 min home cage access to the CS was followed by 0, 1, 1.5, 2 or 2.5 g/kg ethanol i.p., with testing 2 days later. Attenuated CTA relative to controls was seen among early and late AIE animals at both CTA1 and CTA2, an effect particularly pronounced at CTA1 after late AIE. Thus, adolescent exposure to ethanol was found to induce an insensitivity to ethanol CTA seen soon after exposure and lasting into adulthood, and evident with ethanol exposures not only early but also later in adolescence.

  3. Consequences of repeated ethanol exposure during early or late adolescence on conditioned taste aversions in rats.

    Science.gov (United States)

    Saalfield, Jessica; Spear, Linda

    2015-12-01

    Alcohol use is prevalent during adolescence, yet little is known about possible long-lasting consequences. Recent evidence suggests that adolescents are less sensitive than adults to ethanol's aversive effects, an insensitivity that may be retained into adulthood after repeated adolescent ethanol exposure. This study assessed whether intermittent ethanol exposure during early or late adolescence (early-AIE or late-AIE, respectively) would affect ethanol conditioned taste aversions 2 days (CTA1) and >3 weeks (CTA2) post-exposure using supersaccharin and saline as conditioning stimuli (CS), respectively. Pair-housed male Sprague-Dawley rats received 4g/kg i.g. ethanol (25%) or water every 48 h from postnatal day (P) 25-45 (early AIE) or P45-65 (late AIE), or were left non-manipulated (NM). During conditioning, 30 min home cage access to the CS was followed by 0, 1, 1.5, 2 or 2.5g/kg ethanol i.p., with testing 2 days later. Attenuated CTA relative to controls was seen among early and late AIE animals at both CTA1 and CTA2, an effect particularly pronounced at CTA1 after late AIE. Thus, adolescent exposure to ethanol was found to induce an insensitivity to ethanol CTA seen soon after exposure and lasting into adulthood, and evident with ethanol exposures not only early but also later in adolescence. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  4. Micronucleus induction by repeated exposure of diagnostic X-ray on oral buccal mucosa

    International Nuclear Information System (INIS)

    Lohith Tejashvi, K.; Suchetha Kumari, N.; Shetty, Shishir Ram

    2012-01-01

    Radiography is the important diagnostic tools essential for diagnosis and planning of orthodontic treatment. X-ray is ionizing radiation which showed various effects include breaking the bond of biological molecules, inducing loss of ability of cell death, increases nuclear alterations. Micronuclei - x000D - (MN) are small chromatin bodies that appear in the cytoplasm by the - x000D - condensation of acrocentric chromosomal fragments or by whole chromosomes. This - x000D - is a sensitive indicator of genetic damage. - x000D - x000D - . To evaluate micronucleus induction by repeated exposure of diagnostic X-ray on human buccal cell. Methods: 25 patients who visiting to ABSMIDS, Department of Oral medicine and Radiology for dental checkup exposed to diagnostic X-ray more than 4 times have been selected for this study. The buccal cell for analysis was collected from the cheek mucosa by means of gentle scraping of epithelial using ice-cream sticks and placed in Buffer saline. This sample was smeared on glass slide and then fixed in methanol:glacial acetic acid (3:1). Air dried and stained with Giemsa for 15-25 minutes. Then 250 cells in each slides were analyzed under microscope and frequency of micronucleus was scored (n=4). Repeated X-ray exposed cells showed micronucleus (1.25%) and nuclear alteration (2.3%) compare to the control. Repeated X-ray exposure leads to induces detectable number of micronucleus and nuclear alterations. (author)

  5. Dealing with consumer differences in liking during repeated exposure to food; typical dynamics in rating behavior.

    Science.gov (United States)

    Dalenberg, Jelle R; Nanetti, Luca; Renken, Remco J; de Wijk, René A; Ter Horst, Gert J

    2014-01-01

    Consumers show high interindividual variability in food liking during repeated exposure. To investigate consumer liking during repeated exposure, data is often interpreted on a product level by averaging results over all consumers. However, a single product may elicit inconsistent behaviors in consumers; averaging will mix and hide possible subgroups of consumer behaviors, leading to a misinterpretation of the results. To deal with the variability in consumer liking, we propose to use clustering on data from consumer-product combinations to investigate the nature of the behavioral differences within the complete dataset. The resulting behavioral clusters can then be used to describe product acceptance. To test this approach we used two independent data sets in which young adults were repeatedly exposed to drinks and snacks, respectively. We found that five typical consumer behaviors existed in both datasets. These behaviors differed both in the average level of liking as well as its temporal dynamics. By investigating the distribution of a single product across typical consumer behaviors, we provide more precise insight in how consumers divide in subgroups based on their product liking (i.e. product modality). This work shows that taking into account and using interindividual differences can unveil information about product acceptance that would otherwise be ignored.

  6. Effect of repeated benzene inhalation exposures on benzene metabolism, binding to hemoglobin, and induction of micronuclei

    International Nuclear Information System (INIS)

    Sabourin, P.J.; Sun, J.D.; MacGregor, J.T.; Wehr, C.M.; Birnbaum, L.S.; Lucier, G.; Henderson, R.F.

    1990-01-01

    Metabolism of benzene is thought to be necessary to produce the toxic effects, including carcinogenicity, associated with benzene exposure. To extrapolate from the results of rodent studies to potential health risks in man, one must know how benzene metabolism is affected by species, dose, dose rate, and repeated versus single exposures. The purpose of our studies was to determine the effect of repeated inhalation exposures on the metabolism of [14C]benzene by rodents. Benzene metabolism was assessed by characterizing and quantitating urinary metabolites, and by quantitating 14C bound to hemoglobin and micronuclei induction. F344/N rats and B6C3F1 mice were exposed, nose-only, to 600 ppm benzene or to air (control) for 6 hr/day, 5 days/week for 3 weeks. On the last day, both benzene-pretreated and control animals were exposed to 600 ppm, 14C-labeled benzene for 6 hr. Individual benzene metabolites in urine collected for 24 hr after the exposure were analyzed. There was a significant decrease in the respiratory rate of mice (but not rats) pretreated with benzene which resulted in lower levels of urinary [14C]benzene metabolites. The analyses indicated that the only effects of benzene pretreatment on the metabolite profile in rat or mouse urine were a slight shift from glucuronidation to sulfation in mice and a shift from sulfation to glucuronidation in rats. Benzene pretreatment also had no effect, in either species, on formation of [14C]benzene-derived hemoglobin adducts. Mice and rats had similar levels of hemoglobin adduct binding, despite the higher metabolism of benzene by mice. This indicates that hemoglobin adduct formation occurs with higher efficiency in rats. After 1 week of exposure to 600 ppm benzene, the frequency of micronucleated, polychromatic erythrocytes (PCEs) in mice was significantly increased

  7. The effects of multiple UV exposures on HIV-LTR (long terminal repeat) expression

    International Nuclear Information System (INIS)

    Schreck, S.; Milton, J.; Panozzo, J.; Libertin, C.R.; Woloschak, G.E.; Loyola Univ., Maywood, IL

    1995-01-01

    Previous studies have shown that cellular stress agents such as UV radiation induce transcription from the long terminal repeat (LTR) of the human immunodeficiency virus (HIV). Using HeLa cells stably transfected with the HIV-LTR sequence, which transcriptionally drives the chloramphenicol acetyl transferase (CAT) reporter gene, we examined the effects of multiple exposures to UVC (254 nm) on HIV-LTR-CAT expression. Low doses (≤ 5 J m -2 ) had no effect on CAT expression, but up to 29-fold induction was observed with 10 J m -2 when cells were harvested 48 h after completion of the exposure. Little difference was noted in induction levels when cells were exposed to one 25 J m -2 dose, viable cells were harvested at 24 h, 48 h or 72 h, and cell lysates were assayed for CAT expression. Two sequential 12.5 J m -2 exposures, given 24 h apart, resulted in an additive effect on CAT expression; these two exposures produced CAT activity equivalent to that induced following a single 25 J m -2 dose. Our data suggest that HIV-LTR requires a specific threshold UV dose in order to elicit induction; a maximal induction dose is also evident; exposures higher than this maximal dose contribute no more to HIV-LTR induction in viable cells. (author)

  8. Cortical and sub-cortical effects in primate models of cocaine use: implications for addiction and the increased risk of psychiatric illness.

    Science.gov (United States)

    Bradberry, Charles W

    2011-02-01

    Drug abuse is a serious risk factor for the incidence and severity of multiple psychiatric illnesses. Understanding the neurobiological consequences of repeated exposure to abused drugs can help to inform how those risks are manifested in terms of specific neurochemical mechanisms and brain networks. This review examines selective studies in non-human primates that employed a cocaine self-administration model. Neurochemical consequences of chronic exposure appear to differ from observations in rodent studies. Whereas chronic intermittent exposure in the rodent is usually associated with a dose-dependent increase in dopaminergic response to a cocaine challenge, in the rhesus monkey, high cumulative exposure was not observed to cause a sensitized dopamine response. These non-human primate observations are concordant with clinical findings in human users. The results of cue exposure studies on dopaminergic transmission are also reviewed. Direct microdialysis measurements indicate that there is not a sustained increase in dopamine associated with cocaine-linked cues. As an alternative to striatal dopaminergic mechanisms mediating cue effects, single unit studies in prefrontal cortex during self-administration in monkeys suggests the orbitofrontal and anterior cingulate cortex are strongly engaged by cocaine cues. Based on the strong clinical imaging literature on cortical and cognitive dysfunction associated with addiction, it is proposed that the strong engagement of cortical systems during repeated cocaine reinforcement results in maladaptive changes that contribute to the risks of drug use for exacerbation of other psychiatric disorders.

  9. Repeated allergen exposure reduce early phase airway response and leukotriene release despite upregulation of 5-lipoxygenase pathways

    Directory of Open Access Journals (Sweden)

    Cui Zhi-Hua

    2012-03-01

    Full Text Available Abstract Background Allergen induced early phase airway response and airway plasma exudation are predominantly mediated by inflammatory mast cell mediators including histamine, cysteinyl leukotrienes (cysLTs and thromboxane A2 (TXA2. The aim of the present study was to evaluate whether repeated allergen exposure affects early phase airway response to allergen challenge. Methods A trimellitic anhydride (TMA sensitized guinea pig model was used to investigate the effects of low dose repeated allergen exposure on cholinergic airway responsiveness, early phase airway response and plasma exudation, as well as local airway production of mast cell derived cysteinyl leukotrienes and thromboxane B2 (TXB2 after allergen challenge. Results Repeated low dose allergen exposure increased cholinergic airway responsiveness. In contrast, early phase airway response and plasma exudation in response to a high-dose allergen challenge were strongly attenuated after repeated low dose allergen exposure. Inhibition of the airway response was unspecific to exposed allergen and independent of histamine receptor blocking. Furthermore, a significant reduction of cysteinyl leukotrienes and TXB2 was found in the airways of animals repeatedly exposed to a low dose allergen. However, in vitro stimulation of airway tissue from animals repeatedly exposed to a low dose allergen with arachidonic acid and calcium ionophore (A23187 induced production of cysteinyl leukotrienes and TXB2, suggesting enhanced activity of 5-lipoxygenase and cyclooxygenase pathways. Conclusions The inhibition of the early phase airway response, cysteinyl leukotriene and TXB2 production after repeated allergen exposure may result from unresponsive effector cells.

  10. The effects of exercise on cocaine self-administration, food-maintained responding, and locomotor activity in female rats: importance of the temporal relationship between physical activity and initial drug exposure.

    Science.gov (United States)

    Smith, Mark A; Witte, Maryam A

    2012-12-01

    Previous studies have reported that exercise decreases cocaine self-administration in rats with long-term access (8+ weeks) to activity wheels in the home cage. The purpose of this study was to (a) examine the importance of the temporal relationship between physical activity and initial drug exposure, (b) determine the effects of exercise on responding maintained by a nondrug reinforcer (i.e., food), and (c) investigate the effects of exercise on cocaine-induced increases in locomotor activity. To this end, female rats were obtained at weaning and divided into 4 groups: (a) EXE-SED rats were housed in exercise cages for 6 weeks and then transferred to sedentary cages after the first day of behavioral testing; (b) SED-EXE rats were housed in sedentary cages for 6 weeks and then transferred to exercise cages after the first day of behavioral testing; (c) SED-SED rats remained in sedentary cages for the duration of the study; and (d) EXE-EXE rats remained in exercise cages for the duration of the study. Relative to the sedentary group (SED-SED), exercise reduced cocaine self-administration in both groups with access to activity wheels after initial drug exposure (EXE-EXE, SED-EXE) but did not reduce cocaine self-administration in the group with access to activity wheels only before drug exposure (EXE-SED). Exercise also decreased the effects of cocaine on locomotor activity but did not reduce responding maintained by food. These data suggest that exercise may reduce cocaine use in drug-experienced individuals with no prior history of aerobic activity without decreasing other types of positively reinforced behaviors.

  11. Repeated prenatal exposure to valproic acid results in cerebellar hypoplasia and ataxia.

    Science.gov (United States)

    Main, Stacey L; Kulesza, Randy J

    2017-01-06

    Autism spectrum disorder (ASD) is a developmental brain disorder characterized by restricted and repetitive patterns of behavior, social and communication defects, and is commonly associated with difficulties with motor coordination. The etiology of ASD, while mostly idiopathic, has been linked to hereditary factors and teratogens, such as valproic acid (VPA). VPA is used clinically to treat epilepsy, mood disorders, and in the prevention of migraines. The use of VPA during pregnancy significantly increases the risk of ASD in the offspring. Neuropathological studies show decreased cerebellar function in patients with ASD, resulting in gait, balance and coordination impairments. Herein, we have exposed pregnant rats to a repeated oral dose of VPA on embryonic days 10 and 12 and performed a detailed investigation of the structure and function of the cerebellar vermis. We found that throughout all ten lobules of the cerebellar vermis, Purkinje cells were significantly smaller and expression of the calcium binding protein calbindin (CB) was significantly reduced. We also found that dendritic arbors of Purkinje cells were shorter and less complex. Additionally, animals exposed to a repeated dose of VPA performed significantly worse in a number of motor tasks, including beam walking and the rotarod. These results suggest that repeated embryonic exposure to VPA induces significant cerebellar dysfunction and is an effective animal model to study the cerebellar alterations in ASD. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  12. Biological effects of repeated inhalation exposure of beagle dogs to relatively insoluble aerosols of 144Ce

    International Nuclear Information System (INIS)

    Boecker, B.B.; Hahn, F.F.; Muggenburg, B.A.; McClellan, R.O.; Mauderly, J.L.; Pickrell, J.A.

    1980-01-01

    Beagle dogs were exposed repeatedly to a relatively insoluble form of 144 Ce (in fused aluminosilicate particles) to study the deposition, retention, and long-term biological effects for comparison with data from dogs that were exposed only once to a similar aerosol. Four groups of nine dogs each were exposed once every 8 weeks for 2 years (13 exposures) to achieve specified exposure goals. These goals were: to increase the lung burden by 2.5 μCi 144 Ce/kg body weight with each exposure; to reestablish lung burdens of 9 or 4.5 μCi 144 Ce/kg body weight and to expose controls to fused aluminosilicate particles containing nonradioactive cerium. To date, 19 exposed dogs and 2 control dogs have died or were euthanized. The most prevalent findings to date have been pulmonary carcinomas (7 dogs) and hemangiosarcomas in the tracheobronchial lymph nodes (3 dogs). Observations are continuing on the surviving 8 144 Ce-exposed and 7 control dogs who are now at approximately 2500 days (6.8 years) after the first exposure

  13. The effects of repeated low-level blast exposure on hearing in marines

    Directory of Open Access Journals (Sweden)

    Lina R Kubli

    2017-01-01

    Full Text Available Background: The study evaluates a group of Military Service Members specialized in blast explosive training called “Breachers” who are routinely exposed to multiple low-level blasts while teaching breaching at the U.S. Marine Corps in Quantico Virginia. The objective of this study was to determine if there are any acute or long-term auditory changes due to repeated low-level blast exposures used in training. The performance of the instructor group “Breachers” was compared to a control group, “Engineers”. Methods: A total of 11 Breachers and four engineers were evaluated in the study. The participants received comprehensive auditory tests, including pure-tone testing, speech-in-noise (SIN measures, and central auditory behavioral and objective tests using early and late (P300 auditory evoked potentials over a period of 17 months. They also received shorter assessments immediately following the blast-exposure onsite at Quantico. Results: No acute or longitudinal effects were identified. However, there were some interesting baseline effects found in both groups. Contrary to the expected, the onsite hearing thresholds and distortion product otoacoustic emissions were slightly better at a few frequencies immediately after blast-exposure than measurements obtained with the same equipment weeks to months after each blast-exposure. Conclusions: To date, the current study is the most comprehensive study that evaluates the long-term effects of blast-exposure on hearing. Despite extensive testing to assess changes, the findings of this study suggest that the levels of current exposures used in this military training environment do not seem to have an obvious deleterious effect on hearing.

  14. Physiological responses and manual performance in humans following repeated exposure to severe cold at night.

    Science.gov (United States)

    Ozaki, H; Nagai, Y; Tochihara, Y

    2001-04-01

    We evaluated human physiological responses and the performance of manual tasks during exposure to severe cold (-25 degrees C) at night (0300-0500 hours) and in the afternoon (1500-1700 hours). Thirteen male students wearing standard cold protective clothing occupied a severely cold room (-25 degrees C) for 20 min, and were then transferred to a cool room (10 degrees C) for 20 min. This pattern of exposure was repeated three times, for a total time of exposure to extreme cold of 60 min. The experiments were started either at 1500 hours or 0300 hours and measurements of rectal temperature, skin temperature, blood pressure, performance in a counting task, hand tremor, and subjective responses were made in each condition. At the end of the experiment at night the mean decrease in rectal temperature [0.68 (SEM 0.04) degree C] was significantly greater than that at the end of the experiment in the afternoon [0.55 (SEM 0.08) degree C, P second cold exposure at night the mean increase in diastolic blood pressure [90 (SEM 2.0) mmHg] was significantly greater than that at the end of the second cold exposure in the afternoon [82 (SEM 2.8) mmHg, P second cold exposure at night, mean finger skin temperature [11.8 (SEM 0.8) degrees C] was significantly higher than that at the comparable time in the afternoon [9.0 (SEM 0.7) degrees C, P second cold exposure at night [25.6 (SEM 1.5) degrees C] was significantly higher than in the afternoon [20.1 (SEM 0.8) degrees C, P < 0.01]. The increased skin temperatures in the periphery resulted in increased heat loss. Since peripheral skin temperatures were highest at night, the subjects noted diminished sensations of thermal cold and pain at that time. Manual dexterity at the end of the first cold exposure at night [mean 83.7 (SEM 3.6) times.min-1] had decreased significantly more than at the end of the first cold exposure in the afternoon [mean 89.4 (SEM 3.5) times.min-1, P < 0.01]. These findings of a lowered rectal temperature and

  15. Pneumorachis after cocaine sniffing

    Directory of Open Access Journals (Sweden)

    S. Challita

    2014-01-01

    Full Text Available Air in the epidural space is called pneumorachis. The usual mechanism of pneumorachis is air diffusion from the mediastinal tissue layers through the inter-vertebral foramen. Alternatively, air can diffuse directly after spine traumas (e.g., blunt deceleration with vertebral dislocation or medical procedures. Several mechanisms could explain pneumomediastinum and pneumorachis after cocaine sniffing. Passive apnea and/or cough that occur after sniffing can cause intra alveolar hyper-pressure, which is responsible for alveolar rupture and air diffusion. Another mechanism is alveolar wall fragility and rupture induced by repeated cocaine sniffing, in turn causing air diffusion to the mediastinum, sub-cutaneous tissues and the epidural space. The diagnosis is usually made on Chest tomography scan. Management consists in close monitoring in the intensive care unit to detect aggravation of pneumomediastinum and pneumorachis, which would require surgical management. Supplemental nasal oxygen can be given to accelerate nitrogen washout. We present a case of a 28 years old male who presented to the emergency department for chest pain directly after sniffing cocaine. A computed tomography scan of the chest showed pneumomediastinum, pneumorachis and sub-cutaneous emphysema. The patient was admitted for 24 h: after that delay, surveillance chest tomodensitometry showed stability, and he could be discharged without further treatment.

  16. Pneumorachis after cocaine sniffing.

    Science.gov (United States)

    Challita, S; Daher, M; Roche, N; Alifano, M; Revel, M P; Rabbat, A

    2014-01-01

    Air in the epidural space is called pneumorachis. The usual mechanism of pneumorachis is air diffusion from the mediastinal tissue layers through the inter-vertebral foramen. Alternatively, air can diffuse directly after spine traumas (e.g., blunt deceleration with vertebral dislocation) or medical procedures. Several mechanisms could explain pneumomediastinum and pneumorachis after cocaine sniffing. Passive apnea and/or cough that occur after sniffing can cause intra alveolar hyper-pressure, which is responsible for alveolar rupture and air diffusion. Another mechanism is alveolar wall fragility and rupture induced by repeated cocaine sniffing, in turn causing air diffusion to the mediastinum, sub-cutaneous tissues and the epidural space. The diagnosis is usually made on Chest tomography scan. Management consists in close monitoring in the intensive care unit to detect aggravation of pneumomediastinum and pneumorachis, which would require surgical management. Supplemental nasal oxygen can be given to accelerate nitrogen washout. We present a case of a 28 years old male who presented to the emergency department for chest pain directly after sniffing cocaine. A computed tomography scan of the chest showed pneumomediastinum, pneumorachis and sub-cutaneous emphysema. The patient was admitted for 24 h: after that delay, surveillance chest tomodensitometry showed stability, and he could be discharged without further treatment.

  17. Clinical ratings and plasma HVA during cocaine abstinence.

    Science.gov (United States)

    Martin, S D; Yeragani, V K; Lodhi, R; Galloway, M P

    1989-08-01

    Six patients were evaluated over a 21-day period during inpatient recovery from chronic repeated cocaine use. Serial evaluations of Hamilton depression rating, cocaine craving, plasma homovanillic acid (pHVA), and plasma 3-methoxy-4-hydroxyphenylethyleneglycol (pMHPG) concentrations were determined. There was a distinct increase in cocaine craving between 1 and 2 weeks after the last cocaine use. Levels of pHVA also increased at the time of heightened craving. The data provide preliminary evidence to suggest that changes in cocaine craving during abstinence are positively correlated with changes in dopamine turnover.

  18. The role of temporal delay and repeated prospective memory cue exposure on the deactivation of completed intentions.

    Science.gov (United States)

    Walser, Moritz; Plessow, Franziska; Goschke, Thomas; Fischer, Rico

    2014-07-01

    Previous studies have shown that completed prospective memory (PM) intentions entail aftereffects in terms of ongoing-task-performance decrements in trials containing repeated PM cues which previously served as PM cues triggering the intended action. Previous research reported that PM aftereffects decrease over time, thus revealing a specific time course of PM aftereffects. In the present study, we tested two accounts for this pattern, assuming either that the decline of aftereffects is related to the temporal distance to PM task completion or may be a result of the repeated exposure of repeated PM cues in the ongoing task. In three experiments, we manipulated both the temporal distance to PM task completion and the frequency of repeated PM cues and demonstrated that aftereffects of completed intentions declined with repeated exposure of formerly relevant PM cues. In addition, effects of repeated exposure were not only limited to the repetition of specific PM-cue exemplars but also generalized to other semantically related PM cues within the PM-cue category. Together, findings show that decreased aftereffects of completed intentions are not related to the temporal duration of the subsequent test block, but crucially depend on the repeated exposure of the previously relevant PM cues.

  19. Thermal responses from repeated exposures to severe cold with intermittent warmer temperatures.

    Science.gov (United States)

    Ozaki, H; Enomoto-Koshimizu, H; Tochihara, Y; Nakamura, K

    1998-09-01

    This study was conducted to evaluate physiological reaction and manual performance during exposure to warm (30 degrees C) and cool (10 degrees C) environments after exposure to very low temperatures (-25 degrees C). Furthermore, this experiment was conducted to study whether it is desirable to remove cold-protective jackets in warmer rooms after severe cold exposure. Eight male students remained in an extremely cold room for 20 min, after which they transferred into either the warm room or the cool room for 20 min. This pattern was repeated three times, and the total cold exposure time was 60 min. In the warm and cool rooms, the subjects either removed their cold-protective jackets (Condition A), or wore them continuously (Condition B). Rectal temperature, skin temperatures, manual performance, blood pressure, thermal, comfort and pain sensations were measured during the experiment. The effects of severe cold on almost all measurements in the cool (10 degrees C) environment were greater than those in the warm (30 degrees C) environment under both clothing conditions. The effects of severe cold on all measurements under Condition A except rectal temperature and toe skin temperature were significantly greater than those under Condition B in the cool environment but, not at all differences between Condition A and Condition B in the warm environments were significant. It was recognized that to remove cold-protective jackets in the cool room (10 degrees C) after severe cold exposure promoted the effects of severe cold. When rewarming in the warm resting room (30 degrees C), the physiological and psychological responses and manual performance were not influenced by the presence or absence of cold-protective clothing. These results suggest that it is necessary for workers to make sure to rewarm in the warm room outside of the cold storage and continue to wear cold-protective clothing in the cool room.

  20. Analysis of Dextromethorphan and Dextrorphan in Skeletal Remains Following Differential Microclimate Exposure: Comparison of Acute vs. Repeated Drug Exposure.

    Science.gov (United States)

    Morrison, Lucas M; Unger, Kirk A; Watterson, James H

    2017-07-01

    Analysis of dextromethorphan (DXM) and its metabolite dextrorphan (DXT) in skeletal remains of rats following acute (ACU, 75 mg/kg, IP, n = 10) or three repeated (REP, 25 mg/kg, IP, n = 10, 40-min interval) doses of DXM is described. Following dosing and euthanasia, rats decomposed outdoors to skeleton in two different microclimate environments (n = 5 ACU and n = 5 REP at each site): Site A (shaded forest microenvironment) and Site B (rocky substrate exposed to direct sunlight, 600 m from Site A). Two drug-free rats at each site served as negative controls. Skeletal elements (vertebrae, ribs, pelvic girdles, femora, tibiae, skulls and scapulae) were recovered, pulverized and underwent methanolic microwave assisted extraction (MAE). Extracts were analyzed by GC-MS following clean-up by solid-phase extraction (SPE). Drug levels, expressed as mass-normalized response ratios and the ratios of DXT and DXM levels (RRDXT/RRDXM) were compared between drug exposures, microclimate sites, and across skeletal elements. DXM levels differed significantly (P < 0.05) between corresponding bone elements across exposure groups (5/7-site A; 4/7-site B), but no significant differences in DXT levels were observed between corresponding elements. RRDXT/RRDXM differed significantly (P < 0.05) between corresponding bone elements across exposure groups (6/7-site A; 5/7-site B). No significant differences were observed in levels of DXM, DXT or RRDXT/RRDXM between corresponding elements from either group between sites. When data from all bone elements was pooled, levels of DXM and RRDXT/RRDXM differed significantly between exposure groups at each site, while those of DXT did not. For both exposure groups, comparison of pooled data between sites showed no significant differences in levels of DXM, DXT or RRDXT/RRDXM. Different decomposition microclimates did not impede the discrimination of DXM exposure patterns from the analyses of DXM, DXT and RRDXT/RRDXM in bone samples. © The Author 2017

  1. Adaptive Changes in Sensorimotor Coordination and Motion Sickness Following Repeated Exposures to Virtual Environments

    Science.gov (United States)

    Harm, D. L.; Taylor, L. C.; Bloomberg, J. J.

    2007-01-01

    Virtual environments offer unique training opportunities, particularly for training astronauts and preadapting them to the novel sensory conditions of microgravity. Two unresolved human factors issues in virtual reality (VR) systems are: 1) potential "cybersickness", and 2) maladaptive sensorimotor performance following exposure to VR systems. Interestingly, these aftereffects are often quite similar to adaptive sensorimotor responses observed in astronauts during and/or following space flight. Initial interpretation of novel sensory information may be inappropriate and result in perceptual errors. Active exploratory behavior in a new environment, with resulting feedback and the formation of new associations between sensory inputs and response outputs, promotes appropriate perception and motor control in the new environment. Thus, people adapt to consistent, sustained alterations of sensory input such as those produced by microgravity, unilateral labyrinthectomy and experimentally produced stimulus rearrangements. The purpose of this research was to compare disturbances in sensorimotor coordination produced by dome and head-mounted virtual environment displays and to examine the effects of exposure duration, and repeated exposures to VR systems. The first study examined disturbances in balance control, and the second study examined disturbances in eye-head-hand (EHH) and eye-head coordination.

  2. Repeated exposure to immobilization or two different footshock intensities reveals differential adaptation of the hypothalamic-pituitary-adrenal axis.

    Science.gov (United States)

    Rabasa, Cristina; Muñoz-Abellán, Cristina; Daviu, Núria; Nadal, Roser; Armario, Antonio

    2011-05-03

    Factors involved in adaptation to repeated stress are not well-characterized. For instance, acute footshock (FS) of high intensity appears to be less severe than immobilization (IMO) in light of the speed of post-stress recovery of the hypothalamic-pituitary-adrenal (HPA) axis and other physiological variables. However, repeated exposure to IMO consistently resulted in reduction of the HPA response to the same stressor (adaptation), whereas failure to adapt has been usually reported after FS. Thus, in the present work we directly compared the activation of HPA axis and other physiological changes in response to both acute and repeated exposure to IMO and two intensities of FS (medium and high) in adult male rats. Control rats were exposed to the FS boxes but they did not receive shocks. Daily repeated exposure to IMO resulted in significant adaptation of the overall ACTH and corticosterone responses to the stressor. Such a reduction was also observed with repeated exposure to FS boxes and FS-medium, whereas repeated exposure to FS-high only resulted in a small reduction of the corticosterone response during the post-stress period. This suggests that some properties of FS-high make adaptation to it difficult. Interestingly, overall changes in food intake and body weight gain throughout the week of exposure to the stressors reveal a greater impact of IMO than FS-high, indicating that factors other than the intensity of a stressor, at least when evaluated in function of the above physiological variables, can influence HPA adaptation. Since FS exposure is likely to cause more pain than IMO, activation of nociceptive signals above a certain level may negatively affect HPA adaptation to repeated stressors. Copyright © 2011 Elsevier Inc. All rights reserved.

  3. Mast Cells Limit the Exacerbation of Chronic Allergic Contact Dermatitis in Response to Repeated Allergen Exposure.

    Science.gov (United States)

    Gimenez-Rivera, Vladimir-Andrey; Siebenhaar, Frank; Zimmermann, Carolin; Siiskonen, Hanna; Metz, Martin; Maurer, Marcus

    2016-12-01

    Allergic contact dermatitis is a chronic T cell-driven inflammatory skin disease that is caused by repeated exposure to contact allergens. Based on murine studies of acute contact hypersensitivity, mast cells (MCs) are believed to play a role in its pathogenesis. The role of MCs in chronic allergic contact dermatitis has not been investigated, in part because of the lack of murine models for chronic contact hypersensitivity. We developed and used a chronic contact hypersensitivity model in wild-type and MC-deficient mice and assessed skin inflammatory responses to identify and characterize the role of MCs in chronic allergic contact dermatitis. Ear swelling chronic contact hypersensitivity responses increased markedly, up to 4-fold, in MC-deficient Kit W-sh/W-sh (Sash) and MCPT5-Cre + iDTR + mice compared with wild-type mice. Local engraftment with MCs protected Sash mice from exacerbated ear swelling after repeated oxazolone challenge. Chronic contact hypersensitivity skin of Sash mice exhibited elevated levels of IFN-γ, IL-17α, and IL-23, as well as increased accumulation of Ag-specific IFN-γ-producing CD8 + tissue-resident memory T (T RM ) cells. The CD8 + T cell mitogen IL-15, which was increased in oxazolone-challenged skin of Sash mice during the accumulation of cutaneous T RM cells, was efficiently degraded by MCs in vitro. MCs protect from the exacerbated allergic skin inflammation induced by repeated allergen challenge, at least in part, via effects on CD8 + T RM cells. MCs may notably influence the course of chronic allergic contact dermatitis. A better understanding of their role and the underlying mechanisms may lead to better approaches for the treatment of this common, disabling, and costly condition. Copyright © 2016 by The American Association of Immunologists, Inc.

  4. Repeated exposure to iron oxide nanoparticles causes testicular toxicity in mice.

    Science.gov (United States)

    Sundarraj, Kiruthika; Manickam, Vijayprakash; Raghunath, Azhwar; Periyasamy, Madhivadhani; Viswanathan, Mangala Priya; Perumal, Ekambaram

    2017-02-01

    The aim of this study was to determine whether repeated exposure to iron oxide nanoparticles (Fe 2 O 3 -NPs) could be toxic to mice testis. Fe 2 O 3 -NPs (25 and 50 mg/kg) were intraperitoneally administered into mice once a week for 4 weeks. Our study showed that Fe 2 O 3 -NPs have the ability to cross the blood-testis barrier to get into the testis. The findings showed that exposure resulted in the accumulation of Fe 2 O 3 -NPs which was evidenced from the iron content and accumulation in the testis. Furthermore, 25 and 50 mg/kg Fe 2 O 3 -NPs administration increased the reactive oxygen species, lipid peroxidation, protein carbonyl content, glutathione peroxidase activity, and nitric oxide levels with a concomitant decrease in the levels of antioxidants-superoxide dismutase, catalase, glutathione, and vitamin C. Increased expression of Bax, cleaved-caspase-3, and cleaved-PARP confirms apoptosis. Serum testosterone levels increased with increased concentration of Fe 2 O 3 -NPs exposure. In addition, the histopathological lesions like vacuolization, detachment, and sloughing of germ cells were also observed in response to Fe 2 O 3 -NPs treatment. The data from our study entailed that testicular toxicity caused by Fe 2 O 3 -NPs exposure may be associated with Fe 2 O 3 -NPs accumulation leading to oxidative stress and apoptosis. Therefore, precautions should be taken in the safe use of Fe 2 O 3 -NPs to avoid complications in the fertility of males. Further research will unravel the possible molecular mechanisms on testicular toxicity of Fe 2 O 3 -NPs. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 594-608, 2017. © 2016 Wiley Periodicals, Inc.

  5. The hidden price of repeated traumatic exposure: Different cognitive deficits in different first-responders

    Directory of Open Access Journals (Sweden)

    Einat eLevy-Gigi

    2014-08-01

    Full Text Available Studies on first responders who are repeatedly exposed to traumatic events report low levels of PTSD symptoms and diagnosis. However, neuroimaging and behavioral studies show that traumatic exposure is associated with brain and cognitive dysfunctions. Taking together it may suggest that traumatic exposure have a price, which is not sufficiently defined by the standard PTSD measures. In a recent study we revealed that similar to individuals with PTSD, non-PTSD highly exposed firefighters display a selective impairment in hippocampal related functions. In the current study we aimed to test whether different first responders display a similar impairment. We concentrated on unique populations of active duty firefighters and criminal scene-investigators (CSI police, who are frequently exposed to similar levels and types of traumatic events, and compared them to civilian matched-controls with no history of trauma-exposure. We used a hippocampal dependent cue-context reversal paradigm, which separately evaluates reversal of negative and positive outcomes of cue and context related information. We predicted and found that all participants were equally able to acquire and retain stimulus-outcome associations. However, there were significant differences in reversal learning between the groups. Performance among firefighters replicated our prior findings; they struggled to learn that a previously negative context is later associated with a positive outcome. CSI police on the other hand showed a selective impairment in reversing the outcome of a negative cue. Hence after learning that a specific cue is associated with a negative outcome, they could not learn that later it is associated with a positive outcome. Performance in both groups did not correlate with levels of PTSD, anxiety, depression or behavioral inhibition symptoms. The results provide further evidence of the hidden price of traumatic exposure, suggesting that this price may differ as a

  6. Effect of squatting on sprinting performance and repeated exposure to complex training in male rugby players.

    Science.gov (United States)

    Comyns, Thomas M; Harrison, Andrew J; Hennessy, Liam K

    2010-03-01

    This study was undertaken to examine the effect of a heavy weight training exercise on sprinting performance and on the effect of repeated exposure to a complex training protocol. Eleven male rugby union players (age 20.9 +/- 3.1 years) participated in the study, which involved 5 separate testing sessions. Back squat 3 repetition maximum (3RM) was established in session 1. Sessions 2-5 were identical and involved the subjects completing a 30-m sprint before and after a 3RM back squat protocol. Four minutes of rest was given between the back squatting and the posttest 30-m sprint. All sprint trials were measured with a laser measurement device (LAVEG, Jenoptik, Jena, Germany). Sprint time and instantaneous, average, and maximum velocity were the dependent variables. The criterion for significance was set at an alpha level of p > or = 0.05. No significant improvement was evident for any of the testing sessions (p > or = 0.05). In session 1, there was a significant increase in 30-m time and a significant reduction in average 30-m velocity and maximum velocity (p benefits in sprinting may not have been realized because of intra and intersubject variations in sprint technique. The session x phase interaction revealed a significant improvement in the pre to posttest changes in instantaneous velocity at 20 m (p = 0.035) and 30 m (p = 0.036) from session 1 to session 4. This indicates that the rugby players may be able to learn to apply the potentiation effects of complex training. From a practical perspective, players may need repeated exposure to this training modality to gain benefit from it, and this should be reflected in program planning.

  7. Levamisole and cocaine synergism: a prevalent adulterant enhances cocaine's action in vivo.

    Science.gov (United States)

    Tallarida, Christopher S; Egan, Erin; Alejo, Gissel D; Raffa, Robert; Tallarida, Ronald J; Rawls, Scott M

    2014-04-01

    Levamisole is estimated by the Drug Enforcement Agency (DEA) to be present in about 80% of cocaine seized in the United States and linked to debilitating, and sometimes fatal, immunologic effects in cocaine abusers. One explanation for the addition of levamisole to cocaine is that it increases the amount of product and enhances profits. An alternative possibility, and one investigated here, is that levamisole alters cocaine's action in vivo. We specifically investigated effects of levamisole on cocaine's stereotypical and place-conditioning effects in an established invertebrate (planarian) assay. Acute exposure to levamisole or cocaine produced concentration-dependent increases in stereotyped movements. For combined administration of the two agents, isobolographic analysis revealed that the observed stereotypical response was enhanced relative to the predicted effect, indicating synergism for the interaction. In conditioned place preference (CPP) experiments, cocaine produced a significant preference shift; in contrast, levamisole was ineffective at all concentrations tested. For combination experiments, a submaximal concentration of cocaine produced CPP that was enhanced by inactive concentrations of levamisole, indicating synergism. The present results provide the first experimental evidence that levamisole enhances cocaine's action in vivo. Most important is the identification of synergism for the levamisole/cocaine interaction, which now requires further study in mammals. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. Fatal cardiac arrhythmia after repeated exposure to 1,1-difluoroethane (DFE).

    Science.gov (United States)

    Avella, Joseph; Wilson, James C; Lehrer, Michael

    2006-03-01

    A 42-year-old man was found dead after repeated exposure to 1,1-difluoroethane (DFE, Freon 152a), a propellant found in CRC Duster, a product intended for the removal of dust and lint. Toxicologic analysis detected DFE in femoral blood 136.3 mg/L, brain 117.5 mg/kg, liver 87.6 mg/kg, lung 60.3 mg/kg, adipose 235.7 mg/kg, and vitreous fluid 25.1 mg/L. The cause of death was determined to be a fatal cardiac arrhythmia due to intoxication with 1,1-difluoroethane. After comparison to previously published cases involving DFE, we suggest that analysis of adipose tissue for DFE and similar compounds, along with blood and other tissues, may be useful in distinguishing between acute versus chronic exposure. Adipose may also be a valuable alternate specimen for detection in cases where loss or elimination from blood is likely to have occurred.

  9. Occupational hazards of traditional healers: repeated unprotected blood exposures risk infectious disease transmission.

    Science.gov (United States)

    Audet, Carolyn M; Salato, José; Blevins, Meridith; Silva, Wilson; González-Calvo, Lázaro; Vermund, Sten H; Gaspar, Felisbela

    2016-11-01

    Healers provide support for acute and chronic illnesses in rural Mozambique, such as socially acceptable traditional 'vaccinations' (subcutaneous cuts in the skin to rub herbs directly into the bloody lesion). We aimed to document the frequency of blood exposure by traditional practitioners in Mozambique. We conducted surveys with a simple random sample of 236 traditional healers in Zambézia province. Chi-square and Wilcoxon rank-sum tests were used to compare 'injection' behaviours across districts. Healers treated a median of eight patients in the past month (IQR: 4-15). About 75% conducted 'injections'. These healers 'injected' a median of four patients (IQR: 1-8), used a new razor a median of three times (IQR: 1-8), and almost never used gloves. Lifetime blood exposures among those who provided 'injections' during treatments were estimated to be 1758 over a healer's career. The majority of healers are exposed repeatedly to patient blood. Given the high prevalence of HIV, hepatitis B and C virus, and other blood-borne agents, specific healer practices are an occupational hazard and reuse of razors is risky for their clients. © 2016 John Wiley & Sons Ltd.

  10. Repeated Exposure to Dissection Does Not Influence Students' Attitudes towards Human Body Donation for Anatomy Teaching

    Science.gov (United States)

    Mwachaka, Philip Maseghe; Mandela, Pamela; Saidi, Hassan

    2016-01-01

    The use of unclaimed bodies for anatomical dissection has been the main method of instruction at our institution. There is however a shortage of cadavers for dissection given the increase in the number of medical schools as well as in the number of students enrolling in these schools. This shortage could be mitigated by having voluntary human body donation programs. This study aimed at assessing the attitudes of medical students and surgical residents towards body donation for anatomy learning. We conducted an online survey involving 72 first-year medical students and 41 surgical residents at University of Nairobi who had completed one year of anatomy dissection. For the medical students, this was their first dissection experience while it was the second exposure for the surgery trainees. Most of the surgical trainees (70.7%) and medical students (68.1%) were opposed to self-body donation. This was mainly due to cultural (37%) and religious (20%) barriers. Surprisingly, of those not willing to donate themselves, 67.9% (82.8% surgical trainees, 59.2% medical students) would recommend the practice to other people. Exposure to repeated dissection does not change the perceptions towards body donation. It is noteworthy that culture and religion rank high as clear barriers amongst this “highly informed” group of potential donors. PMID:27190650

  11. Repeated exposure to media violence is associated with diminished response in an inhibitory frontolimbic network.

    Directory of Open Access Journals (Sweden)

    Christopher R Kelly

    Full Text Available BACKGROUND: Media depictions of violence, although often claimed to induce viewer aggression, have not been shown to affect the cortical networks that regulate behavior. METHODOLOGY/PRINCIPAL FINDINGS: Using functional magnetic resonance imaging (fMRI, we found that repeated exposure to violent media, but not to other equally arousing media, led to both diminished response in right lateral orbitofrontal cortex (right ltOFC and a decrease in right ltOFC-amygdala interaction. Reduced function in this network has been previously associated with decreased control over a variety of behaviors, including reactive aggression. Indeed, we found reduced right ltOFC responses to be characteristic of those subjects that reported greater tendencies toward reactive aggression. Furthermore, the violence-induced reduction in right ltOFC response coincided with increased throughput to behavior planning regions. CONCLUSIONS: These novel findings establish that even short-term exposure to violent media can result in diminished responsiveness of a network associated with behaviors such as reactive aggression.

  12. Repeated Exposure to Dissection Does Not Influence Students' Attitudes towards Human Body Donation for Anatomy Teaching.

    Science.gov (United States)

    Mwachaka, Philip Maseghe; Mandela, Pamela; Saidi, Hassan

    2016-01-01

    The use of unclaimed bodies for anatomical dissection has been the main method of instruction at our institution. There is however a shortage of cadavers for dissection given the increase in the number of medical schools as well as in the number of students enrolling in these schools. This shortage could be mitigated by having voluntary human body donation programs. This study aimed at assessing the attitudes of medical students and surgical residents towards body donation for anatomy learning. We conducted an online survey involving 72 first-year medical students and 41 surgical residents at University of Nairobi who had completed one year of anatomy dissection. For the medical students, this was their first dissection experience while it was the second exposure for the surgery trainees. Most of the surgical trainees (70.7%) and medical students (68.1%) were opposed to self-body donation. This was mainly due to cultural (37%) and religious (20%) barriers. Surprisingly, of those not willing to donate themselves, 67.9% (82.8% surgical trainees, 59.2% medical students) would recommend the practice to other people. Exposure to repeated dissection does not change the perceptions towards body donation. It is noteworthy that culture and religion rank high as clear barriers amongst this "highly informed" group of potential donors.

  13. Repeated exposures to roadside particulate matter extracts suppresses pulmonary defense mechanisms, resulting in lipid and protein oxidative damage.

    Science.gov (United States)

    Pardo, Michal; Porat, Ziv; Rudich, Assaf; Schauer, James J; Rudich, Yinon

    2016-03-01

    Exposure to particulate matter (PM) pollution in cities and urban canyons can be harmful to the exposed population. However, the underlying mechanisms that lead to health effects are not yet elucidated. It is postulated that exposure to repeated, small, environmentally relevant concentrations can affect lung homeostasis. This study examines the impact of repeated exposures to urban PM on mouse lungs with focus on inflammatory and oxidative stress parameters. Aqueous extracts from collected urban PM were administered to mice by 5 repeated intra-tracheal instillations (IT). Multiple exposures, led to an increase in cytokine levels in both bronchoalveolar lavage fluid and in the blood serum, indicating a systemic reaction. Lung mRNA levels of antioxidant/phase II detoxifying enzymes decreased by exposure to the PM extract, but not when metals were removed by chelation. Finally, disruption of lung tissue oxidant-inflammatory/defense balance was evidenced by increased levels of lipid and protein oxidation. Unlike response to a single IT exposure to the same dose and source of extract, multiple exposures result in lung oxidative damage and a systemic inflammatory reaction. These could be attributed to compromised capacity to activate the protective Nrf2 tissue defense system. It is suggested that water-soluble metals present in urban PM, potentially from break and tire wear, may constitute major drivers of the pulmonary and systemic responses to multiple exposure to urban PM. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Prior exposure to repeated immobilization or chronic unpredictable stress protects from some negative sequels of an acute immobilization.

    Science.gov (United States)

    Pastor-Ciurana, Jordi; Rabasa, Cristina; Ortega-Sánchez, Juan A; Sanchís-Ollè, Maria; Gabriel-Salazar, Marina; Ginesta, Marta; Belda, Xavier; Daviu, Núria; Nadal, Roser; Armario, Antonio

    2014-05-15

    Exposure to chronic unpredictable stress (CUS) is gaining acceptance as a putative animal model of depression. However, there is evidence that chronic exposure to stress can offer non-specific stress protection from some effects of acute superimposed stressors. We then compared in adult male rats the protection afforded by prior exposure to CUS with the one offered by repeated immobilization on boards (IMO) regarding some of the negative consequences of an acute exposure to IMO. Repeated exposure to IMO protected from the negative consequences of an acute IMO on activity in an open-field, saccharin intake and body weight gain. Active coping during IMO (struggling) was markedly reduced by repeated exposure to the same stressor, but it was not affected by a prior history of CUS, suggesting that our CUS protocol does not appear to impair active coping responses. CUS exposure itself caused a strong reduction of activity in the open-field but appeared to protect from the hypo-activity induced by acute IMO. Moreover, prior CUS offered partial protection from acute IMO-induced reduction of saccharin intake and body weight gain. It can be concluded that a prior history of CUS protects from some of the negative consequences of exposure to a novel severe stressor, suggesting the development of partial cross-adaptation whose precise mechanisms remain to be studied. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Impact of product information and repeated exposure on consumer liking, sensory perception and concept associations of local apple juice

    DEFF Research Database (Denmark)

    Stolzenbach, Sandra; Bredie, Wender Laurentius Petrus; Christensen, Rune Haubo Bojesen

    2013-01-01

    The impact of product information and repeated exposure of local apple juice on consumer liking, sensory perception and concept associations was studied. Findings showed that consumers had high expectations towards the studied local apples juices. Consequently, the liking for the local apple juices...... did not fully determine consumer liking. Thus the sensory characteristics were also found to be of importance. Besides liking, the concept associations were also affected by product information. All local apple juices were associated as being more exclusive under informed tasting conditions....... No effects were found for liking of the apple juices over repeated exposure. Also, the consumers did not change their sensory perception over repeated consumption. However, the local apple juices were conceptualised as more familiar but remained exclusive after repeated consumption. When local producers have...

  16. Pharmacological blockade of either cannabinoid CB1 or CB2 receptors prevents both cocaine-induced conditioned locomotion and cocaine-induced reduction of cell proliferation in the hippocampus of adult male rat

    Science.gov (United States)

    Blanco-Calvo, Eduardo; Rivera, Patricia; Arrabal, Sergio; Vargas, Antonio; Pavón, Francisco Javier; Serrano, Antonia; Castilla-Ortega, Estela; Galeano, Pablo; Rubio, Leticia; Suárez, Juan; Rodriguez de Fonseca, Fernando

    2014-01-01

    Addiction to major drugs of abuse, such as cocaine, has recently been linked to alterations in adult neurogenesis in the hippocampus. The endogenous cannabinoid system modulates this proliferative response as demonstrated by the finding that pharmacological activation/blockade of cannabinoid CB1 and CB2 receptors not only modulates neurogenesis but also modulates cell death in the brain. In the present study, we evaluated whether the endogenous cannabinoid system affects cocaine-induced alterations in cell proliferation. To this end, we examined whether pharmacological blockade of either CB1 (Rimonabant, 3 mg/kg) or CB2 receptors (AM630, 3 mg/kg) would affect cell proliferation [the cells were labeled with 5-bromo-2′-deoxyuridine (BrdU)] in the subventricular zone (SVZ) of the lateral ventricle and the dentate subgranular zone (SGZ). Additionally, we measured cell apoptosis (as monitored by the expression of cleaved caspase-3) and glial activation [by analyzing the expression of glial fibrillary acidic protein (GFAP) and Iba-1] in the striatum and hippocampus during acute and repeated (4 days) cocaine administration (20 mg/kg). The results showed that acute cocaine exposure decreased the number of BrdU-immunoreactive (ir) cells in the SVZ and SGZ. In contrast, repeated cocaine exposure reduced the number of BrdU-ir cells only in the SVZ. Both acute and repeated cocaine exposure increased the number of cleaved caspase-3-, GFAP- and Iba1-ir cells in the hippocampus, and this effect was counteracted by AM630 or Rimonabant, which increased the number of BrdU-, GFAP-, and Iba1-ir cells in the hippocampus. These results indicate that the changes in neurogenic, apoptotic and gliotic processes that were produced by repeated cocaine administration were normalized by pharmacological blockade of CB1 and CB2. The restorative effects of cannabinoid receptor blockade on hippocampal cell proliferation were associated with the prevention of the induction of conditioned

  17. Cocaine locomotor activation, sensitization and place preference in six inbred strains of mice

    Science.gov (United States)

    2011-01-01

    Background The expanding set of genomics tools available for inbred mouse strains has renewed interest in phenotyping larger sets of strains. The present study aims to explore phenotypic variability among six commonly-used inbred mouse strains to both the rewarding and locomotor stimulating effects of cocaine in a place conditioning task, including several strains or substrains that have not yet been characterized for some or all of these behaviors. Methods C57BL/6J (B6), BALB/cJ (BALB), C3H/HeJ (C3H), DBA/2J (D2), FVB/NJ (FVB) and 129S1/SvImJ (129) mice were tested for conditioned place preference to 20 mg/kg cocaine. Results Place preference was observed in most strains with the exception of D2 and 129. All strains showed a marked increase in locomotor activity in response to cocaine. In BALB mice, however, locomotor activation was context-dependent. Locomotor sensitization to repeated exposure to cocaine was most significant in 129 and D2 mice but was absent in FVB mice. Conclusions Genetic correlations suggest that no significant correlation between conditioned place preference, acute locomotor activation, and locomotor sensitization exists among these strains indicating that separate mechanisms underlie the psychomotor and rewarding effects of cocaine. PMID:21806802

  18. A variant in ANKK1 modulates acute subjective effects of cocaine: a preliminary study

    Science.gov (United States)

    Spellicy, Catherine J.; Harding, Mark J.; Hamon, Sara C.; Mahoney, James J.; Reyes, Jennifer A.; Kosten, Thomas R.; Newton, Thomas F.; De La Garza, Richard; Nielsen, David A.

    2014-01-01

    This study aimed to evaluate whether functional variants in the ankyrin repeat and kinase domain-containing 1 gene (ANKK1) and/or the dopamine receptor D2 gene (DRD2) modulate the subjective effects (reward or non-reward response to a stimulus) produced by cocaine administration. Cocaine-dependent participants (N = 47) were administered 40 mg of cocaine or placebo at time 0, and a subjective effects questionnaire (visual analog scale) was administered 15 minutes prior to cocaine administration, and at 5, 10,15, and 20 minutes following administration. The influence of polymorphisms in the ANKK1 and DRD2 genes on subjective experience of cocaine in the laboratory was tested. Participants with a T allele of ANKK1 rs1800497 experienced greater subjective ‘high’ (p = 0.00006), ‘any drug effect’ (p = 0.0003), and ‘like’ (p = 0.0004) relative to the CC genotype group. Although the variant in the DRD2 gene was shown to be associated with subjective effects, LD analysis revealed this association was driven by the ANKK1 rs1800497 variant. A participant’s ANKK1 genotype may identify individuals who are likely to experience greater positive subjective effects following cocaine exposure, including greater ‘high’ and ‘like’, and these individuals may have increased vulnerability to continue using cocaine or they may be at greater risk to relapse during periods of abstinence. However, these results are preliminary and replication is necessary to confirm these findings. PMID:24528631

  19. Optogenetic inhibition of D1R containing nucleus accumbens neurons alters cocaine- mediated regulation of Tiam1

    Directory of Open Access Journals (Sweden)

    Ramesh eChandra

    2013-05-01

    Full Text Available Exposure to psychostimulants results in structural and synaptic plasticity in striatal medium spiny neurons (MSNs. These cellular adaptations arise from alterations in genes that are highly implicated in the rearrangement of the actin cytoskeleton, such as Tiam1. Previous studies have demonstrated a crucial role for dopamine receptor 1 (D1-containing striatal MSNs in mediating psychostimulant induced plasticity changes. These D1-MSNs in the nucleus accumbens (NAc positively regulate drug seeking, reward, and locomotor behavioral effects as well as the morphological adaptations of psychostimulant drugs. Here, we demonstrate that rats that actively self-administer cocaine display reduced levels of Tiam1 in the NAc. To further examine the cell type specific contribution to these changes in Tiam1 we used optogenetics to selectively manipulate NAc D1-MSNs or dopamine receptor 2 (D2 expressing MSNs. We find that repeated ChR2 activation of D1-MSNs but not D2-MSNs caused a down-regulation of Tiam1 levels similar to the effects of cocaine. Further, activation of D2-MSNs, which caused a late blunted cocaine-mediated locomotor behavioral response, did not alter Tiam1 levels. We then examined the contribution of D1-MSNs to the cocaine-mediated decrease of Tiam1. Using the light activated chloride pump, eNpHR3.0, we selectively inhibited D1-MSNs during cocaine exposure, which resulted in a behavioral blockade of cocaine-induced locomotor sensitization. Moreover, inhibiting these NAc D1-MSNs during cocaine exposure reversed the down-regulation of Tiam1 gene expression and protein levels. These data demonstrate that altering activity in specific neural circuits with optogenetics can impact the underlying molecular substrates of psychostimulant mediated behavior and function.

  20. Cocaine Self-Administration Experience Induces Pathological Phasic Accumbens Dopamine Signals and Abnormal Incentive Behaviors in Drug-Abstinent Rats

    Science.gov (United States)

    Wang, Xuefei; Sugam, Jonathan A.; Carelli, Regina M.

    2016-01-01

    Chronic exposure to drugs of abuse is linked to long-lasting alterations in the function of limbic system structures, including the nucleus accumbens (NAc). Although cocaine acts via dopaminergic mechanisms within the NAc, less is known about whether phasic dopamine (DA) signaling in the NAc is altered in animals with cocaine self-administration experience or if these animals learn and interact normally with stimuli in their environment. Here, separate groups of rats self-administered either intravenous cocaine or water to a receptacle (controls), followed by 30 d of enforced abstinence. Next, all rats learned an appetitive Pavlovian discrimination and voltammetric recordings of real-time DA release were taken in either the NAc core or shell of cocaine and control subjects. Cocaine experience differentially impaired DA signaling in the core and shell relative to controls. Although phasic DA signals in the shell were essentially abolished for all stimuli, in the core, DA did not distinguish between cues and was abnormally biased toward reward delivery. Further, cocaine rats were unable to learn higher-order associations and even altered simple conditioned approach behaviors, displaying enhanced preoccupation with cue-associated stimuli (sign-tracking; ST) but diminished time at the food cup awaiting reward delivery (goal-tracking). Critically, whereas control DA signaling correlated with ST behaviors, cocaine experience abolished this relationship. These findings show that cocaine has persistent, differential, and pathological effects on both DA signaling and DA-dependent behaviors and suggest that psychostimulant experience may remodel the very circuits that bias organisms toward repeated relapse. SIGNIFICANCE STATEMENT Relapsing to drug abuse despite periods of abstinence and sincere attempts to quit is one of the most pernicious facets of addiction. Unfortunately, little is known about how the dopamine (DA) system functions after periods of drug abstinence

  1. Cocaine Self-Administration Experience Induces Pathological Phasic Accumbens Dopamine Signals and Abnormal Incentive Behaviors in Drug-Abstinent Rats.

    Science.gov (United States)

    Saddoris, Michael P; Wang, Xuefei; Sugam, Jonathan A; Carelli, Regina M

    2016-01-06

    Chronic exposure to drugs of abuse is linked to long-lasting alterations in the function of limbic system structures, including the nucleus accumbens (NAc). Although cocaine acts via dopaminergic mechanisms within the NAc, less is known about whether phasic dopamine (DA) signaling in the NAc is altered in animals with cocaine self-administration experience or if these animals learn and interact normally with stimuli in their environment. Here, separate groups of rats self-administered either intravenous cocaine or water to a receptacle (controls), followed by 30 d of enforced abstinence. Next, all rats learned an appetitive Pavlovian discrimination and voltammetric recordings of real-time DA release were taken in either the NAc core or shell of cocaine and control subjects. Cocaine experience differentially impaired DA signaling in the core and shell relative to controls. Although phasic DA signals in the shell were essentially abolished for all stimuli, in the core, DA did not distinguish between cues and was abnormally biased toward reward delivery. Further, cocaine rats were unable to learn higher-order associations and even altered simple conditioned approach behaviors, displaying enhanced preoccupation with cue-associated stimuli (sign-tracking; ST) but diminished time at the food cup awaiting reward delivery (goal-tracking). Critically, whereas control DA signaling correlated with ST behaviors, cocaine experience abolished this relationship. These findings show that cocaine has persistent, differential, and pathological effects on both DA signaling and DA-dependent behaviors and suggest that psychostimulant experience may remodel the very circuits that bias organisms toward repeated relapse. Relapsing to drug abuse despite periods of abstinence and sincere attempts to quit is one of the most pernicious facets of addiction. Unfortunately, little is known about how the dopamine (DA) system functions after periods of drug abstinence, particularly its role in

  2. Repeated exposures to cobalt or chromate on the hands of patients with hand eczema and contact allergy to that metal

    DEFF Research Database (Denmark)

    Nielsen, N H; Kristiansen, J; Borg, L

    2000-01-01

    The present study aimed at evaluating the effects of daily repeated exposures to low cobalt or chromate concentrations on the hands of patients with hand eczema and cobalt or chromate allergy. For 2 weeks, the patients immersed a finger for 10 min daily into the appropriate metal salt solution in...... of providing evidence-based medicine in the area of allergic contact dermatitis in the future.......-sensitive patients. During the exposure period, accumulation of cobalt or chromate in the nail was demonstrated. Standardization of chemical methods of quantification of skin exposure to allergens, combined with experimental exposure studies in patients with specific contact allergy, will increase the possibility...

  3. Deterioration of neurobehavioral performance in resident physicians during repeated exposure to extended duration work shifts.

    Science.gov (United States)

    Anderson, Clare; Sullivan, Jason P; Flynn-Evans, Erin E; Cade, Brian E; Czeisler, Charles A; Lockley, Steven W

    2012-08-01

    Although acute sleep loss during 24- to 30-h extended duration work shifts (EDWS) has been shown to impair the performance of resident physicians, little is known about the effects of cumulative sleep deficiency on performance during residency training. Chronic sleep restriction induces a gradual degradation of neurobehavioral performance and exacerbates the effects of acute sleep loss in the laboratory, yet the extent to which this occurs under real-world conditions is unknown. In this study, the authors quantify the time course of neurobehavioral deterioration due to repeated exposure to EDWS during a 3-week residency rotation. A prospective, repeated-measures, within-subject design. Medical and cardiac intensive care units, Brigham and Women's Hospital, Boston, MA. Thirty-four postgraduate year one resident physicians (23 males; age 28.0 ± 1.83 (standard deviation) years) Residents working a 3-week Q3 schedule (24- to 30-h work shift starts every 3(rd) day), consisting of alternating 24- to 30-h (EDWS) and approximately 8-h shifts, underwent psychomotor vigilance testing before, during, and after each work shift. Mean response time, number of lapses, and slowest 10% of responses were calculated for each test. Residents also maintained daily sleep/wake/work logs. EDWS resulted in cumulative sleep deficiency over the 21-day rotation (6.3 h sleep obtained per day; average 2.3 h sleep obtained per extended shift). Response times deteriorated over a single 24- to 30-h shift (P Performance on the fifth and sixth shift was significantly worse than on the first shift (P performance and exacerbated the effects of acute sleep loss inherent in the 24- to 30-h EDWS that are commonly used in resident schedules.

  4. Impact of repeated daily exposure to intermittent hypoxia and mild sustained hypercapnia on apnea severity.

    Science.gov (United States)

    Yokhana, Sanar S; Gerst, David G; Lee, Dorothy S; Badr, M Safwan; Qureshi, Tabarak; Mateika, Jason H

    2012-02-01

    We examined whether exposure to intermittent hypoxia (IH) during wakefulness impacted on the apnea/hypopnea index (AHI) during sleep in individuals with sleep apnea. Participants were exposed to twelve 4-min episodes of hypoxia in the presence of sustained mild hypercapnia each day for 10 days. A control group was exposed to sustained mild hypercapnia for a similar duration. The intermittent hypoxia protocol was completed in the evening on day 1 and 10 and was followed by a sleep study. During all sleep studies, the change in esophageal pressure (ΔPes) from the beginning to the end of an apnea and the tidal volume immediately following apneic events were used to measure respiratory drive. Following exposure to IH on day 1 and 10, the AHI increased above baseline measures (day 1: 1.95 ± 0.42 fraction of baseline, P ≤ 0.01, vs. day 10: 1.53 ± 0.24 fraction of baseline, P < 0.06). The indexes were correlated to the hypoxic ventilatory response (HVR) measured during the IH protocol but were not correlated to the magnitude of ventilatory long-term facilitation (vLTF). Likewise, ΔPes and tidal volume measures were greater on day 1 and 10 compared with baseline (ΔPes: -8.37 ± 0.84 vs. -5.90 ± 1.30 cmH(2)0, P ≤ 0.04; tidal volume: 1,193.36 ± 101.85 vs. 1,015.14 ± 119.83 ml, P ≤ 0.01). This was not the case in the control group. Interestingly, the AHI on day 10 (0.78 ± 0.13 fraction of baseline, P ≤ 0.01) was significantly less than measures obtained during baseline and day 1 in the mild hypercapnia control group. We conclude that enhancement of the HVR initiated by exposure to IH may lead to increases in the AHI during sleep and that initiation of vLTF did not appear to impact on breathing stability. Lastly, our results suggest that repeated daily exposure to mild sustained hypercapnia may lead to a decrease in breathing events.

  5. An observation of histological evidence on internal organ damages in mice caused by repeated exposures to motorcycle emissions

    Science.gov (United States)

    Wardoyo, Arinto Y. P.; Juswono, Unggul P.; Noor, Johan A. E.

    2017-05-01

    Motor vehicle emissions have been identified as a source of ultrafine particles, which have significant impacts on human health. Repeated and prolonged exposure to ultrafine particles may have a significant association with organ damage. Here, we evaluated the correlation between repeated exposure to ultrafine particles and organ damage in mice. Motorcycle emissions were injected into an exposure chamber with mice for a period of 20 seconds. This treatment was conducted over 10 days. The mice were sacrificed on the 2nd, 4th, 6th, 8th, and 10th days for organ preparations. Based on the results, motorcycle emission exposure caused organ damage in mice, with different severities depending on the organ. The highest damage was found for the lung, followed by the kidney, erythrocytes, and liver.

  6. Sensitivity to cocaine in adult mice is due to interplay between genetic makeup, early environment and later experience.

    Science.gov (United States)

    Di Segni, Matteo; Andolina, Diego; Coassin, Alessandra; Accoto, Alessandra; Luchetti, Alessandra; Pascucci, Tiziana; Luzi, Carla; Lizzi, Anna Rita; D'Amato, Francesca R; Ventura, Rossella

    2017-10-01

    Although early aversive postnatal events are known to increase the risk to develop psychiatric disorders later in life, rarely they determine alone the nature and outcome of the psychopathology, indicating that interaction with genetic factors is crucial for expression of psychopathologies in adulthood. Moreover, it has been suggested that early life experiences could have negative consequences or confer adaptive value in different individuals. Here we suggest that resilience or vulnerability to adult cocaine sensitivity depends on a "triple interaction" between genetic makeup x early environment x later experience. We have recently showed that Repeated Cross Fostering (RCF; RCF pups were fostered by four adoptive mothers from postnatal day 1 to postnatal day 4. Pups were left with the last adoptive mother until weaning) experienced by pups affected the response to a negative experience in adulthood in opposite direction in two genotypes leading DBA2/J, but not C57BL/6J mice, toward an "anhedonia-like" phenotype. Here we investigate whether exposure to a rewarding stimulus, instead of a negative one, in adulthood induces an opposite behavioral outcome. To test this hypothesis, we investigated the long-lasting effects of RCF on cocaine sensitivity in C57 and DBA female mice by evaluating conditioned place preference induced by different cocaine doses and catecholamine prefrontal-accumbal response to cocaine using a "dual probe" in vivo microdialysis procedure. Moreover, cocaine-induced c-Fos activity was assessed in different brain regions involved in processing of rewarding stimuli. Finally, cocaine-induced spine changes were evaluated in the prefrontal-accumbal system. RCF experience strongly affected the behavioral, neurochemical and morphological responses to cocaine in adulthood in opposite direction in the two genotypes increasing and reducing, respectively, the sensitivity to cocaine in C57 and DBA mice. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Relapse to cocaine seeking in an invertebrate.

    Science.gov (United States)

    Amaning-Kwarteng, Akua O; Asif-Malik, Aman; Pei, Yue; Canales, Juan J

    2017-06-01

    Addiction is characterised by cycles of compulsive drug taking, periods of abstinence and episodes of relapse. The extinction/reinstatement paradigm has been extensively used in rodents to model human relapse and explore underlying mechanisms and therapeutics. However, relapse to drug seeking behaviour has not been previously demonstrated in invertebrates. Here, we used a cocaine conditioned place preference (CPP) paradigm in the flatworm, planarian, followed by extinction and reinstatement of drug seeking. Once baseline preference was established for one of two distinctly textured environments (i.e. compartments with a coarse or smooth surface), planarian received pairings of cocaine (5μM) in the non-preferred, and vehicle in the most preferred, environment, and were tested for conditioning thereafter. Cocaine produced robust CPP, measured as a significant increase in the time spent in the cocaine-paired compartment. Subsequently, planarian underwent extinction training, reverting back to their original preference within three sessions. Brief exposure to cocaine (5μM) or methamphetamine (5μM) reinstated cocaine-seeking behaviour. By contrast, the high affinity dopamine transporter inhibitor, (N-(n-butyl)-3α-[bis (4-fluorophenyl) methoxy]-tropane) (JHW007), which in rodents exhibits a neurochemical and behavioural profile distinct from cocaine, was ineffective. The present findings demonstrate for the first time reinstatement of extinguished cocaine seeking in an invertebrate model and suggest that the long-term adaptations underlying drug conditioning and relapse are highly conserved through evolution. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Adaptive Changes In Postural Equilibrium And Motion Sickness Following Repeated Exposures To Virtual Environments

    Science.gov (United States)

    Harm, D. L.; Taylor, L. C.

    2006-01-01

    Virtual environments offer unique training opportunities, particularly for training astronauts and preadapting them to the novel sensory conditions of microgravity. Two unresolved human factors issues in virtual reality (VR) systems are: 1) potential "cybersickness", and 2) maladaptive sensorimotor performance following exposure to VR systems. Interestingly, these aftereffects are often quite similar to adaptive sensorimotor responses observed in astronauts during and/or following space flight. Changes in the environmental sensory stimulus conditions and the way we interact with the new stimuli may result in motion sickness, and perceptual, spatial orientation and sensorimotor disturbances. Initial interpretation of novel sensory information may be inappropriate and result in perceptual errors. Active exploratory behavior in a new environment, with resulting feedback and the formation of new associations between sensory inputs and response outputs, promotes appropriate perception and motor control in the new environment. Thus, people adapt to consistent, sustained alterations of sensory input such as those produced by microgravity, unilateral labyrinthectomy and experimentally produced stimulus rearrangements. Adaptation is revealed by aftereffects including perceptual disturbances and sensorimotor control disturbances. The purpose of the current study was to compare disturbances in postural control produced by dome and head-mounted virtual environment displays, and to examine the effects of exposure duration, and repeated exposures to VR systems. Forty-one subjects (21 men, 20 women) participated in the study with an age range of 21-49 years old. One training session was completed in order to achieve stable performance on the posture and VR tasks before participating in the experimental sessions. Three experimental sessions were performed each separated by one day. The subjects performed a navigation and pick and place task in either a dome or head-mounted display

  9. Hearing loss associated with repeated MRI acquisition procedure-related acoustic noise exposure: an occupational cohort study

    NARCIS (Netherlands)

    Bongers, Suzan; Slottje, Pauline; Kromhout, Hans

    2017-01-01

    OBJECTIVE: To study the effects of repeated exposure to MRI-related acoustic noise during image acquisition procedures (scans) on hearing. METHODS: A retrospective occupational cohort study was performed among workers of an MRI manufacturing facility (n=474). Longitudinal audiometry data from the

  10. Cocaine is pharmacologically active in the nonhuman primate fetal brain

    DEFF Research Database (Denmark)

    Benveniste, Helene; Fowler, Joanna S; Rooney, William D

    2010-01-01

    Cocaine use during pregnancy is deleterious to the newborn child, in part via its disruption of placental blood flow. However, the extent to which cocaine can affect the function of the fetal primate brain is still an unresolved question. Here we used PET and MRI and show that in third-trimester ......Cocaine use during pregnancy is deleterious to the newborn child, in part via its disruption of placental blood flow. However, the extent to which cocaine can affect the function of the fetal primate brain is still an unresolved question. Here we used PET and MRI and show that in third...... are influenced by the state of pregnancy. Our findings have clinical implications because they imply that the adverse effects of prenatal cocaine exposure to the newborn child include not only cocaine's deleterious effects to the placental circulation, but also cocaine's direct pharmacological effect...

  11. Evaluation of cocaine-induced hepatotoxicity

    International Nuclear Information System (INIS)

    Wang, G.J.; Som, P.; Volkow, N.D.; Oster, Z.H.

    1991-01-01

    The effect of repeated administrations (1,5 weeks) of cocaine on the liver was studied using two radiopharmaceuticals, 99m Tc sulfur colloid (SC) and 99m Tc DISIDA. Uptake and clearance kinetics as well as liver enzyme determinations and histopathology were compared. In cocaine-treated animals hepatomegaly was noted (36% increase in liver weight over non-treated animals), and SGPT levels were 5 times higher than in non-treated animals. Periportal necrosis, fatty infiltration, and inflammation were noted on histological sections. The total uptake of 99m Tc SC in cocaine-treated mice was 8% higher, but the concentration (% ID/gm) was 18% lower, than in non-treated animals. Decreased uptake and concentration of 99m Tc SC was seen in the spleen. In contrast, the uptake and clearance of 99m Tc DISIDA were not affected by cocaine treatment. It is concluded that in this model 99m Tc DISIDA was not a sensitive agent for evaluation of cocaine-induced hepatoxicity, and that 99m Tc SC was a more sensitive agent for the determination of hepatic and splenic toxicity due to cocaine. Cocaine-mediated hepato-splenic toxicity warrants further clinical investigations. (orig.) [de

  12. Damage of rat liver tissue caused by repeated and sustained +Gz exposure and the mechanism thereof

    Directory of Open Access Journals (Sweden)

    Wen-bing LI

    2014-03-01

    Full Text Available Objective  To explore the mechanisms of positive acceleration (+Gz on the damage of rat liver tissue and the effect of +Gz on the expression of JNK/c-Jun in liver cells. Methods  Twenty four male Wistar rats were randomly divided into 4 groups (n=6: control, +2Gz, +6Gz and +10Gz group. With prone position, the rats in control group were fixed to the turning arm of centrifuge with head towards the axis for 5 minutes. The fixation method in +2Gz, +6Gz and +10Gz group was the same as in the control group. The increase rate of acceleration was 1G/s with a peak-time of 3 minutes, and each +Gz exposure repeated 5 times with an interval of 30 minutes. HE staining was used to observe the morphological changes of liver tissue, fluorescence real-time quantitative PCR to detect the expression of hepatic c-Jun mRNA, and Western blotting to detect the hepatic protein expression of p-c-Jun, c-Jun, p-JNK and JNK. Plasma aspartate aminotransferase (AST and alanine aminotransferase (ALT were determined. Results  The levels of serum ALT and AST increased significantly in +6Gz and, especially, the +10Gz group than in control group and +2Gz group (P<0.05. The same situation also existed in the increase of c-Jun mRNA expression (P<0.05. Hepatic c-jun and p-c-Jun (c-Jun activated form protein expression increased with the increase of G value. Compared with control group, no change was found in JNK protein expression in the other three groups, but the expression of p-JNK (activated form of JNK increased in +6Gz and +10Gz groups (P<0.05. HE staining showed the disorganized liver cells with irregular shapes, the unclear cell gap and the vacuolar changes in +6Gz and +10Gz groups. Conclusions  Repeated and sustained +Gz may cause enhanced expression of c-Jun/ p-c-Jun and p-JNK in hepatic cells. JNK/c-Jun signaling pathway may play an important role in the process of hepatic stress injury. DOI: 10.11855/j.issn.0577-7402.2014.03.15

  13. Genetic Variation of the Dopamine Transporter (DAT1) Influences the Acute Subjective Responses to Cocaine in Volunteers with Cocaine Use Disorders

    Science.gov (United States)

    Brewer, Alex J.; Nielsen, David A.; Spellicy, Catherine J.; Hamon, Sara C.; Gingrich, Justin; Thompson-Lake, Daisy G. Y.; Nielsen, Ellen M.; Mahoney, James J.; Kosten, Thomas R.; Newton, Thomas F.; De La Garza, Richard

    2015-01-01

    Objective : The aim of this study was to identify gene variants of DAT1 (SLC6A3) that modulate subjective responses to acute cocaine exposure. Methods Non-treatment seeking volunteers with cocaine use disorders (CUDs) received a single bolus infusion of saline and cocaine (40 mg, IV) in randomized order. Subjective effects were assessed with visual analog scales administered before (-15 min) and up to 20 min after infusion. Subjective effects ratings were normalized to baseline and saline infusion values were subtracted. Data was analyzed using repeated measures ANOVA. DNA from subjects was genotyped for the DAT1 intron 8 (rs3836790) and 3’ UTR (rs28363170) variable number of tandem repeats. Results Participants were mostly male (~80%) and African American (~70%). No differences were found among drug use variables between groups for either polymorphism. Carriers of the 9-allele of the DAT1 3’ UTR (9,9 and 9,10) (n = 24) exhibited greater responses to cocaine for “high”, “any drug effect”, “anxious”, and “stimulated” (all p-values < 0.001) compared to individuals homozygous for the 10-allele (n = 33). For the intron 8 polymorphism, individuals homozygous for the 6 allele exhibited greater responses for “anxious” than carriers of the 5 allele (p < 0.001). Individuals possessing the genotype pattern of 10,10 and at least one 5-allele reported lower responses to “good effects”, “bad effects”, “depressed”, and “anxious” (all p-values < 0.01). Conclusions The data presented here support the hypothesis that genetic differences of DAT1 contribute to variation of subjective responses to cocaine among participants with CUDs. PMID:25850966

  14. An investigation of interactions between hypocretin/orexin signaling and glutamate receptor surface expression in the rat nucleus accumbens under basal conditions and after cocaine exposure.

    Science.gov (United States)

    Plaza-Zabala, Ainhoa; Li, Xuan; Milovanovic, Mike; Loweth, Jessica A; Maldonado, Rafael; Berrendero, Fernando; Wolf, Marina E

    2013-12-17

    Hypocretin peptides are critical for the effects of cocaine on excitatory synaptic strength in the ventral tegmental area (VTA). However, little is known about their role in cocaine-induced synaptic plasticity in the nucleus accumbens (NAc). First, we tested whether hypocretin-1 by itself could acutely modulate glutamate receptor surface expression in the NAc, given that hypocretin-1 in the VTA reproduces cocaine's effects on glutamate transmission. We found no effect of hypocretin-1 infusion on AMPA or NMDA receptor surface expression in the NAc, measured by biotinylation, either 30 min or 3h after the infusion. Second, we were interested in whether changes in hypocretin receptor-2 (Hcrtr-2) expression contribute to cocaine-induced plasticity in the NAc. As a first step towards addressing this question, Hcrtr-2 surface expression was compared in the NAc after withdrawal from extended-access self-administration of saline (control) versus cocaine. We found that surface Hcrtr-2 levels remain unchanged following 14, 25 or 48 days of withdrawal from cocaine, a time period in which high conductance GluA2-lacking AMPA receptors progressively emerge in the NAc. Overall, our results fail to support a role for hypocretins in acute modulation of glutamate receptor levels in the NAc or a role for altered Hcrtr-2 expression in withdrawal-dependent synaptic adaptations in the NAc following cocaine self-administration. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  15. Glucometabolic effects of single and repeated exposure to forced-swimming stressor in Sprague-Dawley rats.

    Science.gov (United States)

    Morakinyo, Ayodele Olufemi; Iranloye, Bolanle Olubusola; Ogunsola, Oluseyi Abimbola

    2018-04-01

    We aimed to evaluate the effects of a single (acute) and repeated (chronic) exposure to forced-swimming stressor on glucose tolerance, insulin sensitivity, lipid profile and glycogen content in male rats. Thirty adult male Sprague-Dawley rats (12 weeks old) were divided randomly into five groups: control group, single exposure (SE) to forced-swim stressor, repeated exposure to forced-swim stressor for 7 days (RE7), 14 days (RE14) and 28 days (RE28). Glucose tolerance test and Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) were undertaken on fasting rats to obtain glucose and insulin profiles. ELISA was performed to assess plasma insulin and corticosterone levels. Total cholesterol, triglyceride, high- and low-density lipoproteins, hepatic and skeletal glycogen content were also determined. Repeated exposure to stressor induced glucose intolerance and insulin resistance in the experimental rats. Results showed that all RE groups exhibited a significantly higher area under the curve compared with others (p=0.0001); similarly, HOMA-IR increased (p=0.0001) in all RE groups compared with control. Prolonged exposure to stressor significantly increased the plasma insulin and corticosterone levels but decreased the glycogen content in the liver and skeletal muscle when compared with the control group. Additionally, chronic stressor significantly increased the total cholesterol and triglyceride levels, however, acute stressor produced significantly elevated high-density lipoproteins level. In conclusion, repeated exposure to forced-swimming stressor induced glucose intolerance and insulin resistance in rats by disrupting the insulin sensitivity as well as heightening the glycogenolysis in the liver and skeletal muscle. Acute stressor was unable to cause glucose intolerance and insulin resistance but it appears that may have a positive effect on the lipid metabolism.

  16. Effects of moxifloxacin exposure on the conjunctival flora and antibiotic resistance profile following repeated intravitreal injections

    Directory of Open Access Journals (Sweden)

    Mustafa Ataş

    2014-10-01

    Full Text Available AIM:To evaluate the effects of moxifloxacin exposure on the conjunctival flora and antibiotic resistance profile following repeated intravitreal injections.METHODS:Seventy-two eyes of 36 patients [36 eyes in control group, 36 eyes in intravitreal injection (IVI group] were enrolled in the study. All the eyes had at least one IVI and had diabetic macular edema (DME or age-related macular degeneration (ARMD. Moxifloxacin was prescribed to all the patients four times a day for five days following injection. Conjunctival cultures were obtained from the lower fornix via standardized technique with every possible effort made to minimize contamination from the lids, lashes, or skin. Before the application of any ophthalmic medication, conjunctival cultures were obtained from both eyes using sterile cotton culture. An automated microbiology system was used to identify the growing bacteria and determine antibiotic sensitivity. RESULTS:The bacterial cultures were isolated from 72 eyes of 36 patients, sixteen of whom patients (44.4% were male and twenty (55.6% were female. Average age was 68.4±9.0 (range 50-86. The average number of injections before taking cultures was 3.1+1.0. Forty-eight (66.7% of 72 eyes had at least one significant organism. There was no bacterial growth in 8 (20.5% of IVI eyes and in 16 (44.4% of control eyes (P=0.03. Of the bacteria isolated from culture, 53.8% of coagulase negative staphylococci (CoNS in IVI eyes and 47.2% CoNS in control eyes. This difference between IVI eyes and control eyes about bacteria isolated from culture was not statistically significant (P=0.2. Eleven of 25 bacteria (44.0% isolated from IVI eyes and 11 (57.9% of 19 bacteria isolated from control eyes were resistant to oxacillin. The difference in frequency of moxifloxacine resistance between two groups was not statistically significant (12.0% in IVI eyes and 21.1% in control eyes (P=0.44. There were no cases of resistance to vancomycin, teicoplanin and

  17. Neurophysiological effects of modafinil on cue-exposure in cocaine dependence: a randomized placebo-controlled cross-over study using pharmacological fMRI.

    Science.gov (United States)

    Goudriaan, Anna E; Veltman, Dick J; van den Brink, Wim; Dom, Geert; Schmaal, Lianne

    2013-02-01

    Enhanced reactivity to substance related cues is a central characteristic of addiction and has been associated with increased activity in motivation, attention, and memory related brain circuits and with a higher probability of relapse. Modafinil was promising in the first clinical trials in cocaine dependence, and was able to reduce craving in addictive disorders. However, its mechanism of action remains to be elucidated. In this functional magnetic resonance imaging (fMRI) study therefore, cue reactivity in cocaine dependent patients was compared to cue reactivity in healthy controls (HCs) under modafinil and placebo conditions. An fMRI cue reactivity study, with a double-blind, placebo-controlled cross-over challenge with a single dose of modafinil (200mg) was employed in 13 treatment seeking cocaine dependent patients and 16 HCs. In the placebo condition, watching cocaine-related pictures (versus neutral pictures) resulted in higher brain activation in the medial frontal cortex, anterior cingulate cortex, angular gyrus, left orbitofrontal cortex, and ventral tegmental area (VTA) in the cocaine dependent group compared to HCs. However, in the modafinil condition, no differences in brain activation patterns were found between cocaine dependent patients and HCs. Group interactions revealed decreased activity in the VTA and increased activity in the right ACC and putamen in the modafinil condition relative to the placebo condition in cocaine dependent patients, whereas such changes were not present in healthy controls. Decreases in self-reported craving when watching cocaine-related cues after modafinil administration compared to the placebo condition were associated with modafinil-induced increases in ACC and putamen activation. Enhanced cue reactivity in the cocaine dependent group compared to healthy controls was found in brain circuitries related to reward, motivation, and autobiographical memory processes. In cocaine dependent patients, these enhanced brain

  18. Long-term health outcomes after exposure to repeated concussion in elite level: rugby union players.

    Science.gov (United States)

    McMillan, T M; McSkimming, P; Wainman-Lefley, J; Maclean, L M; Hay, J; McConnachie, A; Stewart, W

    2017-06-01

    There is continuing concern about effects of concussion in athletes, including risk of the neurodegenerative disease chronic traumatic encephalopathy. However, information on long-term health and wellbeing in former athletes is limited. Outcome after exposure to repeated brain injury was investigated in 52 retired male Scottish international rugby players (RIRP) and 29 male controls who were similar in age and social deprivation. Assessment included history of playing rugby and traumatic brain injury, general and mental health, life stress, concussion symptoms, cognitive function, disability and markers of chronic stress (allostatic load). The estimated number of concussions in RIRP averaged 14 (median=7; IQR 5-40). Performance was poorer in RIRP than controls on a test of verbal learning (p=0.022) and of fine co-ordination of the dominant hand (p=0.038) and not significantly different on other cognitive tests (p>0.05). There were no significant associations between number of concussions and performance on cognitive tests. Other than a higher incidence of cardiovascular disease in controls, no group differences were detected in general or mental health or estimates of allostatic load. In RIRP, persisting symptoms attributed to concussion were more common if reporting more than nine concussions (p=0.028), although these symptoms were not perceived to affect social or work functioning. Despite a high number of concussions in RIRP, differences in mental health, social or work functioning were not found late after injury. Subtle group differences were detected on two cognitive tests, the cause of which is uncertain. Prospective group comparison studies on representative cohorts are required. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  19. The impact of cocaine on adult hippocampal neurogenesis: Potential neurobiological mechanisms and contributions to maladaptive cognition in cocaine addiction disorder.

    Science.gov (United States)

    Castilla-Ortega, Estela; Ladrón de Guevara-Miranda, David; Serrano, Antonia; Pavón, Francisco J; Suárez, Juan; Rodríguez de Fonseca, Fernando; Santín, Luis J

    2017-10-01

    After discovering that addictive drugs alter adult neurogenesis, the potential role of adult-born hippocampal neurons in drug addiction has become a promising research field, in which cocaine is the most frequently investigated drug. Although a substantial amount of pre-clinical evidence has accumulated, additional studies are required to reveal the mechanisms by which cocaine modulates adult hippocampal neurogenesis (AHN) and determine whether these adult-born neurons have a role in cocaine-related behaviors, such as cocaine-mediated cognitive symptoms. First, this review will summarize the cocaine-induced alterations in a number of neurobiological factors (neurotransmitters, neurotrophins, glucocorticoids, inflammatory mediators) that likely regulate both hippocampal-dependent learning and adult hippocampal neurogenesis after cocaine exposure. A separate section will provide a detailed review of the available literature that challenges the common view that cocaine reduces adult hippocampal neurogenesis. In fact, cocaine has a short-term anti-proliferative role, but the young adult-born neurons are apparently spared, or even enhanced, following certain cocaine protocols. Thus, we will try to reconcile this evidence with the hippocampal-dependent cognitive symptoms that are typically observed in cocaine addicts, and we will propose new directions for future studies to test the relevant hypothesis. Based on the evidence presented here, the regulation of adult hippocampal neurogenesis might be one of the many mechanisms by which cocaine sculpts hippocampus-dependent learning. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Cocaine-associated odor cue re-exposure increases blood oxygenation level dependent signal in memory and reward regions of the maternal rat brain.

    Science.gov (United States)

    Caffrey, Martha K; Febo, Marcelo

    2014-01-01

    Cue triggered relapse during the postpartum period can negatively impact maternal care. Given the high reward value of pups in maternal rats, we designed an fMRI experiment to test whether offspring presence reduces the neural response to a cocaine associated olfactory cue. Cocaine conditioned place preference was carried out before pregnancy in the presence of two distinct odors that were paired with cocaine or saline (+Cue and -Cue). The BOLD response to +Cue and -Cue was measured in dams on postpartum days 2-4. Odor cues were delivered to dams in the absence and then the presence of pups. Our data indicate that several limbic and cognitive regions of the maternal rat brain show a greater BOLD signal response to a +Cue versus -Cue. These include dorsal striatum, prelimbic cortex, parietal cortex, habenula, bed nucleus of stria terminalis, lateral septum and the mediodorsal and the anterior thalamic nucleus. Of the aforementioned brain regions, only the parietal cortex of cocaine treated dams showed a significant modulatory effect of pup presence. In this area of the cortex, cocaine exposed maternal rats showed a greater BOLD activation in response to the +Cue in the presence than in the absence of pups. Specific regions of the cocaine exposed maternal rat brain are strongly reactive to drug associated cues. The regions implicated in cue reactivity have been previously reported in clinical imaging work, and previous work supports their role in various motivational and cognitive functions. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  1. COCAINE-ASSOCIATED ODOR CUE RE-EXPOSURE INCREASES BLOOD OXYGENATION LEVEL DEPENDENT SIGNAL IN MEMORY AND REWARD REGIONS OF THE MATERNAL RAT BRAIN*

    Science.gov (United States)

    Caffrey, Martha K.; Febo, Marcelo

    2013-01-01

    BACKGROUND Cue triggered relapse during the postpartum period can negatively impact maternal care. Given the high reward value of pups in maternal rats, we designed an fMRI experiment to test whether offspring presence reduces the neural response to a cocaine associated olfactory cue. METHODS Cocaine conditioned place preference was carried out before pregnancy in the presence of two distinct odors that were paired with cocaine or saline (+Cue and −Cue). The BOLD response to +Cue and −Cue was measured in dams on postpartum days 2–4. Odor cues were delivered to dams in the absence and then the presence of pups. RESULTS Our data indicate that several limbic and cognitive regions of the maternal rat brain show a greater BOLD signal response to a +Cue versus −Cue. These include dorsal striatum, prelimbic cortex, parietal cortex, habenula, bed nucleus of stria terminalis, lateral septum and the mediodorsal and the anterior thalamic nucleus. Of the aforementioned brain regions, only the parietal cortex of cocaine treated dams showed a significant modulatory effect of pup presence. In this area of the cortex, cocaine exposed maternal rats showed a greater BOLD activation in response to the +Cue in the presence than in the absence of pups. CONCLUSIONS Specific regions of the cocaine exposed maternal rat brain are strongly reactive to drug associated cues. The regions implicated in cue reactivity have been previously reported in clinical imaging work, and previous work supports their role in various motivational and cognitive functions. PMID:24183499

  2. Cocaine induces state-dependent learning of sexual conditioning in male Japanese quail.

    Science.gov (United States)

    Gill, Karin E; Rice, Beth Ann; Akins, Chana K

    2015-01-01

    State dependent learning effects have been widely studied in a variety of drugs of abuse. However, they have yet to be studied in relation to sexual motivation. The current study investigated state-dependent learning effects of cocaine in male Japanese quail (Coturnix japonica) using a sexual conditioning paradigm. Cocaine-induced state-dependent learning effects were investigated using a 2×2 factorial design with training state as one factor and test state as the other factor. During a 14-day training phase, male quail were injected once daily with 10mg/kg cocaine or saline and then placed in a test chamber after 15min. In the test chamber, sexual conditioning trials consisted of presentation of a light conditioned stimulus (CS) followed by sexual reinforcement. During the state dependent test, half of the birds received a shift in drug state from training to testing (Coc→Sal or Sal→Coc) while the other half remained in the same drug state (Coc→Coc or Sal→Sal). Results showed that male quail that were trained and tested in the same state (Coc→Coc or Sal→Sal) showed greater sexual conditioning than male quail that were trained and tested in different states (Sal→Coc) except when cocaine was administered chronically prior to the test (Coc→Sal). For the latter condition, sexual conditioning persisted from cocaine training to the saline test. The findings suggest that state dependent effects may alter sexual motivation and that repeated exposure to cocaine during sexual activity may increase sexual motivation which, in turn, may lead to high risk sexual activities. An alternative explanation for the findings is also discussed. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Dermal damage promoted by repeated low-level UV-A1 exposure despite tanning response in human skin.

    Science.gov (United States)

    Wang, Frank; Smith, Noah R; Tran, Bao Anh Patrick; Kang, Sewon; Voorhees, John J; Fisher, Gary J

    2014-04-01

    Solar UV irradiation causes photoaging, characterized by fragmentation and reduced production of type I collagen fibrils that provide strength to skin. Exposure to UV-B irradiation (280-320 nm) causes these changes by inducing matrix metalloproteinase 1 and suppressing type I collagen synthesis. The role of UV-A irradiation (320-400 nm) in promoting similar molecular alterations is less clear yet important to consider because it is 10 to 100 times more abundant in natural sunlight than UV-B irradiation and penetrates deeper into the dermis than UV-B irradiation. Most (approximately 75%) of solar UV-A irradiation is composed of UV-A1 irradiation (340-400 nm), which is also the primary component of tanning beds. To evaluate the effects of low levels of UV-A1 irradiation, as might be encountered in daily life, on expression of matrix metalloproteinase 1 and type I procollagen (the precursor of type I collagen). In vivo biochemical analyses were conducted after UV-A1 irradiation of normal human skin at an academic referral center. Participants included 22 healthy individuals without skin disease. Skin pigmentation was measured by a color meter (chromometer) under the L* variable (luminescence), which ranges from 0 (black) to 100 (white). Gene expression in skin samples was assessed by real-time polymerase chain reaction. Lightly pigmented human skin (L* >65) was exposed up to 4 times (1 exposure/d) to UV-A1 irradiation at a low dose (20 J/cm2), mimicking UV-A levels from strong sun exposure lasting approximately 2 hours. A single exposure to low-dose UV-A1 irradiation darkened skin slightly and did not alter matrix metalloproteinase 1 or type I procollagen gene expression. With repeated low-dose UV-A1 irradiation, skin darkened incrementally with each exposure. Despite this darkening, 2 or more exposures to low-dose UV-A1 irradiation significantly induced matrix metalloproteinase 1 gene expression, which increased progressively with successive exposures. Repeated UV-A1

  4. Microprocessor-controlled inhalation system for repeated exposure of animals to aerosols

    International Nuclear Information System (INIS)

    Carpenter, R.L.; Barr, F.P.; Leydig, R.L.; Rajala, R.E.

    1979-01-01

    A microprocessor-controlled inhalation exposure system (MCIES) has been built to automate aerosol generation and sampling while controlling exposure time for animal toxicity studies. The system has a time resolution of 0.1 s and automatically sequences the exposure events from initiation to temination of the exposure. The operator is required to preset all airflows, read in a paper tape containing the time sequence of events, and initiate the automatic sequence by closing a switch

  5. Amiodarone biokinetics, the formation of its major oxidative metabolite and neurotoxicity after acute and repeated exposure of brain cell cultures.

    Science.gov (United States)

    Pomponio, Giuliana; Zurich, Marie-Gabrielle; Schultz, Luise; Weiss, Dieter G; Romanelli, Luca; Gramowski-Voss, Alexandra; Di Consiglio, Emma; Testai, Emanuela

    2015-12-25

    The difficulty in mimicking nervous system complexity and cell-cell interactions as well as the lack of kinetics information has limited the use of in vitro neurotoxicity data. Here, we assessed the biokinetic profile as well as the neurotoxicity of Amiodarone after acute and repeated exposure in two advanced rodent brain cell culture models, consisting of both neurons and glial cells organized in 2 or 3 dimensions to mimic the brain histiotypic structure and function. A strategy was applied to evidence the abiotic processes possibly affecting Amiodarone in vitro bioavailability, showing its ability to adsorb to the plastic devices. At clinically relevant Amiodarone concentrations, known to induce neurotoxicity in some patients during therapeutic treatment, a complete uptake was observed in both models in 24 h, after single exposure. After repeated treatments, bioaccumulation was observed, especially in the 3D cell model, together with a greater alteration of neurotoxicity markers. After 14 days, Amiodarone major oxidative metabolite (mono-N-desethylamiodarone) was detected at limited levels, indicating the presence of active drug metabolism enzymes (i.e. cytochrome P450) in both models. The assessment of biokinetics provides useful information on the relevance of in vitro toxicity data and should be considered in the design of an Integrated Testing Strategy aimed to identify specific neurotoxic alerts, and to improve the neurotoxicity assay predictivity for human acute and repeated exposure. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Impaired inhibitory control in recreational cocaine users.

    Directory of Open Access Journals (Sweden)

    Lorenza S Colzato

    Full Text Available Chronic use of cocaine is associated with impairment in response inhibition but it is an open question whether and to which degree findings from chronic users generalize to the upcoming type of recreational users. This study compared the ability to inhibit and execute behavioral responses in adult recreational users and in a cocaine-free-matched sample controlled for age, race, gender distribution, level of intelligence, and alcohol consumption. Response inhibition and response execution were measured by a stop-signal paradigm. Results show that users and non users are comparable in terms of response execution but users need significantly more time to inhibit responses to stop-signals than non users. Interestingly, the magnitude of the inhibitory deficit was positively correlated with the individuals lifetime cocaine exposure suggesting that the magnitude of the impairment is proportional to the degree of cocaine consumed.

  7. Cumulative effects of repeated exposure to pO2 = 200 kPa (2 atm).

    Science.gov (United States)

    Shykoff, Barbara E

    2014-01-01

    Even asymptomatic exposures to elevated oxygen partial pressure (pO2) can influence subsequent exposures. Dry chamber dives of three hours' duration at pO2 of 200 kPa were conducted to examine cumulative effects. Experiments were single (n = 27), or paired exposures with surface intervals (SIs) 15 to 17 hours (n = 30), six hours (n = 33), or three hours (n = 36). Flow-volume loops, diffusing capacity, and symptoms were recorded before and after exposures. Immediately after surfacing from second exposures, some significant (p < 0.05) mean changes from baseline in pulmonary function indices occurred for all SIs and persisted for two days for three-hour SIs and for one day for 15-hour SIs. Incidences of symptoms were 15% immediately after one exposure and 28%, 38% and 31% immediately after a second exposure following 15-, six- , or three-hour SIs, respectively. Incidences of changes in pulmonary function indices (deltaPF) were 5%, 11%, 12% and 14% for single exposures or two with 15-, six-, or three-hour SIs, respectively. Two days following the second exposure, resolution of symptoms was incomplete after six- or 15-hour SIs, as was resolution of deltaPF after 15-hour SIs. The incidences indicate non-linear superposition of effects of a first and second exposure, and are not readily explained by delayed-onset injury.

  8. Hearing loss associated with repeated MRI acquisition procedure-related acoustic noise exposure: an occupational cohort study.

    Science.gov (United States)

    Bongers, Suzan; Slottje, Pauline; Kromhout, Hans

    2017-11-01

    To study the effects of repeated exposure to MRI-related acoustic noise during image acquisition procedures (scans) on hearing. A retrospective occupational cohort study was performed among workers of an MRI manufacturing facility (n=474). Longitudinal audiometry data from the facility's medical surveillance scheme collected from 1973 to 2010 were analysed by studying the association of cumulative exposure to MRI-related acoustic noise from voluntary (multiple) MRI scans and the hearing threshold of the volunteer. Repeated acoustic noise exposure during volunteer MRI scans was found to be associated with a small exposure-dependent increased rate change of hearing threshold level (dB/year), but the association was only found related to the number of voluntary MRI scans and not to modelled cumulative noise exposure (dB*hour) based on MRI-system type. The increased rate change of hearing threshold level was found to be statistically significant for the frequencies 500, 1000, 2000, 3000 and 4000 Hz in the right ear. From our longitudinal cohort study, it appeared that exposure to noise from voluntarily MRI scans may have resulted in a slight amount of hearing loss. Mandatory use of hearing protection might have prevented more severe hearing loss. Lack of consistency in findings between the left and right ears and between the two exposure measures prohibits definitive conclusions. Further research that addresses the study's methodological limitations is warranted to corroborate our findings. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  9. No impact of repeated extinction exposures on operant responding maintained by different reinforcer rates.

    Science.gov (United States)

    Bai, John Y H; Podlesnik, Christopher A

    2017-05-01

    Greater rates of intermittent reinforcement in the presence of discriminative stimuli generally produce greater resistance to extinction, consistent with predictions of behavioral momentum theory. Other studies reveal more rapid extinction with higher rates of reinforcers - the partial reinforcement extinction effect. Further, repeated extinction often produces more rapid decreases in operant responding due to learning a discrimination between training and extinction contingencies. The present study examined extinction repeatedly with training with different rates of intermittent reinforcement in a multiple schedule. We assessed whether repeated extinction would reverse the pattern of greater resistance to extinction with greater reinforcer rates. Counter to this prediction, resistance to extinction was consistently greater across twelve assessments of training followed by six successive sessions of extinction. Moreover, patterns of responding during extinction resembled those observed during satiation tests, which should not alter discrimination processes with repeated testing. These findings join others suggesting operant responding in extinction can be durable across repeated tests. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Perspectives on repeated low-level blast and the measurement of neurotrauma in humans as an occupational exposure risk

    Science.gov (United States)

    Carr, W.; Dell, K. C.; Yanagi, M. A.; Hassan, D. M.; LoPresti, M. L.

    2017-11-01

    A pressing question in military medical research is the nature and degree of effects on the human brain from occupational repeated exposure to low-level explosive blast, but reliable and effective means to objectively measure such effects remain elusive. In survey results, headache, difficulty sleeping, irritability, cognitive impairment, and a variety of other symptoms consistent with post-concussive syndrome have been reported by those exposed to blast and there was positive correlation between degree of blast exposure and degree of symptomology, but an important goal is to obtain more objective evidence of an effect than self-report alone. This review reflects recent efforts to measure and evaluate such hypothesized effects and current recommendations for ongoing study. Optimal measures are likely those with sensitivity and specificity to systemic effects in mild neurotrauma, that have minimal to no volitional component, and that can be sampled relatively quickly with minimal intrusion in prospective, observational field studies during routine training with explosives. An understanding of an association between parameters of exposure to repeated low-level blast and negative neurologic effects would support the evaluation of clinical implications and development of protective equipment and surveillance protocols where warranted. At present, low-level blast exposure surveillance measurements do not exist as a systematic record for any professional community.

  11. Effects of repeated exposure to malathion on growth, food consumption, and locomotor performance of the western fence lizard (Sceloporus occidentalis)

    Energy Technology Data Exchange (ETDEWEB)

    Holem, Ryan R. [University of Georgia, Savannah River Ecology Laboratory, Aiken, SC 29801 (United States); ENTRIX, Inc., Okemos, MI 48864 (United States); Hopkins, William A. [University of Georgia, Savannah River Ecology Laboratory, Aiken, SC 29801 (United States); Department of Fisheries and Wildlife Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061 (United States)], E-mail: hopkinsw@vt.edu; Talent, Larry G. [Natural Resource Ecology and Management, Oklahoma State University, Stillwater, OK 74078 (United States)

    2008-03-15

    Effects of repeated pollutant exposure on growth, locomotor performance, and behavior have rarely been evaluated in reptiles. We administered three doses of malathion (2.0, 20, or 100 mg/kg body weight) to western fence lizards (Sceloporus occidentalis) over an 81 day period. Eight and 23% mortality occurred at 20 and 100 mg/kg (p = 0.079) and 85% of lizards in the 100 mg/kg group exhibited clinical symptoms of poisoning. Growth, food consumption, body condition index, and terrestrial locomotor performance were not significantly influenced by malathion. However, arboreal sprint velocity was significantly reduced in lizards receiving 100 mg/kg. Fifty percent of lizards in the 100 mg/kg group also refused to sprint in the arboreal setting (p = 0.085). Based on these results, arboreal locomotor performance was the most sensitive metric of exposure we evaluated. Further study of compounds such as malathion is warranted due to highly variable application rates and exposure scenarios. - Repeated exposure of western fence lizards to malathion caused reduced arboreal performance and some mortality but growth, food consumption, and terrestrial performance were not affected.

  12. Effects of repeated exposure to malathion on growth, food consumption, and locomotor performance of the western fence lizard (Sceloporus occidentalis)

    International Nuclear Information System (INIS)

    Holem, Ryan R.; Hopkins, William A.; Talent, Larry G.

    2008-01-01

    Effects of repeated pollutant exposure on growth, locomotor performance, and behavior have rarely been evaluated in reptiles. We administered three doses of malathion (2.0, 20, or 100 mg/kg body weight) to western fence lizards (Sceloporus occidentalis) over an 81 day period. Eight and 23% mortality occurred at 20 and 100 mg/kg (p = 0.079) and 85% of lizards in the 100 mg/kg group exhibited clinical symptoms of poisoning. Growth, food consumption, body condition index, and terrestrial locomotor performance were not significantly influenced by malathion. However, arboreal sprint velocity was significantly reduced in lizards receiving 100 mg/kg. Fifty percent of lizards in the 100 mg/kg group also refused to sprint in the arboreal setting (p = 0.085). Based on these results, arboreal locomotor performance was the most sensitive metric of exposure we evaluated. Further study of compounds such as malathion is warranted due to highly variable application rates and exposure scenarios. - Repeated exposure of western fence lizards to malathion caused reduced arboreal performance and some mortality but growth, food consumption, and terrestrial performance were not affected

  13. Secondhand tobacco smoke exposure and heart rate variability and inflammation among non-smoking construction workers: a repeated measures study.

    Science.gov (United States)

    Zhang, Jinming; Fang, Shona C; Mittleman, Murray A; Christiani, David C; Cavallari, Jennifer M

    2013-10-02

    Although it has been well recognized that exposure to secondhand tobacco smoke (SHS) is associated with cardiovascular mortality, the mechanisms and time course by which SHS exposure may lead to cardiovascular effects are still being explored. Non-smoking workers were recruited from a local union and monitored inside a union hall while exposed to SHS over approximately 6 hours. Participants were fitted with a continuous electrocardiographic monitor upon enrollment which was removed at the end of a 24-hr monitoring period. A repeated measures study design was used where resting ECGs and blood samples were taken from individuals before SHS exposure (baseline), immediately following SHS exposure (post) and the morning following SHS exposure (next-morning).Inflammatory markers, including high sensitivity C-reactive protein (CRP) and white blood cell count (WBC) were analyzed. Heart rate variability (HRV) was analyzed from the ECG recordings in time (SDNN, rMSSD) and frequency (LF, HF) domain parameters over 5-minute periods. SHS exposure was quantified using a personal fine particulate matter (PM2.5) monitor.Linear mixed effects regression models were used to examine within-person changes in inflammatory and HRV parameters across the 3 time periods. Exposure-response relationships with PM2.5 were examined using mixed effects models. All models were adjusted for age, BMI and circadian variation. A total of 32 male non-smokers were monitored between June 2010 and June 2012. The mean PM2.5 from SHS exposure was 132 μg/m3. Immediately following SHS exposure, a 100 μg/m3 increase in PM2.5 was associated with declines in HRV (7.8% [standard error (SE) =3%] SDNN, 8.0% (SE = 3.9%) rMSSD, 17.2% (SE = 6.3%) LF, 29.0% (SE = 10.1%) HF) and increases in WBC count 0.42 (SE = 0.14) k/μl. Eighteen hours following SHS exposure, a 100 μg/m3 increase in PM2.5 was associated with 24.2% higher CRP levels. Our study suggest that short-term SHS exposure is associated

  14. Radiation dose exposure in patients affected by lymphoma undergoing repeat CT examinations: how to manage the radiation dose variability.

    Science.gov (United States)

    Paolicchi, Fabio; Bastiani, Luca; Guido, Davide; Dore, Antonio; Aringhieri, Giacomo; Caramella, Davide

    2018-03-01

    To assess the variability of radiation dose exposure in patients affected by lymphoma undergoing repeat CT (computed tomography) examinations and to evaluate the influence of different scan parameters on the overall radiation dose. A series of 34 patients (12 men and 22 women with a median age of 34.4 years) with lymphoma, after the initial staging CT underwent repeat follow-up CT examinations. For each patient and each repeat examination, age, sex, use of AEC system (Automated Exposure Control, i.e. current modulation), scan length, kV value, number of acquired scans (i.e. number of phases), abdominal size diameter and dose length product (DLP) were recorded. The radiation dose of just one venous phase was singled out from the DLP of the entire examination. All scan data were retrieved by our PACS (Picture Archiving and Communication System) by means of a dose monitoring software. Among the variables we considered, no significant difference of radiation dose was observed among patients of different ages nor concerning tube voltage. On the contrary the dose delivered to the patients varied depending on sex, scan length and usage of AEC. No significant difference was observed depending on the behaviour of technologists, while radiologists' choices had indirectly an impact on the radiation dose due to the different number of scans requested by each of them. Our results demonstrate that patients affected by lymphoma who undergo repeat whole body CT scanning may receive unnecessary overexposure. We quantified and analyzed the most relevant variables in order to provide a useful tool to manage properly CT dose variability, estimating the amount of additional radiation dose for every single significant variable. Additional scans, incorrect scan length and incorrect usage of AEC system are the most relevant cause of patient radiation exposure.

  15. Prevention and reversal of social stress-escalated cocaine self-administration in mice by intra-VTA CRFR1 antagonism.

    Science.gov (United States)

    Han, Xiao; DeBold, Joseph F; Miczek, Klaus A

    2017-09-01

    A history of brief intermittent social defeat stress can escalate cocaine self-administration and induce long-term adaptations in the mesolimbic dopamine system. Extra-hypothalamic corticotrophin releasing factor (CRF) has been shown to be closely associated with stress-induced escalation of drug use. How repeated stress modulates CRF release in the ventral tegmental area (VTA) and the roles of CRF receptors during different phases of stress-induced cocaine self-administration remain to be defined. The current study examines the roles of CRF and CRF receptor 1 (CRFR1) in escalated intravenous cocaine self-administration after exposure to social defeat stress in mice. First, CRFR1 antagonist (CP 376,395, 15 mg/kg, i.p.) given 30 min prior to each social defeat episode prevented later escalated cocaine self-administration. When CP 376,395 (5 and 15 mg/kg, i.p.) was administered 10 days after the last episode of social stress, the escalation of cocaine intake was dose-dependently reversed. Moreover, socially defeated mice showed increased CRF release in the VTA compared to controls. To further explore the role of CRFR1, CP 376,395 (0.5 and 1 μg/0.2 μl) was infused directly into the VTA before the cocaine self-administration session. Intra-VTA antagonism of CRFR1 was sufficient to reverse social defeat stress-escalated cocaine self-administration. These findings suggest that CRF and CRFR1 exert multiple roles in the response to social stress that are relevant to escalated cocaine self-administration.

  16. Chronic restraint stress during withdrawal increases vulnerability to drug priming-induced cocaine seeking via a dopamine D1-like receptor-mediated mechanism.

    Science.gov (United States)

    Ball, Kevin T; Stone, Eric; Best, Olivia; Collins, Tyler; Edson, Hunter; Hagan, Erin; Nardini, Salvatore; Neuciler, Phelan; Smolinsky, Michael; Tosh, Lindsay; Woodlen, Kristin

    2018-06-01

    A major obstacle in the treatment of individuals with cocaine addiction is their high propensity for relapse. Although the clinical scenario of acute stress-induced relapse has been well studied in animal models, few pre-clinical studies have investigated the role of chronic stress in relapse or the interaction between chronic stress and other relapse triggers. We tested the effect of chronic restraint stress on cocaine seeking in rats using both extinction- and abstinence-based animal relapse models. Rats were trained to press a lever for I.V. cocaine infusions (0.50 mg/kg/infusion) paired with a discrete tone + light cue in daily 3-h sessions. Following self-administration, rats were exposed to a chronic restraint stress procedure (3 h/day) or control procedure (unstressed) during the first seven days of a 13-day extinction period during which lever presses had no programmed consequences. This was followed by cue- and cocaine priming-induced drug seeking tests. In a separate group of rats, cocaine seeking was assessed during forced abstinence both before and after the same chronic stress procedure. A history of chronic restraint stress was associated with increased cocaine priming-induced drug seeking, an effect attenuated by co-administration of SCH-23390 (10.0 μg/kg; i.p.), a dopamine D 1 -like receptor antagonist, with daily restraint. Repeated SCH-23390 administration but not stress during extinction increased cue-induced reinstatement. Exposure to chronic stress during early withdrawal may confer lasting vulnerability to some types of relapse, and dopamine D 1 -like receptors appear to mediate both chronic stress effects on cocaine seeking and extinction of cocaine seeking. Copyright © 2018 Elsevier B.V. All rights reserved.

  17. Repeated CT scans in trauma transfers: An analysis of indications, radiation dose exposure, and costs

    International Nuclear Information System (INIS)

    Hinzpeter, Ricarda; Sprengel, Kai; Wanner, Guido A.; Mildenberger, Peter; Alkadhi, Hatem

    2017-01-01

    Highlights: • Repetition of CT in trauma patients occurs relatively often. • Repetition of CT is mainly caused by inadequate image data transfer. • Potentially preventable CT examinations add radiation dose to patients. • Repeated CT is associated with excess costs to the health care system. - Abstract: Objectives: To identify the number of CT scans repeated in acute trauma patients receiving imaging before being referred to a trauma center, to define indications, and to assess radiation doses and costs of repeated CT. Methods: This retrospective study included all adult trauma patients transferred from other hospitals to a Level-I trauma center during 2014. Indications for repeated CT scans were categorized into: inadequate CT image data transfer, poor image quality, repetition of head CT after head injury together with completion to whole-body CT (WBCT), and follow-up of injury known from previous CT. Radiation doses from repeated CT were determined; costs were calculated using a nation-wide fee schedule. Results: Within one year, 85/298 (28.5%) trauma patients were transferred from another hospital because of severe head injury (n = 45,53%) and major body trauma (n = 23;27%) not manageable in the referring hospital, repatriation from a foreign country (n = 14;16.5%), and no ICU-capacity (n = 3;3.5%). Of these 85 patients, 74 (87%) had repeated CT in our center because of inadequate CT data transfer (n = 29;39%), repetition of head CT with completion to WBCT (n = 24;32.5%), and follow-up of known injury (n = 21;28.5%). None occurred because of poor image quality. Cumulative dose length product (DLP) and annual costs of potential preventable, repeated CT (inadequate data transfer) was 631mSv (81′304mGy*cm) and 35′233€, respectively. Conclusion: A considerable number of transferred trauma patients undergo potentially preventable, repeated CT, adding radiation dose to patients and costs to the health care system.

  18. Repeated CT scans in trauma transfers: An analysis of indications, radiation dose exposure, and costs

    Energy Technology Data Exchange (ETDEWEB)

    Hinzpeter, Ricarda, E-mail: Ricarda.Hinzpeter@usz.ch [Institute of Diagnostic and Interventional Radiology, University Hospital Zurich, University of Zurich, Raemistr. 100, Zurich CH-8091 (Switzerland); Sprengel, Kai, E-mail: Kai.Sprengel@usz.ch [Division of Trauma Surgery, Department of Surgery, University Hospital Zurich, University of Zurich, Raemistr. 100, CH-8091 Zurich (Switzerland); Wanner, Guido A., E-mail: Guido.Wanner@sbk-vs.de [Division of Trauma Surgery, Department of Surgery, University Hospital Zurich, University of Zurich, Raemistr. 100, CH-8091 Zurich (Switzerland); Department of General Surgery, Schwarzwald-Baar Klinikum, University of Freiburg, Klinikstr. 11, D-78052 Villingen-Schwenningen (Germany); Mildenberger, Peter, E-mail: peter.mildenberger@unimedizin-mainz.de [Department of Diagnostic and Interventional Radiology, University Hospital of Mainz, Langenbeckstr. 1, D-55131 Mainz (Germany); Alkadhi, Hatem, E-mail: hatem.alkadhi@usz.ch [Institute of Diagnostic and Interventional Radiology, University Hospital Zurich, University of Zurich, Raemistr. 100, Zurich CH-8091 (Switzerland)

    2017-03-15

    Highlights: • Repetition of CT in trauma patients occurs relatively often. • Repetition of CT is mainly caused by inadequate image data transfer. • Potentially preventable CT examinations add radiation dose to patients. • Repeated CT is associated with excess costs to the health care system. - Abstract: Objectives: To identify the number of CT scans repeated in acute trauma patients receiving imaging before being referred to a trauma center, to define indications, and to assess radiation doses and costs of repeated CT. Methods: This retrospective study included all adult trauma patients transferred from other hospitals to a Level-I trauma center during 2014. Indications for repeated CT scans were categorized into: inadequate CT image data transfer, poor image quality, repetition of head CT after head injury together with completion to whole-body CT (WBCT), and follow-up of injury known from previous CT. Radiation doses from repeated CT were determined; costs were calculated using a nation-wide fee schedule. Results: Within one year, 85/298 (28.5%) trauma patients were transferred from another hospital because of severe head injury (n = 45,53%) and major body trauma (n = 23;27%) not manageable in the referring hospital, repatriation from a foreign country (n = 14;16.5%), and no ICU-capacity (n = 3;3.5%). Of these 85 patients, 74 (87%) had repeated CT in our center because of inadequate CT data transfer (n = 29;39%), repetition of head CT with completion to WBCT (n = 24;32.5%), and follow-up of known injury (n = 21;28.5%). None occurred because of poor image quality. Cumulative dose length product (DLP) and annual costs of potential preventable, repeated CT (inadequate data transfer) was 631mSv (81′304mGy*cm) and 35′233€, respectively. Conclusion: A considerable number of transferred trauma patients undergo potentially preventable, repeated CT, adding radiation dose to patients and costs to the health care system.

  19. Repeated exposure to the thin ideal and implications for the self : Two weight loss program studies

    NARCIS (Netherlands)

    Klesse, A.K.; Goukens, C.; Geyskens, K.; de Ruyter, K.

    2012-01-01

    Exposure to thin models results in self-esteem shifts that influence people's motivation to diet. This research study applies a goal perspective to explain the effect of exposure to thin models on dieters' motivation to lose weight. Two (one-week) weight loss program studies that included treatment

  20. Hippocampal Regulation of Contextual Cue-Induced Reinstatement of Cocaine-Seeking Behavior

    OpenAIRE

    Atkins, Alison L.; Mashhoon, Yasmin; Kantak, Kathleen M.

    2008-01-01

    Associations between cocaine and cues facilitate development and maintenance of addiction. We hypothesized that the ventral hippocampus is important for acquisition of these associations. Rats were trained to self-administer cocaine, with or without pre-exposure to distinct sets of cocaine- and saline-paired contextual cues. Next, rats were conditioned for 3 days with the distinct sets of contextual cues paired with cocaine and saline along with distinct discrete cues. Vehicle or lidocaine wa...

  1. Repeated exposures to blue light-activated eosin Y enhance inactivation of E. faecalis biofilms, in vitro.

    Science.gov (United States)

    Marinic, Karlo; Manoil, Daniel; Filieri, Anna; Wataha, John C; Schrenzel, Jacques; Lange, Norbert; Bouillaguet, Serge

    2015-09-01

    In dentistry, antibacterial photodynamic therapy (a-PDT) has shown promising results for inactivating bacterial biofilms causing carious, endodontic and periodontal diseases. In the current study, we assessed the ability of eosin Y exposed to 3 irradiation protocols at inactivating Enterococcus faecalis biofilms, in vitro. E. faecalis biofilms formed on hydroxyapatite disks were incubated with eosin Y (10-80μM), then activated with blue light using different irradiation protocols. Biofilms exposed to continuous exposure were incubated for 40min before being light-activated for 960 s. For the intermittent exposure, biofilms were exposed 4 times to the light/photosensitizer combination (960 s total) without renewing the photosensitizer. For repeated a-PDT, the same light dose was delivered in a series of 4 irradiation periods separated by dark periods; fresh photosensitizer was added between each light irradiation. After treatment, bacteria were immediately labeled with LIVE/DEAD BacLight Bacterial Viability kit and viability was assessed by flow cytometry (FCM). Results were statistically analyzed using one-way ANOVA and Tukey multiple comparison intervals (α=0.05). The viability of E. faecalis biofilms exposed to 10μM eosin Y, was significantly reduced compared to controls (light only-eosin Y only). After a second exposure to blue light-activated eosin Y, viability significantly decreased from 58% to 12% whereas 6.5% of the bacterial biofilm remained live after a third exposure (p<0.05). Only 3.5% of the bacterial population survived after the fourth exposure. The results of this study indicate that blue light-activated eosin Y can photoinactivate E. faecalis biofilms grown on hydroxyapatite disks. Also, repeated exposures to blue light-activated eosin Y were shown to significantly improve efficacy. Further studies seem warranted to optimize the antibacterial activity of blue light-activated eosin Y on major oral pathogens. Copyright © 2015 Elsevier B.V. All

  2. The root of the problem: increasing root vegetable intake in preschool children by repeated exposure and flavour flavour learning.

    Science.gov (United States)

    Ahern, Sara M; Caton, Samantha J; Blundell, Pam; Hetherington, Marion M

    2014-09-01

    Children's vegetable consumption falls below current recommendations, highlighting the need to identify strategies that can successfully promote intake. The current study aimed to investigate the effectiveness of flavour-flavour learning as one such strategy for increasing vegetable intake in preschool children. Children (N = 29) aged 15 to 56 months were recruited through participating nurseries. Each received a minimum of six and maximium eight exposures to a root vegetable puree with added apple puree (flavour-flavour learning) alternating with six to eight exposures to another with nothing added (repeated exposure). A third puree acted as a control. Pre- and post-intervention intake measures of the three purees with nothing added were taken to assess change in intake. Follow-up measures took place 1 month (n = 28) and 6 months (n = 10) post-intervention. Intake increased significantly from pre- to post-intervention for all purees (~36 g), with no effect of condition. Magnitude of change was smaller in the control condition. Analysis of follow-up data showed that intake remained significantly higher than baseline 1 month (p exposure increases intake of a novel vegetable in young children. Results also suggest that mere exposure (to the food, the experimenters, the procedure) can generalise to other, similar vegetables but the addition of a familiar flavour confers no added advantage above mere exposure. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Changes of lead speciation and microbial toxicity in soil treated with repeated Pb exposure in the presence of BDE209.

    Science.gov (United States)

    Zhang, Rong; Zhang, Wei; Liu, Gao; Lin, Kuangfei; Fu, Rongbing

    2016-03-01

    Lead (Pb) and decabromodiphenyl ether (BDE209) are main pollutants at electric waste (e-waste) recycling sites (EWRSs), and their joint toxicological effects have received extensive attention. Frequently, soil pollution at EWRSs usually results from the occurrence of repeated single or multiple pollution events, with continuous impacts on soil microorganisms. Therefore, a laboratory incubation study was conducted to determine Pb bioavailability and microbial toxicity in repeated Pb-polluted soil in the presence of BDE209 for the first time. We evaluated the impacts of repetitive exposure trials on chemical fractions of Pb, and the results showed that repeated single Pb pollution event resulted in an increase of carbonates fraction of Pb, which was different from one-off single Pb exposure. Moreover, one-off Pb-treated groups exhibited higher I R (reduced partition index) values on day 30 and all treatments remained the same I R level at the end of incubation period. The parameters of microbial toxicity were well reflected by soil enzymes. During the entire incubation, the dehydrogenase and urease activities were significantly inhibited by Pb (P soil enzymes were clearly observed (P < 0.05 or 0.01). Such observations would provide useful information for ecological effects of Pb and BDE209 at EWRSs.

  4. Protective effect of curcumin on pulmonary and cardiovascular effects induced by repeated exposure to diesel exhaust particles in mice.

    Directory of Open Access Journals (Sweden)

    Abderrahim Nemmar

    Full Text Available Particulate air pollution has been associated with increased risk of cardiopulmonary diseases. However, the underlying mechanisms are not fully understood. We have previously demonstrated that single dose exposure to diesel exhaust particle (DEP causes lung inflammation and peripheral thrombotic events. Here, we exposed mice with repeated doses of DEP (15 µg/animal every 2(nd day for 6 days (a total of 4 exposures, and measured several cardiopulmonary endpoints 48 h after the end of the treatments. Moreover, the potential protective effect of curcumin (the yellow pigment isolated from turmeric on DEP-induced cardiopulmonary toxicity was assessed. DEP exposure increased macrophage and neutrophil numbers, tumor necrosis factor α (TNF α in the bronchoalveolar lavage (BAL fluid, and enhanced airway resistance to methacoline measured invasively using Flexivent. DEP also significantly increased plasma C-reactive protein (CRP and TNF α concentrations, systolic blood pressure (SBP as well as the pial arteriolar thrombosis. It also significantly enhanced the plasma D-dimer and plasminogen activator inhibitor-1 (PAI-1. Pretreatment with curcumin by oral gavage (45 mg/kg 1 h before exposure to DEP significantly prevented the influx of inflammatory cells and the increase of TNF α in BAL, and the increased airway resistance caused by DEP. Likewise, curcumin prevented the increase of SBP, CRP, TNF α, D-dimer and PAI-1. The thrombosis was partially but significantly mitigated. In conclusion, repeated exposure to DEP induced lung and systemic inflammation characterized by TNFα release, increased SBP, and accelerated coagulation. Our findings indicate that curcumin is a potent anti-inflammatory agent that prevents the release of TNFα and protects against the pulmonary and cardiovascular effects of DEP.

  5. Combined Study of Titanium Dioxide Nanoparticle Transport and Toxicity on Microbial Nitrifying Communities under Single and Repeated Exposures in Soil Columns.

    Science.gov (United States)

    Simonin, Marie; Martins, Jean M F; Uzu, Gaëlle; Vince, Erwann; Richaume, Agnès

    2016-10-04

    Soils are exposed to nanoparticles (NPs) as a result of their increasing use in many commercial products. Adverse effects of NPs on soil microorganisms have been reported in several ecotoxicological studies using microcosms. Although repeated exposures are more likely to occur in soils, most of these previous studies were performed as a single exposure to NPs. Contrary to single contamination, the study of multiple NP contaminations in soils requires the use of specialized setups. Using a soil column experiment, we compared the influence of single and repeated exposures (one, two, or three exposures that resulted in the same final concentration applied) on the transport of titanium dioxide (TiO 2 ) NPs through soil and the effect of these different exposure scenarios on the abundance and activity of soil nitrifying microbial communities after a 2 month incubation. The transport of TiO 2 NPs was very limited under both single and repeated exposures and was highest for the lowest concentration injected during the first application. Significant decreases in nitrification activity and ammonia-oxidizing archaea and bacteria populations were observed only for the repeated exposure scenario (three TiO 2 NP contaminations). These results suggest that, under repeated exposures, the transport of TiO 2 NPs to deep soil layers and groundwater is limited and that a chronic contamination is more harmful for the soil microbiological functioning than a single exposure.

  6. Repeated exposure of the developing rat brain to magnetic resonance imaging did not affect neurogenesis, cell death or memory function

    International Nuclear Information System (INIS)

    Zhu, Changlian; Gao, Jianfeng; Li, Qian; Huang, Zhiheng; Zhang, Yu; Li, Hongfu; Kuhn, Hans-Georg; Blomgren, Klas

    2011-01-01

    Research highlights: → The effect of MRI on the developing brain is a matter of debate. → Repeated exposure to MRI did not affect neurogenesis. → Memory function was not affected by repeated MRI during development. → Neither late gestation nor young postnatal brains were affected by MRI. → Repeated MRI did not cause cell death in the neurogenic region of the hippocampus. -- Abstract: The effect of magnetic fields on the brain is a matter of debate. The objective of this study was to investigate whether repeated exposure to strong magnetic fields, such as during magnetic resonance imaging (MRI), could elicit changes in the developing rat brain. Embryonic day 15 (E15) and postnatal day 14 (P14) rats were exposed to MRI using a 7.05 T MR system. The animals were anesthetized and exposed for 35 min per day for 4 successive days. Control animals were anesthetized but no MRI was performed. Body temperature was maintained at 37 o C. BrdU was injected after each session (50 mg/kg). One month later, cell proliferation, neurogenesis and astrogenesis in the dentate gyrus were evaluated, revealing no effects of MRI, neither in the E15, nor in the P14 group. DNA damage in the dentate gyrus in the P14 group was evaluated on P18, 1 day after the last session, using TUNEL staining. There was no difference in the number of TUNEL-positive cells after MRI compared with controls, neither in mature neurons, nor in newborn progenitors (BrdU/TUNEL double-labeled cells). Novel object recognition was performed to assess memory function 1 month after MRI. There was no difference in the recognition index observed after MRI compared with the control rats, neither for the E15, nor for the P14 group. In conclusion, repeated exposure to MRI did not appear to affect neurogenesis, cell death or memory function in rats, neither in late gestation (E15-E18) nor in young postnatal (P14-P17) rats.

  7. Evaluation of Pulmonary and Systemic Toxicity of Oil Dispersant (COREXIT EC9500A(®)) Following Acute Repeated Inhalation Exposure.

    Science.gov (United States)

    Roberts, Jenny R; Anderson, Stacey E; Kan, Hong; Krajnak, Kristine; Thompson, Janet A; Kenyon, Allison; Goldsmith, William T; McKinney, Walter; Frazer, David G; Jackson, Mark; Fedan, Jeffrey S

    2014-01-01

    Oil spill cleanup workers come into contact with numerous potentially hazardous chemicals derived from the oil spills, as well as chemicals applied for mitigation of the spill, including oil dispersants. In response to the Deepwater Horizon Macondo well oil spill in the Gulf of Mexico in 2010, a record volume of the oil dispersant, COREXIT EC9500A, was delivered via aerial applications, raising concern regarding potential health effects that may result from pulmonary exposure to the dispersant. The current study examined the effects on pulmonary functions, cardiovascular functions, and systemic immune responses in rats to acute repeated inhalation exposure of COREXIT EC9500A at 25 mg/m(3), five hours per day, over nine work days, or filtered air (control). At one and seven days following the last exposure, a battery of parameters was measured to evaluate lung function, injury, and inflammation; cardiovascular function; peripheral vascular responses; and systemic immune responses. No significant alterations in airway reactivity were observed at one or seven days after exposure either in baseline values or following methacholine (MCh) inhalation challenge. Although there was a trend for an increase in lung neutrophils and phagocyte oxidant production at one-day post exposure, there were no significant differences in parameters of lung inflammation. In addition, increased blood monocytes and neutrophils, and decreased lymphocyte numbers at one-day post exposure also did not differ significantly from air controls, and no alterations in splenocyte populations, or serum or spleen immunoglobulin M (IgM) to antigen were observed. There were no significant differences in peripheral vascular responsiveness to vasoconstrictor and vasodilator agonists or in blood pressure (BP) responses to these agents; however, the baseline heart rate (HR) and HR responses to isoproterenol (ISO) were significantly elevated at one-day post exposure, with resolution by day 7. In summary, acute

  8. Evaluation of Pulmonary and Systemic Toxicity of Oil Dispersant (COREXIT EC9500A following Acute Repeated Inhalation Exposure

    Directory of Open Access Journals (Sweden)

    Jenny R. Roberts

    2014-01-01

    Full Text Available Introduction Oil spill cleanup workers come into contact with numerous potentially hazardous chemicals derived from the oil spills, as well as chemicals applied for mitigation of the spill, including oil dispersants. In response to the Deepwater Horizon Macondo well oil spill in the Gulf of Mexico in 2010, a record volume of the oil dispersant, COREXIT EC9500A, was delivered via aerial applications, raising concern regarding potential health effects that may result from pulmonary exposure to the dispersant. Methods The current study examined the effects on pulmonary functions, cardiovascular functions, and systemic immune responses in rats to acute repeated inhalation exposure of COREXIT EC9500A at 25 mg/m 3 , five hours per day, over nine work days, or filtered air (control. At one and seven days following the last exposure, a battery of parameters was measured to evaluate lung function, injury, and inflammation; cardiovascular function; peripheral vascular responses; and systemic immune responses. Results No significant alterations in airway reactivity were observed at one or seven days after exposure either in baseline values or following metha-choline (MCh inhalation challenge. Although there was a trend for an increase in lung neutrophils and phagocyte oxidant production at one-day post exposure, there were no significant differences in parameters of lung inflammation. In addition, increased blood monocytes and neutrophils, and decreased lymphocyte numbers at one-day post exposure also did not differ significantly from air controls, and no alterations in splenocyte populations, or serum or spleen immunoglobulin M (IgM to antigen were observed. There were no significant differences in peripheral vascular responsiveness to vasoconstrictor and vasodilator agonists or in blood pressure (BP responses to these agents; however, the baseline heart rate (HR and HR responses to isoproterenol (ISO were significantly elevated at one-day post exposure

  9. Functional consequences of cocaine expectation: findings in a non-human primate model of cocaine self-administration.

    Science.gov (United States)

    Porrino, Linda J; Beveridge, Thomas J R; Smith, Hilary R; Nader, Michael A

    2016-05-01

    Exposure to stimuli and environments associated with drug use is considered one of the most important contributors to relapse among substance abusers. Neuroimaging studies have identified neural circuits underlying these responses in cocaine-dependent subjects. But these studies are often difficult to interpret because of the heterogeneity of the participants, substances abused, and differences in drug histories and social variables. Therefore, the goal of this study was to assess the functional effects of exposure to cocaine-associated stimuli in a non-human primate model of cocaine self-administration, providing precise control over these variables, with the 2-[(14) C]deoxyglucose method. Rhesus monkeys self-administered 0.3 mg/kg/injection cocaine (n = 4) under a fixed-interval 3-minute (FI 3-min) schedule of reinforcement (30 injections/session) for 100 sessions. Control animals (n = 4) underwent identical schedules of food reinforcement. Sessions were then discontinued for 30 days, after which time, monkeys were exposed to cocaine- or food-paired cues, and the 2-[(14) C]deoxyglucose experiment was conducted. The presentation of the cocaine-paired cues resulted in significant increases in functional activity within highly restricted circuits that included portions of the pre-commissural striatum, medial prefrontal cortex, rostral temporal cortex and limbic thalamus when compared with control animals presented with the food-paired cues. The presentation of cocaine-associated cues increased brain functional activity in contrast to the decreases observed after cocaine consumption. Furthermore, the topography of brain circuits engaged by the expectation of cocaine is similar to the distribution of effects during the earliest phases of cocaine self-administration, prior to the onset of neuroadaptations that accompany chronic cocaine exposure. © 2015 Society for the Study of Addiction.

  10. Neurophysiological effects of modafinil on cue-exposure in cocaine dependence: a randomized placebo-controlled cross-over study using pharmacological fMRI

    NARCIS (Netherlands)

    Goudriaan, Anna E.; Veltman, Dick J.; van den Brink, Wim; Dom, Geert; Schmaal, Lianne

    2013-01-01

    Enhanced reactivity to substance related cues is a central characteristic of addiction and has been associated with increased activity in motivation, attention, and memory related brain circuits and with a higher probability of relapse. Modafinil was promising in the first clinical trials in cocaine

  11. Distribution of dearomatised white spirit in brain, blood, and fat tissue after repeated exposure of rats

    DEFF Research Database (Denmark)

    Lof, A.; Lam, Henrik Rye; Gullstrand, E.

    1999-01-01

    Petroleum products with low content of aromatics have been increasingly used during the past years. This study investigates tissue disposition of dearomatised white spirit. In addition, brain neurotransmitter concentrations were measured. Male rats were exposed by inhalation to 0, 400 (2.29 mg....../l), or 800 p.p.m. (4.58 mg/l) of dearomatised white spirit, 6 hr/day, 5 days/week up to 3 weeks. Five rats from each group were sacrificed immediately after the exposure for 1, 2, or 3 weeks and 2, 4, 6, or 24 hr after the end of 3 weeks' exposure. After 3 weeks of exposure the concentration of total white...... spirit was 1.5 and 5.6 mg/kg in blood; 7.1 and 17.1 mg/kg in brain; 432 and 1452 mg/kg in fat tissue at the exposure levels of 400 and 800 p.p.m., respectively. The concentrations of n-nonane, n-decane, n-undecane, and total white spirit in blood and brain were not affected by the duration of exposure...

  12. Beyond Extinction: Prolonged Conditioning and Repeated Threat Exposure Abolish Contextual Renewal of Fear-Potentiated Startle Discrimination but Leave Expectancy Ratings Intact.

    Science.gov (United States)

    Leer, Arne; Haesen, Kim; Vervliet, Bram

    2018-01-01

    Extinction treatments decrease fear via repeated exposures to the conditioned stimulus (CS) and are associated with a return of fear. Alternatively, fear can be reduced via reductions in the perceived intensity of the unconditioned stimulus (US), e.g., through repeated exposures to the US. Promisingly, the few available studies show that repeated US exposures outperform standard extinction. US exposure treatments can decrease fear via two routes: (1) by weakening the CS-US association (extinction-like mechanism), and/or (2) by weakening the subjective US aversiveness (habituation-like mechanism). The current study further investigated the conditions under which US exposure treatment may reduce renewal, by adding a group in which CS-US pairings continued following fear acquisition. During acquisition, participants learned that one of two visual stimuli (CS+/CS-) predicted the occurrence of an aversive electrocutaneous stimulus (US). Next, the background context changed and participants received one of three interventions: repeated CS exposures, (2) repeated US exposures, or (3) continued CS-US pairings. Following repeated CS exposures, test presentations of the CSs in the original conditioning context revealed intact CS+/CS- differentiation in the fear-potentiated startle reflex, while the differentiation was abolished in the other two groups. Differential US expectancy ratings, on the other hand, were intact in all groups. Skin conductance data were inconclusive because standard context renewal following CS exposures did not occur. Unexpectedly, there was no evidence for a habituation-like process having taken place during US exposures or continued CS-US pairings. The results provide further evidence that US exposures outperform the standard extinction treatment and show that effects are similar when US exposures are part of CS-US pairings.

  13. Photoprotection due to pigmentation and epidermal thickness after repeated exposure to ultraviolet light and psoralen plus ultraviolet A therapy

    Energy Technology Data Exchange (ETDEWEB)

    Bech-Thomsen, N.; Wulf, H.C. [Rigshospitalet, The National Univ. Hospital, Dept. of Dermatology, Lab. of Photobiology, Copenhagen (Denmark)

    1995-10-01

    Tanning and thickening of the epidermis are cardinal defensive responses of human skin to ultraviolet (UV) radiation that lead to increased photoprotection. Earlier studies have shown that skin pigmentation can be used to predict minimal erythema dose and minimal phototoxic dose. In this study it was calculated how much of the increase in photoprotection after 4 weeks of repeated exposure to suberythemogenic doses of either UVA or UVB radiation sources or psoralen plus UVA (PUVA) therapy that was attributable to melanogenesis. The backs of 12 volunteers were exposed to 6 different UVA and UVB radiation sources 9 times during 4 weeks. Skin pigmentation was assessed by skin reflectance measuring. Photoprotection was determined from the minimal erythema dose. Melanogenesis accounted for 63-95% of the increase in photoprotection after 4 weeks of exposure to UVA radiation. Exposure to two UVB sources induced a significant increase in photoprotection but not in pigmentation. Melanogenesis accounted only for 6-11% of the increase in photoprotection after 4 weeks of UVB exposure. The pigmentary and photoprotective responses to PUVA therapy were followed in 14 patients. After 2 weeks of exposure, the increase in photoprotection was significantly higher than predicted form the increase in skin pigmentation. After 4 weeks, melanogenesis accounted for only 36% of the increase in photoprotection. This study shows that melanogenesis accounts for the increased photoprotection after 2 weeks of exposure to UVA radiation, but after 4 weeks other protective mechanisms occur during suberythemal UVB exposure and during PUVA therapy the importance of skin pigmentation in the overall photoprotection gradually decreases during a 4-week irradiation period. (au) 17 refs.

  14. Photoprotection due to pigmentation and epidermal thickness after repeated exposure to ultraviolet light and psoralen plus ultraviolet A therapy

    International Nuclear Information System (INIS)

    Bech-Thomsen, N.; Wulf, H.C.

    1995-01-01

    Tanning and thickening of the epidermis are cardinal defensive responses of human skin to ultraviolet (UV) radiation that lead to increased photoprotection. Earlier studies have shown that skin pigmentation can be used to predict minimal erythema dose and minimal phototoxic dose. In this study it was calculated how much of the increase in photoprotection after 4 weeks of repeated exposure to suberythemogenic doses of either UVA or UVB radiation sources or psoralen plus UVA (PUVA) therapy that was attributable to melanogenesis. The backs of 12 volunteers were exposed to 6 different UVA and UVB radiation sources 9 times during 4 weeks. Skin pigmentation was assessed by skin reflectance measuring. Photoprotection was determined from the minimal erythema dose. Melanogenesis accounted for 63-95% of the increase in photoprotection after 4 weeks of exposure to UVA radiation. Exposure to two UVB sources induced a significant increase in photoprotection but not in pigmentation. Melanogenesis accounted only for 6-11% of the increase in photoprotection after 4 weeks of UVB exposure. The pigmentary and photoprotective responses to PUVA therapy were followed in 14 patients. After 2 weeks of exposure, the increase in photoprotection was significantly higher than predicted form the increase in skin pigmentation. After 4 weeks, melanogenesis accounted for only 36% of the increase in photoprotection. This study shows that melanogenesis accounts for the increased photoprotection after 2 weeks of exposure to UVA radiation, but after 4 weeks other protective mechanisms occur during suberythemal UVB exposure and during PUVA therapy the importance of skin pigmentation in the overall photoprotection gradually decreases during a 4-week irradiation period. (au) 17 refs

  15. Altered reward sensitivity in female offspring of cocaine-exposed fathers.

    Science.gov (United States)

    Fischer, Delaney K; Rice, Richard C; Martinez Rivera, Arlene; Donohoe, Mary; Rajadhyaksha, Anjali M

    2017-08-14

    Recent rodent studies have demonstrated that parental cocaine exposure can influence offspring behavior, supporting the idea that environmental insults can impact subsequent generations. However, studies on the effects of paternal cocaine exposure are limited and multiple inconsistencies exist. In the current study, we behaviorally characterize the effects of paternal cocaine exposure in a C57BL/6J intergenerational mouse model. Male sires were administered cocaine hydrochloride (20mg/kg) or saline (0.01mL/g) once a day for 75days, and bred with drug naïve females twenty-four hours after the final injection. Offspring, separated by sex, were tested in a battery of behaviors. We found that paternal cocaine exposure altered sensitivity to the rewarding and stimulant effects of psychostimulants and natural reward (sucrose) in female offspring; female cocaine-sired offspring showed blunted cocaine preference using cocaine conditioned place preference (CPP) at a low dose (5mg/kg), but displayed similar preference at a higher dose (10mg/kg) compared to saline-sired controls. Additionally, cocaine-sired female offspring exhibited higher psychomotor sensitivity to cocaine (10mg/kg) and amphetamine (2mg/kg) and consumed more sucrose. Cocaine-sired males exhibited increased psychomotor effects of cocaine and amphetamine. Male offspring also displayed an anxiety-like phenotype. No effect of paternal cocaine exposure was observed on depressive-like, learning and memory or social behavior in male or female offspring. Collectively, our findings show that paternal, chronic cocaine exposure induces intergenerational behavioral effects in male and female offspring with greatest impact on sensitivity to psychostimulants and sucrose in females. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Distribution of silver in rats following 28 days of repeated oral exposure to silver nanoparticles or silver acetate

    DEFF Research Database (Denmark)

    Löschner, Katrin; Hadrup, Niels; Qvortrup, Klaus

    2011-01-01

    Background: The study investigated the distribution of silver after 28 days repeated oral administration of silver nanoparticles (AgNPs) and silver acetate (AgAc) to rats. Oral administration is a relevant route of exposure because of the use of silver nanoparticles in products related to food...... and food contact materials. Results: AgNPs were synthesized with a size distribution of 14 ± 4 nm in diameter (90% of the nanoparticle volume) and stabilized in aqueous suspension by the polymer polyvinylpyrrolidone (PVP). The AgNPs remained stable throughout the duration of the 28-day oral toxicity study...... in rats. The organ distribution pattern of silver following administration of AgNPs and AgAc was similar. However the absolute silver concentrations in tissues were lower following oral exposure to AgNPs. This was in agreement with an indication of a higher fecal excretion following administration of Ag...

  17. Behavioral stress may increase the rewarding valence of cocaine-associated cues through a dynorphin/kappa-opioid receptor-mediated mechanism without affecting associative learning or memory retrieval mechanisms.

    Science.gov (United States)

    Schindler, Abigail G; Li, Shuang; Chavkin, Charles

    2010-08-01

    Stress exposure increases the risk of addictive drug use in human and animal models of drug addiction by mechanisms that are not completely understood. Mice subjected to repeated forced swim stress (FSS) before cocaine develop significantly greater conditioned place preference (CPP) for the drug-paired chamber than unstressed mice. Analysis of the dose dependency showed that FSS increased both the maximal CPP response and sensitivity to cocaine. To determine whether FSS potentiated CPP by enhancing associative learning mechanisms, mice were conditioned with cocaine in the absence of stress, then challenged after association was complete with the kappa-opioid receptor (KOR) agonist U50,488 or repeated FSS, before preference testing. Mice challenged with U50,488 60 min before CPP preference testing expressed significantly greater cocaine-CPP than saline-challenged mice. Potentiation by U50,488 was dose and time dependent and blocked by the KOR antagonist norbinaltorphimine (norBNI). Similarly, mice subjected to repeated FSS before the final preference test expressed significantly greater cocaine-CPP than unstressed controls, and FSS-induced potentiation was blocked by norBNI. Novel object recognition (NOR) performance was not affected by U50,488 given 60 min before assay, but was impaired when given 15 min before NOR assay, suggesting that KOR activation did not potentiate CPP by facilitating memory retrieval or expression. The results from this study show that the potentiation of cocaine-CPP by KOR activation does not result from an enhancement of associative learning mechanisms and that stress may instead enhance the rewarding valence of cocaine-associated cues by a dynorphin-dependent mechanism.

  18. Effect of Acute, Subacute, and Repeated Exposure to High Altitude (5050 m on Psychomotor Vigilance

    Directory of Open Access Journals (Sweden)

    Matiram Pun

    2018-06-01

    Full Text Available Aim: High altitude (HA hypoxia may affect cognitive performance and sleep quality. Further, vigilance is reduced following sleep deprivation. We investigated the effect on vigilance, actigraphic sleep indices, and their relationships with acute mountain sickness (AMS during very HA exposure, acclimatization, and re-exposure.Methods: A total of 21 healthy altitude-naive individuals (25 ± 4 years; 13 females completed 2 cycles of altitude exposure separated by 7 days at low altitude (LA, 520 m. Participants slept at 2900 m and spent the day at HA, (5050 m. We report acute altitude exposure on Day 1 (LA vs. HA1 and after 6 days of acclimatization (HA1 vs. HA6. Vigilance was quantified by reaction speed in the 10-min psychomotor vigilance test reaction speed (PVT-RS. AMS was evaluated using the Environmental Symptoms Questionnaire Cerebral Score (AMS-C score. Nocturnal rest/activity was recorded to estimate sleep duration using actigraphy.Results: In Cycle 1, PVT-RS was slower at HA1 compared to LA (4.1 ± 0.8 vs. 4.5 ± 0.6 s-1, respectively, p = 0.029, but not at HA6 (4.6 ± 0.7; p > 0.05. In Cycle 2, PVT-RS at HA1 (4.6 ± 0.7 and HA6 (4.8 ± 0.6 were not different from LA (4.8 ± 0.6, p > 0.05 and significantly greater than corresponding values in Cycle 1. In both cycles, AMS scores were higher at HA1 than at LA and HA6 (p < 0.05. Estimated sleep durations (TST at LA, 1st and 5th nights were 431.3 ± 28.7, 418.1 ± 48.6, and 379.7 ± 51.4 min, respectively, in Cycle 1 and they were significantly reduced during acclimatization exposures (LA vs. 1st night, p > 0.05; LA vs. 5th night, p = 0.012; and 1st vs. 5th night, p = 0.054. LA, 1st and 5th nights TST in Cycle 2 were 477.5 ± 96.9, 430.9 ± 34, and 341.4 ± 32.2, respectively, and we observed similar deteriorations in TST as in Cycle 1 (LA vs. 1st night, p > 0.05; LA vs. 5th night, p = 0.001; and 1st vs. 5th night, p < 0.0001. At HA1, subjects who reported higher AMS-C scores exhibited slower

  19. Distinctive adaptive response to repeated exposure to hydrogen peroxide associated with upregulation of DNA repair genes and cell cycle arrest

    Directory of Open Access Journals (Sweden)

    Gloria A. Santa-Gonzalez

    2016-10-01

    Full Text Available Many environmental and physiological stresses are chronic. Thus, cells are constantly exposed to diverse types of genotoxic insults that challenge genome stability, including those that induce oxidative DNA damage. However, most in vitro studies that model cellular response to oxidative stressors employ short exposures and/or acute stress models. In this study, we tested the hypothesis that chronic and repeated exposure to a micromolar concentration of hydrogen peroxide (H2O2 could activate DNA damage responses, resulting in cellular adaptations. For this purpose, we developed an in vitro model in which we incubated mouse myoblast cells with a steady concentration of ~50 μM H2O2 for one hour daily for seven days, followed by a final challenge of a 10 or 20X higher dose of H2O2 (0.5 or 1 mM. We report that intermittent long-term exposure to this oxidative stimulus nearly eliminated cell toxicity and significantly decreased genotoxicity (in particular, a >5-fold decreased in double-strand breaks resulting from subsequent acute exposure to oxidative stress. This protection was associated with cell cycle arrest in G2/M and induction of expression of nine DNA repair genes. Together, this evidence supports an adaptive response to chronic, low-level oxidative stress that results in genomic protection and up-regulated maintenance of cellular homeostasis.

  20. Brain imaging studies of the cocaine addict: Implications for reinforcement and addiction

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D.; Fowler, J.S. [Brookhaven National Lab., Upton, NY (United States)]|[SUNY, Stony Brook, Stony Brook, NY (United States). Dept. of Psychiatry

    1995-07-01

    These studies document dopaminergic abnormalities in cocaine abusers. They also suggest a regulatory role of Dopamine (DA) in frontal metabolism. The correlation of striatal D{sub 2} receptor availability with metabolism was strongest for orbital frontal cortex (OFC) cingulate and prefrontal cortices. In cocaine abusers tested during early withdrawal (<1 week) the OFC was found to be hypermetabolic and metabolism in OFC and prefrontal cortices were found to be significantly associated with cocaine craving . Thus, we postulate that repeated and intermittent DA stimulation, as seen during a cocaine binge, activates the prefrontal and OFC cortices increasing the drive to compulsively self-administer cocaine. During cocaine discontinuation and protracted withdrawal and with decreased DA stimulation, these frontal cortical regions become hyponietabolic. Dopaminergic stimulation by a DA-enhancing drug and/or environmental conditioning will reactivate these frontal regions resetting the compulsion to self-administer cocaine and the inability to terminate this behavior. The pharmacokionetic studies with [11C]cocaine are consistent with behavioral and pharmacological studies in animals as well as in vitro studies which have revealed that while the mechanisms for cocaine`s reinforcing properties are complex, they partly involve the brain`s dopamine system and also highlight the importance of cocaine`s pharmacokinetic on its unique reinforcing properties.

  1. Repeated Exposure to Neurotoxic Levels of Chlorpyriphos Alters Hippocampal Expression of Neurotrophins and Neuropeptides

    Science.gov (United States)

    2016-01-13

    hormone bindi Bdnf BDNF Brain-derived neurotrophic factor Mdk MDK Midkine (neurite growth -promoting fa Rbp4 RBP4 Retinol binding protein 4, plasma...cause cholinergic crisis are associated with problems in cognitive function (i.e., learning and memory deficits ), but the biological mechanism(s...neurobehavioral deficits following subchronic exposure to CPF at a level that inhibits hippocampal cholinesterase to less than 20% of control. An equally

  2. Cannabis, Cocaine and Jobs

    NARCIS (Netherlands)

    van Ours, J.C.

    2005-01-01

    This paper uses a dataset collected among inhabitants of Amsterdam, to study the employment effects of the use of cannabis and cocaine.For females no negative effects of drug use on the employment rate are found.For males there is a negative correlation between past cannabis and cocaine use and

  3. Writing content predicts benefit from written expressive disclosure: Evidence for repeated exposure and self-affirmation.

    Science.gov (United States)

    Niles, Andrea N; Byrne Haltom, Kate E; Lieberman, Matthew D; Hur, Christopher; Stanton, Annette L

    2016-01-01

    Expressive disclosure regarding a stressful event improves psychological and physical health, yet predictors of these effects are not well established. The current study assessed exposure, narrative structure, affect word use, self-affirmation and discovery of meaning as predictors of anxiety, depressive and physical symptoms following expressive writing. Participants (N = 50) wrote on four occasions about a stressful event and completed self-report measures before writing and three months later. Essays were coded for stressor exposure (level of detail and whether participants remained on topic), narrative structure, self-affirmation and discovery of meaning. Linguistic Inquiry and Word Count software was used to quantify positive and negative affect word use. Controlling for baseline anxiety, more self-affirmation and detail about the event predicted lower anxiety symptoms, and more negative affect words (very high use) and more discovery of meaning predicted higher anxiety symptoms three months after writing. Findings highlight the importance of self-affirmation and exposure as predictors of benefit from expressive writing.

  4. Perinatal protein deprivation facilitates morphine cross-sensitization to cocaine and enhances ΔFosB expression in adult rats.

    Science.gov (United States)

    Perondi, María Cecilia; Gutiérrez, María Cecilia; Valdomero, Analía; Cuadra, Gabriel Ricardo

    2017-08-30

    Previous studies have indicated that neural changes induced by early nutritional insult cause an altered response to pharmacological treatments, including addictive drugs. This study evaluates the influence of perinatal protein malnutrition in developing cross-sensitization to cocaine-induced rewarding effects in animals pre-exposed to morphine. Different groups of well-nourished (C-rats) and protein-deprived animals (D-rats) were treated twice a day for three days with increasing doses of morphine or with saline. After 3days, the incentive motivational effects of cocaine were assessed in a Conditioned Place Preference paradigm in both groups. In saline pre-treated animals, dose-response curves to cocaine revealed a conditioning effect in D-rats at doses of 5, 7.5 and 10mg/kg, while this effect was observed in C-rats only with 10 and 15mg/kg. Furthermore, when animals of both groups were pre-treated with escalating doses of morphine, cross-sensitization to the conditioning effect of cocaine was elicited only in D-rats with low doses of cocaine (5 and 7.5mg/kg). In contrast, under the same experimental conditions, C-rats show no cross-sensitization. To correlate this differential rewarding response with a molecular substrate linked to the behavioral changes observed after repeated drug exposure, ΔFosB expression was assessed in different brain regions. D-rats showed a significant increase in this transcription factor in the nucleus accumbens, amygdala and medial prefrontal cortex. These results demonstrated that perinatal protein deprivation facilitates rewarding effects and the development of cross-sensitization to cocaine, which correlates with an upregulation of ΔFosB in brain areas related to the reward circuitry. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Preventive effect of curcumin and its highly bioavailable preparation on hearing loss induced by single or repeated exposure to noise: A comparative and mechanistic study

    Directory of Open Access Journals (Sweden)

    Taro Yamaguchi

    2017-08-01

    Full Text Available We sought to determine the preventive effects of curcumin and its highly bioavailable preparation on noise-induced hearing loss in a novel murine model of permanent hearing loss developed by repeated exposure to noise. Upon exposure to noise (8-kHz octave band noise, 90 dB sound pressure level, 1 h, hearing ability was impaired in a temporary and reversible manner. During repeated noise exposure (1-h exposure per day, 5 days, there was a progressive increase in the auditory threshold shift at 12 and 20 kHz. The threshold shift persisted for at least 6 days after noise exposure. Oral administration of curcumin for 3 days before and each day during noise exposure significantly alleviated the hearing loss induced by repeated noise exposure. Curcumin abolished intranuclear translocation of nuclear factor-κB-p65 and generation of 4-hydroxynonenal-adducted proteins found in the cochlea after noise exposure. Theracurmin®, a highly absorbable and bioavailable preparation of curcumin, had strong preventive effects on hearing loss induced by repeated noise exposure. Together, these data suggest that curcumin exerts a preventive effect on noise-induced hearing loss and is therefore a good therapeutic candidate for preventing sensorineural hearing loss.

  6. Preventive effect of curcumin and its highly bioavailable preparation on hearing loss induced by single or repeated exposure to noise: A comparative and mechanistic study.

    Science.gov (United States)

    Yamaguchi, Taro; Yoneyama, Masanori; Onaka, Yusuke; Imaizumi, Atsushi; Ogita, Kiyokazu

    2017-08-01

    We sought to determine the preventive effects of curcumin and its highly bioavailable preparation on noise-induced hearing loss in a novel murine model of permanent hearing loss developed by repeated exposure to noise. Upon exposure to noise (8-kHz octave band noise, 90 dB sound pressure level, 1 h), hearing ability was impaired in a temporary and reversible manner. During repeated noise exposure (1-h exposure per day, 5 days), there was a progressive increase in the auditory threshold shift at 12 and 20 kHz. The threshold shift persisted for at least 6 days after noise exposure. Oral administration of curcumin for 3 days before and each day during noise exposure significantly alleviated the hearing loss induced by repeated noise exposure. Curcumin abolished intranuclear translocation of nuclear factor-κB-p65 and generation of 4-hydroxynonenal-adducted proteins found in the cochlea after noise exposure. Theracurmin ® , a highly absorbable and bioavailable preparation of curcumin, had strong preventive effects on hearing loss induced by repeated noise exposure. Together, these data suggest that curcumin exerts a preventive effect on noise-induced hearing loss and is therefore a good therapeutic candidate for preventing sensorineural hearing loss. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  7. Cue-induced craving in patients with cocaine use disorder predicts cognitive control deficits toward cocaine cues.

    Science.gov (United States)

    DiGirolamo, Gregory J; Smelson, David; Guevremont, Nathan

    2015-08-01

    Cue-induced craving is a clinically important aspect of cocaine addiction influencing ongoing use and sobriety. However, little is known about the relationship between cue-induced craving and cognitive control toward cocaine cues. While studies suggest that cocaine users have an attentional bias toward cocaine cues, the present study extends this research by testing if cocaine use disorder patients (CDPs) can control their eye movements toward cocaine cues and whether their response varied by cue-induced craving intensity. Thirty CDPs underwent a cue exposure procedure to dichotomize them into high and low craving groups followed by a modified antisaccade task in which subjects were asked to control their eye movements toward either a cocaine or neutral drug cue by looking away from the suddenly presented cue. The relationship between breakdowns in cognitive control (as measured by eye errors) and cue-induced craving (changes in self-reported craving following cocaine cue exposure) was investigated. CDPs overall made significantly more errors toward cocaine cues compared to neutral cues, with higher cravers making significantly more errors than lower cravers even though they did not differ significantly in addiction severity, impulsivity, anxiety, or depression levels. Cue-induced craving was the only specific and significant predictor of subsequent errors toward cocaine cues. Cue-induced craving directly and specifically relates to breakdowns of cognitive control toward cocaine cues in CDPs, with higher cravers being more susceptible. Hence, it may be useful identifying high cravers and target treatment toward curbing craving to decrease the likelihood of a subsequent breakdown in control. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Adolescent cocaine self-administration induces habit behavior in adulthood: sex differences and structural consequences

    Science.gov (United States)

    DePoy, L M; Allen, A G; Gourley, S L

    2016-01-01

    Adolescent cocaine use increases the likelihood of drug abuse and addiction in adulthood, and etiological factors may include a cocaine-induced bias towards so-called ‘reward-seeking' habits. To determine whether adolescent cocaine exposure indeed impacts decision-making strategies in adulthood, we trained adolescent mice to orally self-administer cocaine. In adulthood, males with a history of escalating self-administration developed a bias towards habit-based behaviors. In contrast, escalating females did not develop habit biases; rather, low response rates were associated with later behavioral inflexibility, independent of cocaine dose. We focused the rest of our report on understanding how individual differences in young-adolescent females predicted long-term behavioral outcomes. Low, ‘stable' cocaine-reinforced response rates during adolescence were associated with cocaine-conditioned object preference and enlarged dendritic spine head size in the medial (prelimbic) prefrontal cortex in adulthood. Meanwhile, cocaine resilience was associated with enlarged spine heads in deep-layer orbitofrontal cortex. Re-exposure to the cocaine-associated context in adulthood energized responding in ‘stable responders', which could then be reduced by the GABAB agonist baclofen and the putative tyrosine receptor kinase B (trkB) agonist, 7,8-dihydroxyflavone. Together, our findings highlight resilience to cocaine-induced habits in females relative to males when intake escalates. However, failures in instrumental conditioning in adolescent females may precipitate reward-seeking behaviors in adulthood, particularly in the context of cocaine exposure. PMID:27576164

  9. Baseline repeated measures from controlled human exposure studies: associations between ambient air pollution exposure and the systemic inflammatory biomarkers IL-6 and fibrinogen.

    Science.gov (United States)

    Thompson, Aaron M S; Zanobetti, Antonella; Silverman, Frances; Schwartz, Joel; Coull, Brent; Urch, Bruce; Speck, Mary; Brook, Jeffrey R; Manno, Michael; Gold, Diane R

    2010-01-01

    Systemic inflammation may be one of the mechanisms mediating the association between ambient air pollution and cardiovascular morbidity and mortality. Interleukin-6 (IL-6) and fibrinogen are biomarkers of systemic inflammation that are independent risk factors for cardio-vascular disease. We investigated the association between ambient air pollution and systemic inflammation using baseline measurements of IL-6 and fibrinogen from controlled human exposure studies. In this retrospective analysis we used repeated-measures data in 45 nonsmoking subjects. Hourly and daily moving averages were calculated for ozone, nitrogen dioxide, sulfur dioxide, and particulate matter pollutants on systemic IL-6 and fibrinogen. Effect modification by season was considered. We observed a positive association between IL-6 and O3 [0.31 SD per O3 interquartile range (IQR); 95% confidence interval (CI), 0.080.54] and between IL-6 and SO2 (0.25 SD per SO2 IQR; 95% CI, 0.060.43). We observed the strongest effects using 4-day moving averages. Responses to pollutants varied by season and tended to be higher in the summer, particularly for O3 and PM2.5. Fibrinogen was not associated with pollution. This study demonstrates a significant association between ambient pollutant levels and baseline levels of systemic IL-6. These findings have potential implications for controlled human exposure studies. Future research should consider whether ambient pollution exposure before chamber exposure modifies IL-6 response.

  10. 21 CFR 862.3250 - Cocaine and cocaine metabolite test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cocaine and cocaine metabolite test system. 862... Test Systems § 862.3250 Cocaine and cocaine metabolite test system. (a) Identification. A cocaine and cocaine metabolite test system is a device intended to measure cocaine and a cocaine metabolite...

  11. [Cocaine - Characteristics and addiction].

    Science.gov (United States)

    Girczys-Połedniok, Katarzyna; Pudlo, Robert; Jarząb, Magdalena; Szymlak, Agnieszka

    Cocaine use leads to health, social and legal problems. The aim of this paper is to discuss cocaine action, addicts characteristics, use patterns and consequences, as well as addiction treatment methods. A literature review was based on the Medline, PubMed, Polish Medical Bibliography databases and the Silesian Library resources. The Police and Central Statistical Office statistics, as well as the World Health Organization, the European Monitoring Centre for Drugs and Drug Addiction and the National Office for Combating Drug Addiction reports were used. Cocaine leads to mood improvement, appetite decrease, physical and intellectual activity enhancement, euphoria, inflated self-esteem, social networking ease and increased sexual desire. Cocaine hydrochloride is mainly used intranasaly, but also as intravenous and subcutaneous injections. Cocaine use and first addiction treatment fall in later age compared to other psychoactive substances. There is a high men to women ratio among addicts. There is a relationship between cocaine addiction, the presence of other disorders and genetic predisposition to addiction development. Polish reports indicate higher popularity of cocaine among people with a high economic and social status. Although Poland is a country with the low percentage of cocaine use, its popularity is growing. The consequences of cocaine use concern somatic and mental health problems, socioeconomic and legal conditions. The drug plays a role in crimes and traffic accidents. Because of the risks associated with cocaine use, it has been listed in a register of drugs attached to the Act on Counteracting Drug Addiction. Addiction treatment includes psychological, pharmacological and harm reduction strategies. Med Pr 2016;67(4):537-544. This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.

  12. Driving simulator sickness: Impact on driving performance, influence of blood alcohol concentration, and effect of repeated simulator exposures.

    Science.gov (United States)

    Helland, Arne; Lydersen, Stian; Lervåg, Lone-Eirin; Jenssen, Gunnar D; Mørland, Jørg; Slørdal, Lars

    2016-09-01

    Simulator sickness is a major obstacle to the use of driving simulators for research, training and driver assessment purposes. The purpose of the present study was to investigate the possible influence of simulator sickness on driving performance measures such as standard deviation of lateral position (SDLP), and the effect of alcohol or repeated simulator exposure on the degree of simulator sickness. Twenty healthy male volunteers underwent three simulated driving trials of 1h's duration with a curvy rural road scenario, and rated their degree of simulator sickness after each trial. Subjects drove sober and with blood alcohol concentrations (BAC) of approx. 0.5g/L and 0.9g/L in a randomized order. Simulator sickness score (SSS) did not influence the primary outcome measure SDLP. Higher SSS significantly predicted lower average speed and frequency of steering wheel reversals. These effects seemed to be mitigated by alcohol. Higher BAC significantly predicted lower SSS, suggesting that alcohol inebriation alleviates simulator sickness. The negative relation between the number of previous exposures to the simulator and SSS was not statistically significant, but is consistent with habituation to the sickness-inducing effects, as shown in other studies. Overall, the results suggest no influence of simulator sickness on SDLP or several other driving performance measures. However, simulator sickness seems to cause test subjects to drive more carefully, with lower average speed and fewer steering wheel reversals, hampering the interpretation of these outcomes as measures of driving impairment and safety. BAC and repeated simulator exposures may act as confounding variables by influencing the degree of simulator sickness in experimental studies. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Hematological effects of four ethylene glycol monoalkyl ethers in short-term repeated exposure in rats

    Energy Technology Data Exchange (ETDEWEB)

    Starek, Andrzej [Jagiellonian University, Department of Biochemical Toxicology, Medical College, Krakow (Poland); Szymczak, Wieslaw [University of Lodz, Institute of Psychology, Lodz (Poland); Zapor, Lidia [Central Institute for Labour Protection National Research Institute, Laboratory of Toxicology, Department of Chemical and Aerosol Hazards, Warsaw (Poland)

    2008-02-15

    This study was carried out to compare the hematological effects of 2-methoxyethanol (ME), 2-ethoxyethanol (EE), 2-isopropoxyethanol (IPE), and 2-butoxyethanol (BE) in short-term studies in rats. Male rats were subcutaneously treated with ME or EE at a dosage of 0, 1.25, 2.5 and 5.0 mM/kg in saline, 5 days per week, for 4 weeks. Other rats were exposed to IPE or BE at doses of 0, 0.25, 0.5, 0.75 and 1.25 mM/kg in the same manner. Administration of each chemical, except of ME, resulted in a time- and dose-dependent swelling of erythrocytes as evidenced by an increase in mean corpuscular volume (MCV). Subsequently, red blood cells (RBC), packed cell volumes (PCV), hemoglobin concentration (HGB), and mean cell hemoglobin concentration (MCHC) decreased. Furthermore, an increase in mean cell hemoglobin (MCH) and reticulocyte counts was observed. The onset of hemolysis induced by EE, IPE or BE was faster than after ME administration. While in rats exposed to ME hematological changes were strongly pronounced and progressively increased with exposure time beginning from the day 11, those in animals treated with EE were rather persisted at low constant level for all exposure period. In contrast, the rats exposed to IPE and BE demonstrated the dramatic hematological changes more pronounced in case of BE than IPE at the beginning of exposure (on day 4). Despite of exposure duration, these changes were regressed, although the decrease in RBC and MCHC and the increase in MCV and MCH in rats treated with highest doses of both compound (0.5, 0.75, and 1.25 mM/kg) were more persistent, probably due to selective hemolysis of the aged erythrocytes. In addition, significant leukopenia due to reduction of lymphocytes in rats exposed to ME was observed. In summary, this study demonstrated no tolerance to ME- and EE-induced intravascular hemolysis developed under these experimental conditions. On the contrary, tolerance to IPE- and BE-induced hemolysis in rats exposed to these compounds

  14. Arsenic induced apoptosis in rat liver following repeated 60 days exposure

    International Nuclear Information System (INIS)

    Bashir, Somia; Sharma, Yukti; Irshad, M.; Nag, T.C.; Tiwari, Monica; Kabra, M.; Dogra, T.D.

    2006-01-01

    Background: Accumulation of the wide spread environmental toxin arsenic in liver results in hepatotoxcity. Exposure to arsenite and other arsenicals has been previously shown to induce apoptosis in certain tumor cell lines at low (1-3 μM) concentration. Aim: The present study was focused to elucidate the role of free radicals in arsenic toxicity and to investigate the nature of in vivo sodium arsenite induced cell death in liver. Methods: Male wistar rats were exposed to arsenite at three different doses of 0.05, 2.5 and 5 mg/l for 60 days. Oxidative stress in liver was measured by estimating pro-oxidant and antioxidant activity in liver. Histopathological examination of liver was carried out by light and transmission electron microscopy. Analysis of DNA fragmentation by gel electrophoresis was used to identify apoptosis after the exposure. Terminal deoxy-nucleotidyl transferase mediated dUTP Nick end-labeling (TUNEL) assay was used to qualify and quantify apoptosis. Results: A significant increase in cytochrome-P450 and lipid peroxidation accompanied with a significant alteration in the activity of many of the antioxidants was observed, all suggestive of arsenic induced oxidative stress. Histopathological examination under light and transmission electron microscope suggested a combination of ongoing necrosis and apoptosis. DNA-TUNEL showed an increase in apoptotic cells in liver. Agarose gel electrophoresis of DNA of hepatocytes resulted in a characteristic ladder pattern. Conclusion: Chronic arsenic administration induces a specific pattern of apoptosis called post-mitotic apoptosis

  15. Protective effect of SP600125 against liver cell injury in rats under repeated and sustained high +Gz exposure

    Directory of Open Access Journals (Sweden)

    Wen-bing LI

    2015-01-01

    Full Text Available Objective To explore the effect of JNK inhibitor SP600125 on expression of JNK/c-jun in liver cells of rats under repeated and sustained high +Gz exposure and its mechanism of the effect. Methods Eighteen inbred adult male Wistar rats were randomly divided into control group, +10Gz group and SP600125 group (n=6. The rats in +10Gz group and SP600125 group were fixed to the rotating arm of a centrifuge with head towards the axis. The increase rate of acceleration was 1G/s with a peak-time of 3 minutes, and the +Gz exposure was repeated 5 times with an interval of 30 minutes. SP600125 was given to rats of SP600125 group 30 minutes before the first centrifugation by intraperitoneal injection. All of the animals were sacrificed 30 minutes after centrifugation. Blood samples were collected from inferior vena cava to determine the plasma level of aspartate aminotransferase (AST and alanine aminotransferase (ALT. The expression of c-jun mRNA was determined by quantitative real-time RT-PCR (qRTPCR. The expressions of p-JNK, JNK, p-c-jun and c-jun protein were determined by Western blotting. The morphological change in the liver tissue was observed after HE staining. Results The plasma level of ALT and AST, expression level of c-jun mRNA and p-JNK, p-c-jun, c-jun protein in the liver tissue of SP600125 group were significantly higher than those of control group (P0.05. HE staining revealed disorganized hepatic cords, irregular liver cells, vacuolar changes, and marked edema of hepatocytes, and collapsed hepatic sinusoids in +10Gz group, but these changes were alleviated obviously in SP600125 group. Conclusion SP600125 could alleviate the liver cell injury in rats under repeated and sustained high +Gz exposure. DOI: 10.11855/j.issn.2577-7402.2014.11.02

  16. Serotonin 2B Receptors in Mesoaccumbens Dopamine Pathway Regulate Cocaine Responses.

    Science.gov (United States)

    Doly, Stéphane; Quentin, Emily; Eddine, Raphaël; Tolu, Stefania; Fernandez, Sebastian P; Bertran-Gonzalez, Jesus; Valjent, Emmanuel; Belmer, Arnauld; Viñals, Xavier; Callebert, Jacques; Faure, Philippe; Meye, Frank J; Hervé, Denis; Robledo, Patricia; Mameli, Manuel; Launay, Jean-Marie; Maldonado, Rafael; Maroteaux, Luc

    2017-10-25

    Addiction is a maladaptive pattern of behavior following repeated use of reinforcing drugs in predisposed individuals, leading to lifelong changes. Common among these changes are alterations of neurons releasing dopamine in the ventral and dorsal territories of the striatum. The serotonin 5-HT 2B receptor has been involved in various behaviors, including impulsivity, response to antidepressants, and response to psychostimulants, pointing toward putative interactions with the dopamine system. Despite these findings, it remains unknown whether 5-HT 2B receptors directly modulate dopaminergic activity and the possible mechanisms involved. To answer these questions, we investigated the contribution of 5-HT 2B receptors to cocaine-dependent behavioral responses. Male mice permanently lacking 5-HT 2B receptors, even restricted to dopamine neurons, developed heightened cocaine-induced locomotor responses. Retrograde tracing combined with single-cell mRNA amplification indicated that 5-HT 2B receptors are expressed by mesolimbic dopamine neurons. In vivo and ex vivo electrophysiological recordings showed that 5-HT 2B -receptor inactivation in dopamine neurons affects their neuronal activity and increases AMPA-mediated over NMDA-mediated excitatory synaptic currents. These changes are associated with lower ventral striatum dopamine activity and blunted cocaine self-administration. These data identify the 5-HT 2B receptor as a pharmacological intermediate and provide mechanistic insight into attenuated dopamine tone following exposure to drugs of abuse. SIGNIFICANCE STATEMENT Here we report that mice lacking 5-HT 2B receptors totally or exclusively in dopamine neurons exhibit heightened cocaine-induced locomotor responses. Despite the sensitized state of these mice, we found that associated changes include lower ventral striatum dopamine activity and lower cocaine operant self-administration. We described the selective expression of 5-HT 2B receptors in a subpopulation of

  17. Previous Repeated Exposure to Food Limitation Enables Rats to Spare Lipid Stores during Prolonged Starvation.

    Science.gov (United States)

    McCue, Marshall D; Albach, Audrey; Salazar, Giovanni

    The risk of food limitation and, ultimately, starvation dates back to the dawn of heterotrophy in animals, yet starvation remains a major factor in the regulation of modern animal populations. Researchers studying starvation more than a century ago suggested that animals subjected to sublethal periods of food limitation are somehow more tolerant of subsequent starvation events. This possibility has received little attention over the past decades, yet it is highly relevant to modern science for two reasons. First, animals in natural populations are likely to be exposed to bouts of food limitation once or more before they face prolonged starvation, during which the risk of mortality becomes imminent. Second, our current approach to studying starvation physiology in the laboratory focuses on nourished animals with no previous exposure to nutritional stress. We examined the relationship between previous exposure to food limitation and potentially adaptive physiological responses to starvation in adult rats and found several significant differences. On two occasions, rats were fasted until they lost 20% of their body mass maintained lower body temperatures, and had presumably lower energy requirements when subjected to prolonged starvation than their naive cohort that never experienced food limitation. These rats that were trained in starvation also had lower plasma glucose set -points and reduced their reliance on endogenous lipid oxidation. These findings underscore (1) the need for biologists to revisit the classic hypothesis that animals can become habituated to starvation, using a modern set of research tools; and (2) the need to design controlled experiments of starvation physiology that more closely resemble the dynamic nature of food availability.

  18. Extinction Training Regulates Neuroadaptive Responses to Withdrawal from Chronic Cocaine Self-Administration

    OpenAIRE

    Self, David W.; Choi, Kwang-Ho; Simmons, Diana; Walker, John R.; Smagula, Cynthia S.

    2004-01-01

    Cocaine produces multiple neuroadaptations with chronic repeated use. Many of these neuroadaptations can be reversed or normalized by extinction training during withdrawal from chronic cocaine self-administration in rats. This article reviews our past and present studies on extinction-induced modulation of the neuroadaptive response to chronic cocaine in the mesolimbic dopamine system, and the role of this modulation in addictive behavior in rats. Extinction training normalizes tyrosine hydro...

  19. Detection of local inflammation induced by repeated exposure to contact allergens by use of IVIS SpectrumCT analyses

    DEFF Research Database (Denmark)

    Nielsen, Morten M.; Schmidt, Jonas D.; Christensen, Jan P.

    2017-01-01

    Background: Contact allergy is characterized by local skin inflammation that, in some cases, can result in systemic immune activation. Objectives: To investigate whether IVIS SpectrumCT analyses can be used to detect the immune response induced by contact allergens. Methods: Mice were repeatedly...... exposed to vehicle or allergens on the ears. The local and systemic responses were analysed at different times with the ProSense 750 FAST probe in IVIS SpectrumCT measurements. In addition, changes in ear thickness, cytokine profile in the skin and immunological phenotype in the draining lymph nodes...... and spleen were determined. Results: Local inflammation was detected by ProSense 750 FAST and correlated with changes in ear thickness, cytokine profile and immunological phenotype following exposure to the strong contact allergen 2,4-dinitrofluorobenzene. Analysis of the systemic response with ProSense 750...

  20. Gender-specific association of functional prodynorphin 68 bp repeats with cannabis exposure in an African American cohort

    Directory of Open Access Journals (Sweden)

    Yuferov V

    2018-04-01

    Full Text Available Vadim Yuferov,* Eduardo R Butelman,* Mary Jeanne Kreek Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA *These authors contributed equally to this work Background: Cannabis use disorders (CUDs cause substantial neuropsychiatric morbidity and comorbidity. There is evidence for gender-based differences in CUDs, for instance, a greater prevalence in males than in females. The main active component of cannabis is delta 9-tetrahydrocannabinol (delta 9-THC, a partial agonist of the cannabinoid type 1 receptor. Preclinical studies show that genetic or pharmacological manipulation of the kappa opioid receptor/dynorphin system modulates the effects of delta 9-THC. Methods: In this case-control study of adult African Americans (n=476; 206 females, 270 males, we examined the association of the functional prodynorphin 68 bp (PDYN 68 bp promoter repeats with categorical diagnoses of cannabis dependence (Diagnostic and Statistical Manual of Mental Disorders-IV criteria, as well as with a rapid dimensional measure of maximum lifetime cannabis exposure (the Kreek–McHugh–Schluger–Kellogg cannabis scale. Results: The PDYN 68 bp genotype (examined as short–short [SS], short–long [SL], or long–long [LL], based on the number of repeats was not significantly associated with categorical cannabis-dependence diagnoses, either in males or in females. However, in males, the PDYN 68 bp SS+SL genotype was associated with both greater odds of any use of cannabis (p<0.05 and earlier age of first cannabis use, compared to the LL genotype (ie, 15 versus 16.5 years of age; p<0.045. Males in the SS+SL group also had greater odds of high lifetime exposure to cannabis, compared to the LL group (p<0.045. Of interest, none of the aforementioned genetic associations were significant in females. Conclusion: This study provides the first data on how the PDYN 68 bp genotype is associated with gender-specific patterns of

  1. Tualang Honey Protects the Rat Midbrain and Lung against Repeated Paraquat Exposure

    Directory of Open Access Journals (Sweden)

    Suk Peng Tang

    2017-01-01

    Full Text Available Paraquat (PQ is a dopaminergic neurotoxin and a well-known pneumotoxicant that exerts its toxic effect via oxidative stress-mediated cellular injuries. This study investigated the protective effects of Tualang honey against PQ-induced toxicity in the midbrain and lungs of rats. The rats were orally treated with distilled water (2 mL/kg/day, Tualang honey (1.0 g/kg/day, or ubiquinol (0.2 g/kg/day throughout the experimental period. Two weeks after the respective treatments, the rats were injected intraperitoneally with saline (1 mL/kg/week or PQ (10 mg/kg/week once per week for four consecutive weeks. After four weekly exposures to PQ, the glutathione peroxidase activity and the number of tyrosine-hydroxylase immunopositive neurons in the midbrain were significantly decreased in animals from group PQ (p<0.05. The lungs of animals from group PQ showed significantly decreased activity of superoxide dismutase and glutathione-S-transferase. Treatment with Tualang honey ameliorated the toxic effects observed in the midbrain and lungs. The beneficial effects of Tualang honey were comparable to those of ubiquinol, which was used as a positive control. These findings suggest that treatment with Tualang honey may protect against PQ-induced toxicity in the rat midbrain and lung.

  2. Tualang Honey Protects the Rat Midbrain and Lung against Repeated Paraquat Exposure.

    Science.gov (United States)

    Tang, Suk Peng; Kuttulebbai Nainamohamed Salam, Sirajudeen; Jaafar, Hasnan; Gan, Siew Hua; Muzaimi, Mustapha; Sulaiman, Siti Amrah

    2017-01-01

    Paraquat (PQ) is a dopaminergic neurotoxin and a well-known pneumotoxicant that exerts its toxic effect via oxidative stress-mediated cellular injuries. This study investigated the protective effects of Tualang honey against PQ-induced toxicity in the midbrain and lungs of rats. The rats were orally treated with distilled water (2 mL/kg/day), Tualang honey (1.0 g/kg/day), or ubiquinol (0.2 g/kg/day) throughout the experimental period. Two weeks after the respective treatments, the rats were injected intraperitoneally with saline (1 mL/kg/week) or PQ (10 mg/kg/week) once per week for four consecutive weeks. After four weekly exposures to PQ, the glutathione peroxidase activity and the number of tyrosine-hydroxylase immunopositive neurons in the midbrain were significantly decreased in animals from group PQ ( p honey ameliorated the toxic effects observed in the midbrain and lungs. The beneficial effects of Tualang honey were comparable to those of ubiquinol, which was used as a positive control. These findings suggest that treatment with Tualang honey may protect against PQ-induced toxicity in the rat midbrain and lung.

  3. Tualang Honey Protects the Rat Midbrain and Lung against Repeated Paraquat Exposure

    Science.gov (United States)

    Sulaiman, Siti Amrah

    2017-01-01

    Paraquat (PQ) is a dopaminergic neurotoxin and a well-known pneumotoxicant that exerts its toxic effect via oxidative stress-mediated cellular injuries. This study investigated the protective effects of Tualang honey against PQ-induced toxicity in the midbrain and lungs of rats. The rats were orally treated with distilled water (2 mL/kg/day), Tualang honey (1.0 g/kg/day), or ubiquinol (0.2 g/kg/day) throughout the experimental period. Two weeks after the respective treatments, the rats were injected intraperitoneally with saline (1 mL/kg/week) or PQ (10 mg/kg/week) once per week for four consecutive weeks. After four weekly exposures to PQ, the glutathione peroxidase activity and the number of tyrosine-hydroxylase immunopositive neurons in the midbrain were significantly decreased in animals from group PQ (p honey ameliorated the toxic effects observed in the midbrain and lungs. The beneficial effects of Tualang honey were comparable to those of ubiquinol, which was used as a positive control. These findings suggest that treatment with Tualang honey may protect against PQ-induced toxicity in the rat midbrain and lung. PMID:28127418

  4. Conditioned Contribution of Peripheral Cocaine Actions to Cocaine Reward and Cocaine-Seeking

    OpenAIRE

    Wang, Bin; You, Zhi-Bing; Oleson, Erik B; Cheer, Joseph F; Myal, Stephanie; Wise, Roy A

    2013-01-01

    Cocaine has actions in the peripheral nervous system that reliably precede—and thus predict—its soon-to-follow central rewarding effects. In cocaine-experienced animals, the peripheral cocaine signal is relayed to the central nervous system, triggering excitatory input to the ventral tegmental origin of the mesocorticolimbic dopamine system, the system that mediates the rewarding effects of the drug. We used cocaine methiodide, a cocaine analog that does not cross the blood–brain barrier, to ...

  5. Gender-specific association of functional prodynorphin 68 bp repeats with cannabis exposure in an African American cohort.

    Science.gov (United States)

    Yuferov, Vadim; Butelman, Eduardo R; Kreek, Mary Jeanne

    2018-01-01

    Cannabis use disorders (CUDs) cause substantial neuropsychiatric morbidity and comorbidity. There is evidence for gender-based differences in CUDs, for instance, a greater prevalence in males than in females. The main active component of cannabis is delta 9-tetrahydrocannabinol (delta 9-THC), a partial agonist of the cannabinoid type 1 receptor. Preclinical studies show that genetic or pharmacological manipulation of the kappa opioid receptor/dynorphin system modulates the effects of delta 9-THC. In this case-control study of adult African Americans (n=476; 206 females, 270 males), we examined the association of the functional prodynorphin 68 bp ( PDYN 68 bp) promoter repeats with categorical diagnoses of cannabis dependence ( Diagnostic and Statistical Manual of Mental Disorders-IV criteria), as well as with a rapid dimensional measure of maximum lifetime cannabis exposure (the Kreek-McHugh-Schluger-Kellogg cannabis scale). The PDYN 68 bp genotype (examined as short-short [SS], short-long [SL], or long-long [LL], based on the number of repeats) was not significantly associated with categorical cannabis-dependence diagnoses, either in males or in females. However, in males, the PDYN 68 bp SS+SL genotype was associated with both greater odds of any use of cannabis ( p cannabis use, compared to the LL genotype (ie, 15 versus 16.5 years of age; p cannabis, compared to the LL group ( p cannabis. Overall, this study shows that PDYN 68 bp polymorphisms affect behaviors involved in early stages of nonmedical cannabis use and potentially lead to increasing self-exposure. These data may eventually lead to improvements in personalized medicine for the prevention and treatment of highly prevalent CUDs and neuropsychiatric comorbidities.

  6. Chronic cocaine disrupts neurovascular networks and cerebral function: optical imaging studies in rodents

    Science.gov (United States)

    Zhang, Qiujia; You, Jiang; Volkow, Nora D.; Choi, Jeonghun; Yin, Wei; Wang, Wei; Pan, Yingtian; Du, Congwu

    2016-02-01

    Cocaine abuse can lead to cerebral strokes and hemorrhages secondary to cocaine's cerebrovascular effects, which are poorly understood. We assessed cocaine's effects on cerebrovascular anatomy and function in the somatosensory cortex of the rat's brain. Optical coherence tomography was used for in vivo imaging of three-dimensional cerebral blood flow (CBF) networks and to quantify CBF velocities (CBFv), and multiwavelength laser-speckle-imaging was used to simultaneously measure changes in CBFv, oxygenated (Δ[HbO2]) and deoxygenated hemoglobin (Δ[HbR]) concentrations prior to and after an acute cocaine challenge in chronically cocaine exposed rats. Immunofluorescence techniques on brain slices were used to quantify microvasculature density and levels of vascular endothelial growth factor (VEGF). After chronic cocaine (2 and 4 weeks), CBFv in small vessels decreased, whereas vasculature density and VEGF levels increased. Acute cocaine further reduced CBFv and decreased Δ[HbO2] and this decline was larger and longer lasting in 4 weeks than 2 weeks cocaine-exposed rats, which indicates that risk for ischemia is heightened during intoxication and that it increases with chronic exposures. These results provide evidence of cocaine-induced angiogenesis in cortex. The CBF reduction after chronic cocaine exposure, despite the increases in vessel density, indicate that angiogenesis was insufficient to compensate for cocaine-induced disruption of cerebrovascular function.

  7. Neuronal changes and oxidative stress in adolescent rats after repeated exposure to mephedrone

    International Nuclear Information System (INIS)

    López-Arnau, Raúl; Martínez-Clemente, José; Rodrigo, Teresa; Pubill, David; Camarasa, Jorge; Escubedo, Elena

    2015-01-01

    Mephedrone is a new designer drug of abuse. We have investigated the neurochemical/enzymatic changes after mephedrone administration to adolescent rats (3 × 25 mg/kg, s.c. in a day, with a 2 h interval between doses, for two days) at high ambient temperature (26 ± 2 °C), a schedule that intends to model human recreational abuse. In addition, we have studied the effect of mephedrone in spatial learning and memory. The drug caused a transient decrease in weight gain. After the first dose, animals showed hypothermia but, after the subsequent doses, temperature raised over the values of saline-treated group. We observed the development of tolerance to these thermoregulatory effects of mephedrone. Mephedrone induced a reduction of the densities of dopamine (30% in the frontal cortex) and serotonin (40% in the frontal cortex and the hippocampus and 48% in the striatum) transporters without microgliosis. These deficits were also accompanied by a parallel decrease in the expression of tyrosine hydroxylase and tryptophan hydroxylase 2. These changes matched with a down-regulation of D 2 dopamine receptors in the striatum. Mephedrone also induced an oxidative stress evidenced by an increase of lipid peroxidation in the frontal cortex, and accompanied by a rise in glutathione peroxidase levels in all studied brain areas. Drug-treated animals displayed an impairment of the reference memory in the Morris water maze one week beyond the cessation of drug exposure, while the spatial learning process seems to be preserved. These findings raise concerns about the neuronal long-term effects of mephedrone. - Highlights: • We studied the dopaminergic and serotonergic neurotoxicity of mephedrone in rats. • Mephedrone induced a transient hypothermia following sustained hyperthermia. • In a weekend consumption pattern, mephedrone induced selective neurotoxicity. • Mephedrone generated oxidative stress. • Mephedrone induced an impairment in memory function

  8. Neuronal changes and oxidative stress in adolescent rats after repeated exposure to mephedrone

    Energy Technology Data Exchange (ETDEWEB)

    López-Arnau, Raúl; Martínez-Clemente, José [Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section), Faculty of Pharmacy, University of Barcelona (Spain); Institute of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona (Spain); Rodrigo, Teresa [Animal Experimentation Unit of Psychology and Pharmacy, University of Barcelona (Spain); Pubill, David [Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section), Faculty of Pharmacy, University of Barcelona (Spain); Institute of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona (Spain); Camarasa, Jorge, E-mail: jcamarasa@ub.edu [Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section), Faculty of Pharmacy, University of Barcelona (Spain); Institute of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona (Spain); Escubedo, Elena [Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section), Faculty of Pharmacy, University of Barcelona (Spain); Institute of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona (Spain)

    2015-07-01

    Mephedrone is a new designer drug of abuse. We have investigated the neurochemical/enzymatic changes after mephedrone administration to adolescent rats (3 × 25 mg/kg, s.c. in a day, with a 2 h interval between doses, for two days) at high ambient temperature (26 ± 2 °C), a schedule that intends to model human recreational abuse. In addition, we have studied the effect of mephedrone in spatial learning and memory. The drug caused a transient decrease in weight gain. After the first dose, animals showed hypothermia but, after the subsequent doses, temperature raised over the values of saline-treated group. We observed the development of tolerance to these thermoregulatory effects of mephedrone. Mephedrone induced a reduction of the densities of dopamine (30% in the frontal cortex) and serotonin (40% in the frontal cortex and the hippocampus and 48% in the striatum) transporters without microgliosis. These deficits were also accompanied by a parallel decrease in the expression of tyrosine hydroxylase and tryptophan hydroxylase 2. These changes matched with a down-regulation of D{sub 2} dopamine receptors in the striatum. Mephedrone also induced an oxidative stress evidenced by an increase of lipid peroxidation in the frontal cortex, and accompanied by a rise in glutathione peroxidase levels in all studied brain areas. Drug-treated animals displayed an impairment of the reference memory in the Morris water maze one week beyond the cessation of drug exposure, while the spatial learning process seems to be preserved. These findings raise concerns about the neuronal long-term effects of mephedrone. - Highlights: • We studied the dopaminergic and serotonergic neurotoxicity of mephedrone in rats. • Mephedrone induced a transient hypothermia following sustained hyperthermia. • In a weekend consumption pattern, mephedrone induced selective neurotoxicity. • Mephedrone generated oxidative stress. • Mephedrone induced an impairment in memory function.

  9. The Role of Hypothalamic Insulin and Dopamine in the Anorectic Effect of Cocaine and d-amphetamine

    Science.gov (United States)

    1992-08-21

    smoking free-base cocaine, or smoking crack, and (5) smoking coca-paste (cocaine-sulfate, usually smoked with tobacco or cannabis ). Cocaine is a...Exposure to cocaine involves a wide variety of physiological, neurochemical, behavioral, and psychological consequences. The pharmacology and toxicology ...agonists. Neuropharmacology, 21, 885-890. Asghar, K., & De Souza, E. (1989). Pharmacology and toxicology of amphetamine and related designer drugs. NIDA

  10. Blockade of group II metabotropic glutamate receptors produces hyper-locomotion in cocaine pre-exposed rats by interactions with dopamine receptors.

    Science.gov (United States)

    Yoon, Hyung Shin; Jang, Ju Kyong; Kim, Jeong-Hoon

    2008-09-01

    It was previously reported that blockade of group II metabotropic glutamate receptors (mGluRs) produces hyper-locomotion in rats previously exposed to amphetamine, indicating that group II mGluRs are well positioned to modulate the expression of behavioral sensitization by amphetamine. The present study further examined the locomotor activating effects of specific blockade of these receptors after cocaine pre-exposures. First, rats were pre-exposed to seven daily injections of cocaine (15mg/kg, IP). When challenged the next day with an injection of either saline or the group II mGluR antagonist LY341495 (0.5, 1.0 or 2.5mg/kg, IP), they produced hyper-locomotor activity, measured by infrared beam interruptions, to LY341495 compared to saline in a dose-dependent manner. Second, rats were pre-exposed to either saline or seven daily injections of cocaine (15mg/kg, IP). Three weeks later, when they were challenged with an injection of either saline or LY341495 (1.0mg/kg, IP), only rats pre-exposed to cocaine produced hyper-locomotor activity to LY341495 compared to saline. These effects, however, were not present when dopamine D1 (SCH23390; 5 or 10microg/kg), but not D2 (eticlopride; 10 or 50microg/kg), receptor antagonist was pre-injected, indicating that this cocaine-induced hyper-locomotor activity to LY341495 may be mediated in dopamine D1 receptor-dependent manner. These results suggest that group II mGluRs may be adapted to interact with dopaminergic neuronal signaling in mediating the sensitized locomotor activity produced by repeated cocaine pre-exposures.

  11. Language Outcomes at 12 Years for Children Exposed Prenatally to Cocaine

    Science.gov (United States)

    Lewis, Barbara A.; Minnes, Sonia; Short, Elizabeth J.; Min, Meeyoung O.; Wu, Miaoping; Lang, Adelaide; Weishampel, Paul; Singer, Lynn T.

    2013-01-01

    Purpose: In this study, the authors aimed to examine the long-term effects of prenatal cocaine exposure (PCE) on the language development of 12-year-old children using a prospective design, controlling for confounding prenatal drug exposure and environmental factors. Method: Children who were exposed to cocaine in utero (PCE; "n" = 183)…

  12. Adaptation of the pituitary-adrenal axis to daily repeated forced swim exposure in rats is dependent on the temperature of water.

    Science.gov (United States)

    Rabasa, Cristina; Delgado-Morales, Raúl; Gómez-Román, Almudena; Nadal, Roser; Armario, Antonio

    2013-11-01

    Comparison of exposure to certain predominantly emotional stressors reveals a qualitatively similar neuroendocrine response profile as well as a reduction of physiological responses after daily repeated exposure (adaptation). However, particular physical components of the stressor may interfere with adaptation. As defective adaptation to stress can enhance the probability to develop pathologies, we studied in adult male rats (n = 10/group) swimming behavior (struggling, immobility and mild swim) and physiological responses (ACTH, corticosterone and rectal temperature) to daily repeated exposure to forced swim (20 min, 13 d) at 25 or 36 °C (swim25 or swim36). Rats were repeatedly blood-sampled by tail-nick and hormones measured by radioimmunoassay. Some differences were observed between the two swim temperature groups after the first exposure to forced swim: (a) active behaviors were greater in swim25 than swim36 groups; (b) swim25 but not swim36 caused hypothermia; and (c) swim36 elicited the same ACTH response as swim25, but plasma corticosterone concentration was lower for swim36 at 30 min post-swim. After daily repeated exposure, adaptation in ACTH secretion was observed with swim36 already on day 4, whereas with swim25 adaptation was not observed until day 13 and was of lower magnitude. Nevertheless, after repeated exposure to swim25 a partial protection from hypothermia was observed and the two swim conditions resulted in progressive reduction of active behaviors. Thus, daily repeated swim at 25 °C impairs adaptation of the hypothalamic-pituitary-adrenal axis as compared to swim at 36 °C, supporting the hypothesis that certain physical components of predominantly emotional stressors can interfere with the process of adaptation.

  13. Effect of replacing sugar with non-caloric sweeteners in beverages on the reward value after repeated exposure.

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    Sanne Griffioen-Roose

    Full Text Available BACKGROUND: The reward value of food is partly dependent on learned associations. It is not yet known whether replacing sugar with non-caloric sweeteners in food is affecting long-term acceptance. OBJECTIVE: To determine the effect of replacing sugar with non-caloric sweeteners in a nutrient-empty drink (soft drink versus nutrient-rich drink (yoghurt drink on reward value after repeated exposure. DESIGN: We used a randomized crossover design whereby forty subjects (15 men, 25 women with a mean ± SD age of 21 ± 2 y and BMI of 21.5 ± 1.7 kg/m(2 consumed a fixed portion of a non-caloric sweetened (NS and sugar sweetened (SS versions of either a soft drink or a yoghurt drink (counterbalanced for breakfast which were distinguishable by means of colored labels. Each version of a drink was offered 10 times in semi-random order. Before and after conditioning the reward value of the drinks was assessed using behavioral tasks on wanting, liking, and expected satiety. In a subgroup (n=18 fMRI was performed to assess brain reward responses to the drinks. RESULTS: Outcomes of both the behavioral tasks and fMRI showed that conditioning did not affect the reward value of the NS and SS versions of the drinks significantly. Overall, subjects preferred the yoghurt drinks to the soft drinks and the ss drinks to the NS drinks. In addition, they expected the yoghurt drinks to be more satiating, they reduced hunger more, and delayed the first eating episode more. Conditioning did not influence these effects. CONCLUSION: Our study showed that repeated consumption of a non-caloric sweetened beverage, instead of a sugar sweetened version, appears not to result in changes in the reward value. It cannot be ruled out that learned associations between sensory attributes and food satiating capacity which developed preceding the conditioning period, during lifetime, affected the reward value of the drinks.

  14. Effect of replacing sugar with non-caloric sweeteners in beverages on the reward value after repeated exposure.

    Science.gov (United States)

    Griffioen-Roose, Sanne; Smeets, Paul A M; Weijzen, Pascalle L G; van Rijn, Inge; van den Bosch, Iris; de Graaf, Cees

    2013-01-01

    The reward value of food is partly dependent on learned associations. It is not yet known whether replacing sugar with non-caloric sweeteners in food is affecting long-term acceptance. To determine the effect of replacing sugar with non-caloric sweeteners in a nutrient-empty drink (soft drink) versus nutrient-rich drink (yoghurt drink) on reward value after repeated exposure. We used a randomized crossover design whereby forty subjects (15 men, 25 women) with a mean ± SD age of 21 ± 2 y and BMI of 21.5 ± 1.7 kg/m(2) consumed a fixed portion of a non-caloric sweetened (NS) and sugar sweetened (SS) versions of either a soft drink or a yoghurt drink (counterbalanced) for breakfast which were distinguishable by means of colored labels. Each version of a drink was offered 10 times in semi-random order. Before and after conditioning the reward value of the drinks was assessed using behavioral tasks on wanting, liking, and expected satiety. In a subgroup (n=18) fMRI was performed to assess brain reward responses to the drinks. Outcomes of both the behavioral tasks and fMRI showed that conditioning did not affect the reward value of the NS and SS versions of the drinks significantly. Overall, subjects preferred the yoghurt drinks to the soft drinks and the ss drinks to the NS drinks. In addition, they expected the yoghurt drinks to be more satiating, they reduced hunger more, and delayed the first eating episode more. Conditioning did not influence these effects. Our study showed that repeated consumption of a non-caloric sweetened beverage, instead of a sugar sweetened version, appears not to result in changes in the reward value. It cannot be ruled out that learned associations between sensory attributes and food satiating capacity which developed preceding the conditioning period, during lifetime, affected the reward value of the drinks.

  15. High Throughput Measurement of Locomotor Sensitization to Volatilized Cocaine in Drosophila melanogaster.

    Science.gov (United States)

    Filošević, Ana; Al-Samarai, Sabina; Andretić Waldowski, Rozi

    2018-01-01

    Drosophila melanogaster can be used to identify genes with novel functional roles in neuronal plasticity induced by repeated consumption of addictive drugs. Behavioral sensitization is a relatively simple behavioral output of plastic changes that occur in the brain after repeated exposures to drugs of abuse. The development of screening procedures for genes that control behavioral sensitization has stalled due to a lack of high-throughput behavioral tests that can be used in genetically tractable organism, such as Drosophila . We have developed a new behavioral test, FlyBong, which combines delivery of volatilized cocaine (vCOC) to individually housed flies with objective quantification of their locomotor activity. There are two main advantages of FlyBong: it is high-throughput and it allows for comparisons of locomotor activity of individual flies before and after single or multiple exposures. At the population level, exposure to vCOC leads to transient and concentration-dependent increase in locomotor activity, representing sensitivity to an acute dose. A second exposure leads to further increase in locomotion, representing locomotor sensitization. We validate FlyBong by showing that locomotor sensitization at either the population or individual level is absent in the mutants for circadian genes period (per) , Clock (Clk) , and cycle (cyc) . The locomotor sensitization that is present in timeless (tim) and pigment dispersing factor (pdf) mutant flies is in large part not cocaine specific, but derived from increased sensitivity to warm air. Circadian genes are not only integral part of the neural mechanism that is required for development of locomotor sensitization, but in addition, they modulate the intensity of locomotor sensitization as a function of the time of day. Motor-activating effects of cocaine are sexually dimorphic and require a functional dopaminergic transporter. FlyBong is a new and improved method for inducing and measuring locomotor sensitization

  16. High Throughput Measurement of Locomotor Sensitization to Volatilized Cocaine in Drosophila melanogaster

    Directory of Open Access Journals (Sweden)

    Ana Filošević

    2018-02-01

    Full Text Available Drosophila melanogaster can be used to identify genes with novel functional roles in neuronal plasticity induced by repeated consumption of addictive drugs. Behavioral sensitization is a relatively simple behavioral output of plastic changes that occur in the brain after repeated exposures to drugs of abuse. The development of screening procedures for genes that control behavioral sensitization has stalled due to a lack of high-throughput behavioral tests that can be used in genetically tractable organism, such as Drosophila. We have developed a new behavioral test, FlyBong, which combines delivery of volatilized cocaine (vCOC to individually housed flies with objective quantification of their locomotor activity. There are two main advantages of FlyBong: it is high-throughput and it allows for comparisons of locomotor activity of individual flies before and after single or multiple exposures. At the population level, exposure to vCOC leads to transient and concentration-dependent increase in locomotor activity, representing sensitivity to an acute dose. A second exposure leads to further increase in locomotion, representing locomotor sensitization. We validate FlyBong by showing that locomotor sensitization at either the population or individual level is absent in the mutants for circadian genes period (per, Clock (Clk, and cycle (cyc. The locomotor sensitization that is present in timeless (tim and pigment dispersing factor (pdf mutant flies is in large part not cocaine specific, but derived from increased sensitivity to warm air. Circadian genes are not only integral part of the neural mechanism that is required for development of locomotor sensitization, but in addition, they modulate the intensity of locomotor sensitization as a function of the time of day. Motor-activating effects of cocaine are sexually dimorphic and require a functional dopaminergic transporter. FlyBong is a new and improved method for inducing and measuring locomotor

  17. 17β-Estradiol is required for the sexually dimorphic effects of repeated binge-pattern alcohol exposure on the HPA axis during adolescence.

    Directory of Open Access Journals (Sweden)

    Magdalena M Przybycien-Szymanska

    Full Text Available Alcohol consumption during adolescence has long-term sexually dimorphic effects on anxiety behavior and mood disorders. We have previously shown that repeated binge-pattern alcohol exposure increased the expression of two critical central regulators of stress and anxiety, corticotrophin-releasing hormone (CRH and arginine vasopressin (AVP, in adolescent male rats. By contrast, there was no effect of alcohol on these same genes in adolescent females. Therefore, we tested the hypothesis that 17β-estradiol (E(2, the predominant sex steroid hormone in females, prevents alcohol-induced changes in CRH and AVP gene expression in the paraventricular nucleus (PVN of the hypothalamus. To test this hypothesis, postnatal day (PND 26 females were ovariectomized and given E(2 replacement or cholesterol as a control. Next, they were given an alcohol exposure paradigm of 1 saline alone, 2 acute (single dose or 3 a repeated binge-pattern. Our results showed that acute and repeated binge-pattern alcohol treatment increased plasma ACTH and CORT levels in both E(2- and Ch-treated groups, however habituation to repeated binge-pattern alcohol exposure was evident only in E(2-treated animals. Further, repeated binge-pattern alcohol exposure significantly decreased CRH and AVP mRNA in Ch-, but not E(2-treated animals, which was consistent with our previous observations in gonad intact females. We further tested the effects of E(2 and alcohol treatment on the activity of the wild type CRH promoter in a PVN-derived neuronal cell line. Alcohol increased CRH promoter activity in these cells and concomitant treatment with E(2 completely abolished the effect. Together our data suggest that E(2 regulates the reactivity of the HPA axis to a repeated stressor through modulation of the habituation response and further serves to maintain normal steady state mRNA levels of CRH and AVP in the PVN in response to a repeated alcohol stressor.

  18. Kappa-opioid receptor signaling in the striatum as a potential modulator of dopamine transmission in cocaine dependence

    Directory of Open Access Journals (Sweden)

    Pierre eTrifilieff

    2013-06-01

    Full Text Available Cocaine addiction is accompanied by a decrease in striatal dopamine signaling, measured as a decrease in dopamine D2 receptor binding as well as blunted dopamine release in the striatum. These alterations in dopamine transmission have clinical relevance, and have been shown to correlate with cocaine-seeking behavior and response to treatment for cocaine dependence. However, the mechanisms contributing to the hypodopaminergic state in cocaine addiction remain unknown. Here we review the Positron Emission Tomography (PET imaging studies showing alterations in D2 receptor binding potential and dopamine transmission in cocaine abusers and their significance in cocaine-seeking behavior. Based on animal and human studies, we propose that the kappa receptor/dynorphin system, because of its impact on dopamine transmission and upregulation following cocaine exposure, could contribute to the hypodopaminergic state reported in cocaine addiction, and could thus be a relevant target for treatment development.

  19. The effects of N-acetylcysteine on cocaine reward and seeking behaviors in a rat model of depression.

    Science.gov (United States)

    Frankowska, Małgorzata; Jastrzębska, Joanna; Nowak, Ewa; Białko, Magdalena; Przegaliński, Edmund; Filip, Małgorzata

    2014-06-01

    Depression and substance-abuse (e.g., cocaine) disorders are common concurrent diagnoses. In the present study, we combined bilateral olfactory bulbectomy (OBX) with a variety of procedures of intravenous cocaine self-administration and extinction/reinstatement in rats. We also investigated the effects of N-acetylcysteine (NAC) on rewarding and seeking behaviors for cocaine in OBX rats and compared the drug's effects in sham-operated control animals (SHAM). The occurrence of depressive symptoms before introduction to cocaine self-administration enhanced subsequent cocaine-seeking behaviors but did not significantly influence cocaine's rewarding properties or extinction training. NAC (25-100mg/kg) given acutely or repeatedly did not alter the co-occurrence of cocaine reward and depression but effectively reduced the cocaine-seeking behavior observed in both phenotypes. Our results indicate that depression behavior is linked to more pronounced drug craving and a higher propensity to relapse in rats. We also show the lack of efficacy of repeated NAC treatment on SHAM or OBX animals in terms of cocaine self-administration, while the drug was an effective blocker of cocaine-seeking behavior in both studied phenotypes, with a more pronounced drug effect observed in OBX animals. The last finding demonstrates the potential clinical utility of NAC to reduce cocaine seeking enhanced by co-existing depression. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Epigenetic Modulation of Brain Gene Networks for Cocaine and Alcohol Abuse

    Directory of Open Access Journals (Sweden)

    Sean P Farris

    2015-05-01

    Full Text Available Cocaine and alcohol are two substances of abuse that prominently affect the central nervous system (CNS. Repeated exposure to cocaine and alcohol leads to longstanding changes in gene expression, and subsequent functional CNS plasticity, throughout multiple brain regions. Epigenetic modifications of histones are one proposed mechanism guiding these enduring changes to the transcriptome. Characterizing the large number of available biological relationships as network models can reveal unexpected biochemical relationships. Clustering analysis of variation from whole-genome sequencing of gene expression (RNA-Seq and histone H3 lysine 4 trimethylation (H3K4me3 events (ChIP-Seq revealed the underlying structure of the transcriptional and epigenomic landscape within hippocampal postmortem brain tissue of drug abusers and control cases. Distinct sets of interrelated networks for cocaine and alcohol abuse were determined for each abusive substance. The network approach identified subsets of functionally related genes that are regulated in agreement with H3K4me3 changes, suggesting cause and effect relationships between this epigenetic mark and gene expression. Gene expression networks consisted of recognized substrates for addiction, such as the dopamine- and cAMP-regulated neuronal phosphoprotein PPP1R1B / DARPP-32 and the vesicular glutamate transporter SLC17A7 / VGLUT1 as well as potentially novel molecular targets for substance abuse. Through a systems biology based approach our results illustrate the utility of integrating epigenetic and transcript expression to establish relevant biological networks in the human brain for addiction. Future work with laboratory models may clarify the functional relevance of these gene networks for cocaine and alcohol, and provide a framework for the development of medications for the treatment of addiction.

  1. Brain imaging studies of the cocaine addict: Implications for reinforcement and addiction

    International Nuclear Information System (INIS)

    Volkow, N.D.; Fowler, J.S.; SUNY, Stony Brook, Stony Brook, NY

    1995-01-01

    These studies document dopaminergic abnormalities in cocaine abusers. They also suggest a regulatory role of Dopamine (DA) in frontal metabolism. The correlation of striatal D 2 receptor availability with metabolism was strongest for orbital frontal cortex (OFC) cingulate and prefrontal cortices. In cocaine abusers tested during early withdrawal (<1 week) the OFC was found to be hypermetabolic and metabolism in OFC and prefrontal cortices were found to be significantly associated with cocaine craving . Thus, we postulate that repeated and intermittent DA stimulation, as seen during a cocaine binge, activates the prefrontal and OFC cortices increasing the drive to compulsively self-administer cocaine. During cocaine discontinuation and protracted withdrawal and with decreased DA stimulation, these frontal cortical regions become hyponietabolic. Dopaminergic stimulation by a DA-enhancing drug and/or environmental conditioning will reactivate these frontal regions resetting the compulsion to self-administer cocaine and the inability to terminate this behavior. The pharmacokionetic studies with [11C]cocaine are consistent with behavioral and pharmacological studies in animals as well as in vitro studies which have revealed that while the mechanisms for cocaine's reinforcing properties are complex, they partly involve the brain's dopamine system and also highlight the importance of cocaine's pharmacokinetic on its unique reinforcing properties

  2. [Sigmund Freud and cocaine].

    Science.gov (United States)

    Lebzeltern, G

    1983-11-11

    The basic tenet proposed by J. V. Scheidt states that the narcotic drug, cocaine played a role in the development of psychoanalysis which has been underestimated up to the present day. It is a fact that Freud himself took cocaine (in small doses) for about two years, and that he began his dream interpretation approximately ten years later. Scheidt believes that a long, unconscious conflict related to the cocaine-induced states of euphoria (ten years later) suddenly led to the beginnings of dream interpretation. The question to be answered now is: Why did this happen precisely in 1895? The foundations of psychoanalysis had already been laid, the application of the new method to the treatment of nervous disorders (heart complaints, train phobias, etc.) was certainly obvious. During this self-analysis it became necessary, first of all, to come to terms with the self-reproaches-which lay on the surface and were more accessible to consciousness-related to Freud's cocaine period (Fleischl-Marxow becomes addicted to cocaine, the most terrible night ever experienced, death of this friend, Freud's warning came too late). It was only when Freud has come to terms with this phase of his life that the road to the deepest part, the discovery of the Oedipus complex in the fall of 1897, was cleared.

  3. The reinforcing value of vegetables does not increase with repeated exposure during a randomized controlled provided vegetable intervention among overweight and obese adults

    Science.gov (United States)

    Objective: The primary aim of this randomized controlled trial is to determine whether the relative reinforcing value (RRV) of vegetables compared to a snack food can be increased through repeated exposure (incentive sensitization) to amounts of vegetables recommended by the Dietary Guidelines for A...

  4. Is repeated exposure the holy grail for increasing children's vegetable intake? Lessons learned from a Dutch childcare intervention using various vegetable preparations

    NARCIS (Netherlands)

    Zeinstra, Gertrude G.; Vrijhof, Milou; Kremer, Stefanie

    2018-01-01

    Children's failure to eat enough vegetables highlights the need for effective interventions encouraging this behaviour. The aim of this study was to investigate the effect of repeated exposure to three a priori unfamiliar vegetables, each prepared in two ways, on children's vegetable acceptance in a

  5. Anti-Inflammatory and Antioxidant Effects of Repeated Exposure to Cruciferous Allyl Nitrile in Sensitizer-Induced Ear Edema in Mice.

    Science.gov (United States)

    Tanii, Hideji; Sugitani, Kayo; Saijoh, Kiyofumi

    2016-02-29

    Skin sensitizers induce allergic reactions through the induction of reactive oxygen species. Allyl nitrile from cruciferous vegetables has been reported to induce antioxidants and phase II detoxification enzymes in various tissues. We assessed the effects of repeated exposure to allyl nitrile on sensitizer-induced allergic reactions. Mice were dosed with allyl nitrile (0-200 µmol/kg), and then received a dermal application of 1 of 3 sensitizers on the left ear or 1 of 2 vehicles on the right ear. Quantitative assessment of edema was carried out by measuring the difference in weight between the portions taken from the right and left ears. We tested enzymes (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and thiobarbituric acid reactive substances (TBARS) in ears. Repeated exposure to allyl nitrile reduced edemas induced by glutaraldehyde and by 2, 4-dinitrochlorobenzene (DNCB), but not by formaldehyde. The repeated exposure decreased levels of TBARS, a marker of oxidative stress, induced by glutaraldehyde and by DNCB, but not by formaldehyde. Allyl nitrile elevated SOD levels for the 3 sensitizers, and CAT levels for formaldehyde and DNCB. Allyl nitrile also increased GPx levels for formaldehyde and DNCB, but not for glutaraldehyde. The reduced edemas were associated with changes in oxidative stress levels and antioxidant enzymes. Repeated exposure to allyl nitrile reduced allergic reactions induced by glutaraldehyde and by DNCB, but not by formaldehyde. This reduction was associated with changes in ROS levels and antioxidant enzyme activities.

  6. Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment

    NARCIS (Netherlands)

    Chaudhari, U.; Nemade, H.; Wagh, V.; Ellis, J.K.; Srinivasan, S.; Louisse, J.

    2016-01-01

    The currently available techniques for the safety evaluation of candidate drugs are usually cost-intensive and time-consuming and are often insufficient to predict human relevant cardiotoxicity. The purpose of this study was to develop an in vitro repeated exposure toxicity methodology allowing the

  7. In vitro model to study cocaine and its contaminants.

    Science.gov (United States)

    Steinmetz, Aline; Steffens, Luiza; Morás, Ana Moira; Prezzi, Flávia; Braganhol, Elizandra; Saffi, Jenifer; Ortiz, Rafael Scorsatto; Barros, Helena M T; Moura, Dinara Jaqueline

    2018-04-01

    Cocaine is one of the most popular illicit drug worldwide. Due its great addictive potential, which leads to euphoria and hyperactivity, it is considered a public health concern. At the central nervous system, the drug acts inhibiting catecholamine re-uptake. It is now known that in addition to the toxicity of the drug itself, the contaminants present in the street drug have raised concern about the harmful effects on health. Toxicological in vivo and in vitro studies have demonstrated the toxic effects of cocaine correlated with the generation of reactive oxygen species (ROS), which in turn lead to oxidative damage to the cells. Therefore the aim of this work was to propose an in vitro model that reunites the main parameters of toxicity of the cocaine already observed in the literature so far, and we tested this model using cocaine and seizure cocaine sample (SCS), kindly provided by Federal Police of Brazil. For that, we used a C6 glioblastoma cells and evaluated cell death, oxygen reactive species induction, oxidation of macromolecules as membrane lipids and DNA and loss of mitochondrial membrane potential after cocaine exposure. The results showed that cocaine can decrease cellular viability in a dose-dependent way in the C6 cell immortalized and astrocytes primary culture. Cocaine also induced cellular death by apoptosis. However, in the seizure cocaine sample (SCS), the predominant cell death was due to necrosis. Using dichlorofluorescein (DCF) assay, we confirmed ROS production after cocaine exposition. In agreement with these findings, occurred an increasing in MDA production, as well as increased superoxide dismutase (SOD) and catalase (CAT) activity. The induction of DNA damage was observed after cocaine. Our results demonstrate the occurrence of mitochondrial dysfunction by depolarization of mitochondrial membrane as a consequence of cocaine treatment. In summary, these results demonstrated that cocaine can induce reactive oxygen species formation

  8. Effects of Diet and Genetics on Growth Performance of Pigs in Response to Repeated Exposure to Heat Stress

    Directory of Open Access Journals (Sweden)

    Wendy M. Rauw

    2017-10-01

    Full Text Available Heat stress (HS is one of the costliest issues in the U.S. pork industry. Aims of the present study were to determine the consequences of repeated exposure to HS on growth performance, and the effects of a high fiber diet, the genetic potential for high lean tissue accretion, and the genetic potential for residual feed intake (RFI on resilience to HS. Barrows (n = 97 from three genetic lines (commercial, high RFI, low RFI where subjected three times to a 4-day HS treatment (HS1, HS2, and HS3 which was preceded by a 9-day neutral (TN adaptation period (TN1 and alternated by 7-day periods of neutral temperatures (TN2, TN3, and TN4. Body weight gain (BWG, feed intake (FI, feed conversion efficiency (FCE, RFI, and the drop in BWG and FI between TN and HS were estimated for each period, and slaughter traits were measured at the end of TN4. Commercial pigs had lower FI when fed a high fiber diet compared to a regular diet (2.70 ± 0.08 vs. 2.96 ± 0.08 kg/d; P < 0.05, while no differences were found for BWG, RFI or FCE. HS reduced FI, BWG, and FCE, increased RFI, and resulted in leaner pigs that generate smaller carcasses at slaughter. In TN, commercial pigs grew faster than the low and high RFI pigs (1.22 ± 0.06 vs. 0.720 ± 0.05 and 0.657 ± 0.07; P < 0.001 but growth rates were not significantly different between the lines during HS. Growth rates for the low RFI and high RFI pigs were similar both during TN and during HS. Pigs of interest for genetic improvement are those that are able to maintain growth rates during HS. Our results show that response in growth to HS was repeatable over subsequent 4-d HS cycles, which suggests the potential for including this response in the breeding index. The best performing animals during HS are likely those that are not highly superior for growth in TN.

  9. Isoflurane Anesthesia Interferes with the Expression of Cocaine-Induced Sensitization in Female Rats

    OpenAIRE

    Siegal, Nora; Dow-Edwards, Diana

    2009-01-01

    Repeated cocaine administration results in a progressive sensitization of behavior which typically occurs more readily in female rats than in males. Our recent studies of rats undergoing surgical procedures revealed that following anesthesia, females sensitized less than males receiving identical repeated cocaine injections. Since isoflurane acts primarily by increasing the effects of the inhibitory neurotransmitter γ-amino butyric acid (GABA) and reducing the effects of the excitatory amino ...

  10. Is repeated exposure the holy grail for increasing children's vegetable intake? Lessons learned from a Dutch childcare intervention using various vegetable preparations.

    Science.gov (United States)

    Zeinstra, Gertrude G; Vrijhof, Milou; Kremer, Stefanie

    2018-02-01

    Children's failure to eat enough vegetables highlights the need for effective interventions encouraging this behaviour. The aim of this study was to investigate the effect of repeated exposure to three a priori unfamiliar vegetables, each prepared in two ways, on children's vegetable acceptance in a childcare setting. Two hundred fifty children (mean age 25 months; 57% boys) participated in a pre-test and a post-test, where they were offered pumpkin, courgette, and white radish. The intervention group (N = 125) participated in a 5-month exposure period, where they were exposed repeatedly (∼12x) to the vegetables: pumpkin blanched and as a cracker spread; courgette blanched and as soup; white radish raw and as a cracker spread. The control group (N = 125) maintained their normal routine. Mixed model analyses were used to analyse intake data and Chi-square analyses for willingness to taste. At pre-test, children ate about 20 g of pumpkin and courgette, whereas white radish intake was approximately 10 g. There was a significant positive effect of the intervention for pumpkin (+15 g; p < 0.001) and white radish (+16 g; p = 0.01). Results for willingness to taste were in the same direction. There was no repeated exposure effect for courgette (p = 0.54); this may have been due to its less distinct taste profile or familiarity with boiled courgette. From our findings, we conclude that repeated exposure to multiple unfamiliar vegetable tastes within the daily routine of a childcare setting is effective in improving children's willingness to taste and intake of some of these vegetables. However, repeated exposure may not be sufficient for more familiar or blander tasting vegetables. This implies that one size does not fit all and that additional strategies are needed to increase children's intake of these vegetables. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Anticonvulsants for cocaine dependence.

    Science.gov (United States)

    Minozzi, Silvia; Cinquini, Michela; Amato, Laura; Davoli, Marina; Farrell, Michael F; Pani, Pier Paolo; Vecchi, Simona

    2015-04-17

    Cocaine dependence is a major public health problem that is characterised by recidivism and a host of medical and psychosocial complications. Although effective pharmacotherapy is available for alcohol and heroin dependence, none is currently available for cocaine dependence, despite two decades of clinical trials primarily involving antidepressant, anticonvulsivant and dopaminergic medications. Extensive consideration has been given to optimal pharmacological approaches to the treatment of individuals with cocaine dependence, and both dopamine antagonists and agonists have been considered. Anticonvulsants have been candidates for use in the treatment of addiction based on the hypothesis that seizure kindling-like mechanisms contribute to addiction. To evaluate the efficacy and safety of anticonvulsants for individuals with cocaine dependence. We searched the Cochrane Drugs and Alcohol Group Trials Register (June 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 6), MEDLINE (1966 to June 2014), EMBASE (1988 to June 2014), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to June 2014), Web of Science (1991 to June 2014) and the reference lists of eligible articles. All randomised controlled trials and controlled clinical trials that focus on the use of anticonvulsant medications to treat individuals with cocaine dependence. We used the standard methodological procedures expected by The Cochrane Collaboration. We included a total of 20 studies with 2068 participants. We studied the anticonvulsant drugs carbamazepine, gabapentin, lamotrigine, phenytoin, tiagabine, topiramate and vigabatrin. All studies compared anticonvulsants versus placebo. Only one study had one arm by which the anticonvulsant was compared with the antidepressant desipramine. Upon comparison of anticonvulsant versus placebo, we found no significant differences for any of the efficacy and safety measures. Dropouts: risk ratio (RR) 0.95, 95

  12. Behavioral effects of endogenous or exogenous estradiol and progesterone on cocaine sensitization in female rats

    Energy Technology Data Exchange (ETDEWEB)

    Souza, M.F. [Universidade Federal de Ciências da Saúde de Porto Alegre, Laboratório de Neurociência Comportamental, Porto Alegre, RS, Brasil, Laboratório de Neurociência Comportamental, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS (Brazil); Couto-Pereira, N.S. [Universidade Federal do Rio Grande do Sul, Instituto de Ciências Básicas da Saúde, Departamento de Bioquímica, Porto Alegre, RS, Brasil, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Freese, L.; Costa, P.A.; Caletti, G.; Bisognin, K.M. [Universidade Federal de Ciências da Saúde de Porto Alegre, Laboratório de Neurociência Comportamental, Porto Alegre, RS, Brasil, Laboratório de Neurociência Comportamental, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS (Brazil); Nin, M.S. [Universidade Federal de Ciências da Saúde de Porto Alegre, Laboratório de Neurociência Comportamental, Porto Alegre, RS, Brasil, Laboratório de Neurociência Comportamental, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS (Brazil); Instituto Porto Alegre, Centro Metodista do Sul, Curso de Farmácia, Porto Alegre, RS, Brasil, Curso de Farmácia, Centro Metodista do Sul, Instituto Porto Alegre, Porto Alegre, RS (Brazil); Gomez, R. [Universidade Federal do Rio Grande do Sul, Instituto de Ciências Básicas da Saúde, Departamento de Farmacologia, Porto Alegre, RS, Brasil, Departamento de Farmacologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Barros, H.M.T. [Universidade Federal de Ciências da Saúde de Porto Alegre, Laboratório de Neurociência Comportamental, Porto Alegre, RS, Brasil, Laboratório de Neurociência Comportamental, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS (Brazil)

    2014-05-09

    Cocaine sensitization is a marker for some facets of addiction, is greater in female rats, and may be influenced by their sex hormones. We compared the modulatory effects of endogenous or exogenous estradiol and progesterone on cocaine-induced behavioral sensitization in 106 female rats. Ovariectomized female rats received progesterone (0.5 mg/mL), estradiol (0.05 mg/mL), progesterone plus estradiol, or the oil vehicle. Sham-operated control females received oil. Control and acute subgroups received injections of saline, while the repeated group received cocaine (15 mg/kg, ip) for 8 days. After 10 days, the acute and repeated groups received a challenge dose of cocaine, after which locomotion and stereotypy were monitored. The estrous cycle phase was evaluated and blood was collected to verify hormone levels. Repeated cocaine treatment induced overall behavioral sensitization in female rats, with increased locomotion and stereotypies. In detailed analysis, ovariectomized rats showed no locomotor sensitization; however, the sensitization of stereotypies was maintained. Only females with endogenous estradiol and progesterone demonstrated increased locomotor activity after cocaine challenge. Estradiol replacement enhanced stereotyped behaviors after repeated cocaine administration. Cocaine sensitization of stereotyped behaviors in female rats was reduced after progesterone replacement, either alone or concomitant with estradiol. The behavioral responses (locomotion and stereotypy) to cocaine were affected differently, depending on whether the female hormones were of an endogenous or exogenous origin. Therefore, hormonal cycling appears to be an important factor in the sensitization of females. Although estradiol increases the risk of cocaine sensitization, progesterone warrants further study as a pharmacological treatment in the prevention of psychostimulant abuse.

  13. Palmitoylethanolamide attenuates cocaine-induced behavioral sensitization and conditioned place preference in mice.

    Science.gov (United States)

    Zambrana-Infantes, Emma; Rosell Del Valle, Cristina; Ladrón de Guevara-Miranda, David; Galeano, Pablo; Castilla-Ortega, Estela; Rodríguez De Fonseca, Fernando; Blanco, Eduardo; Santín, Luis Javier

    2018-03-01

    Cocaine addiction is a chronically relapsing disorder characterized by compulsive drug-seeking and drug-taking behaviors. Previous studies have demonstrated that cocaine, as well as other drugs of abuse, alters the levels of lipid-based signaling molecules, such as N-acylethanolamines (NAEs). Moreover, brain levels of NAEs have shown sensitivity to cocaine self-administration and extinction training in rodents. Given this background, the aim of this study was to investigate the effects of repeated or acute administration of palmitoylethanolamide (PEA), an endogenous NAE, on psychomotor sensitization and cocaine-induced contextual conditioning. To this end, the potential ability of repeated PEA administration (1 or 10 mg/kg, i.p.) to modulate the acquisition of cocaine-induced behavioral sensitization (BS) and conditioned place preference (CPP) was assessed in male C57BL/6J mice. In addition, the expression of cocaine-induced BS and CPP following acute PEA administration were also studied. Results showed that repeated administration of both doses of PEA were able to block the acquisition of cocaine-induced BS. Furthermore, acute administration of both doses of PEA was able to abolish the expression of BS, while the highest dose also abolished the expression of cocaine-induced CPP. Taken together, these results indicate that exogenous administration of PEA attenuated psychomotor sensitization, while the effect of PEA in cocaine-induced CPP depended on whether PEA was administered repeatedly or acutely. These findings could be relevant to understand the role that NAEs play in processes underlying the development and maintenance of cocaine addiction. Copyright © 2018 Elsevier Inc. All rights reserved.

  14. Behavioral effects of endogenous or exogenous estradiol and progesterone on cocaine sensitization in female rats

    International Nuclear Information System (INIS)

    Souza, M.F.; Couto-Pereira, N.S.; Freese, L.; Costa, P.A.; Caletti, G.; Bisognin, K.M.; Nin, M.S.; Gomez, R.; Barros, H.M.T.

    2014-01-01

    Cocaine sensitization is a marker for some facets of addiction, is greater in female rats, and may be influenced by their sex hormones. We compared the modulatory effects of endogenous or exogenous estradiol and progesterone on cocaine-induced behavioral sensitization in 106 female rats. Ovariectomized female rats received progesterone (0.5 mg/mL), estradiol (0.05 mg/mL), progesterone plus estradiol, or the oil vehicle. Sham-operated control females received oil. Control and acute subgroups received injections of saline, while the repeated group received cocaine (15 mg/kg, ip) for 8 days. After 10 days, the acute and repeated groups received a challenge dose of cocaine, after which locomotion and stereotypy were monitored. The estrous cycle phase was evaluated and blood was collected to verify hormone levels. Repeated cocaine treatment induced overall behavioral sensitization in female rats, with increased locomotion and stereotypies. In detailed analysis, ovariectomized rats showed no locomotor sensitization; however, the sensitization of stereotypies was maintained. Only females with endogenous estradiol and progesterone demonstrated increased locomotor activity after cocaine challenge. Estradiol replacement enhanced stereotyped behaviors after repeated cocaine administration. Cocaine sensitization of stereotyped behaviors in female rats was reduced after progesterone replacement, either alone or concomitant with estradiol. The behavioral responses (locomotion and stereotypy) to cocaine were affected differently, depending on whether the female hormones were of an endogenous or exogenous origin. Therefore, hormonal cycling appears to be an important factor in the sensitization of females. Although estradiol increases the risk of cocaine sensitization, progesterone warrants further study as a pharmacological treatment in the prevention of psychostimulant abuse

  15. Behavioral effects of endogenous or exogenous estradiol and progesterone on cocaine sensitization in female rats

    Directory of Open Access Journals (Sweden)

    M.F. Souza

    2014-06-01

    Full Text Available Cocaine sensitization is a marker for some facets of addiction, is greater in female rats, and may be influenced by their sex hormones. We compared the modulatory effects of endogenous or exogenous estradiol and progesterone on cocaine-induced behavioral sensitization in 106 female rats. Ovariectomized female rats received progesterone (0.5 mg/mL, estradiol (0.05 mg/mL, progesterone plus estradiol, or the oil vehicle. Sham-operated control females received oil. Control and acute subgroups received injections of saline, while the repeated group received cocaine (15 mg/kg, ip for 8 days. After 10 days, the acute and repeated groups received a challenge dose of cocaine, after which locomotion and stereotypy were monitored. The estrous cycle phase was evaluated and blood was collected to verify hormone levels. Repeated cocaine treatment induced overall behavioral sensitization in female rats, with increased locomotion and stereotypies. In detailed analysis, ovariectomized rats showed no locomotor sensitization; however, the sensitization of stereotypies was maintained. Only females with endogenous estradiol and progesterone demonstrated increased locomotor activity after cocaine challenge. Estradiol replacement enhanced stereotyped behaviors after repeated cocaine administration. Cocaine sensitization of stereotyped behaviors in female rats was reduced after progesterone replacement, either alone or concomitant with estradiol. The behavioral responses (locomotion and stereotypy to cocaine were affected differently, depending on whether the female hormones were of an endogenous or exogenous origin. Therefore, hormonal cycling appears to be an important factor in the sensitization of females. Although estradiol increases the risk of cocaine sensitization, progesterone warrants further study as a pharmacological treatment in the prevention of psychostimulant abuse.

  16. Vascular disease in cocaine addiction.

    Science.gov (United States)

    Bachi, Keren; Mani, Venkatesh; Jeyachandran, Devi; Fayad, Zahi A; Goldstein, Rita Z; Alia-Klein, Nelly

    2017-07-01

    Cocaine, a powerful vasoconstrictor, induces immune responses including cytokine elevations. Chronic cocaine use is associated with functional brain impairments potentially mediated by vascular pathology. Although the Crack-Cocaine epidemic has declined, its vascular consequences are increasingly becoming evident among individuals with cocaine use disorder of that period, now aging. Paradoxically, during the period when prevention efforts could make a difference, this population receives psychosocial treatment at best. We review major postmortem and in vitro studies documenting cocaine-induced vascular toxicity. PubMed and Academic Search Complete were used with relevant terms. Findings consist of the major mechanisms of cocaine-induced vasoconstriction, endothelial dysfunction, and accelerated atherosclerosis, emphasizing acute, chronic, and secondary effects of cocaine. The etiology underlying cocaine's acute and chronic vascular effects is multifactorial, spanning hypertension, impaired homeostasis and platelet function, thrombosis, thromboembolism, and alterations in blood flow. Early detection of vascular disease in cocaine addiction by multimodality imaging is discussed. Treatment may be similar to indications in patients with traditional risk-factors, with few exceptions such as enhanced supportive care and use of benzodiazepines and phentolamine for sedation, and avoiding β-blockers. Given the vascular toxicity cocaine induces, further compounded by smoking and alcohol comorbidity, and interacting with aging of the crack generation, there is a public health imperative to identify pre-symptomatic markers of vascular impairments in cocaine addiction and employ preventive treatment to reduce silent disease progression. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Effects of short-term repeated exposure to different flooring surfaces on the behavior and physiology of dairy cattle.

    Science.gov (United States)

    Schütz, K E; Cox, N R

    2014-05-01

    during the stand-off period. We observed no major effect of the repeated stand-off exposure. In summary, adding rubber matting onto concrete surfaces for stand-off purposes is beneficial for animal welfare. A well-managed wood chip surface offered the best welfare for dairy cows removed from pasture, and the findings of this study confirm that a concrete surface decreases the welfare of cows removed from pasture. Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  18. Optogenetically evoked gamma oscillations are disturbed by cocaine administration

    Directory of Open Access Journals (Sweden)

    Jonathan E Dilgen

    2013-11-01

    Full Text Available Drugs of abuse have enormous societal impact by degrading the cognitive abilities, emotional state and social behavior of addicted individuals. Among other events involved in the addiction cycle, the study of a single exposure to cocaine, and the contribution of the effects of that event to the continuous and further use of drugs of abuse are fundamental. Gamma oscillations are thought to be important neural correlates of cognitive processing in the prefrontal cortex (PFC which include decision making, set shifting and working memory. It follows that cocaine exposure might modulate gamma oscillations, which could result in reduced cognitive ability. Parvalbumin-positive fast-spiking interneurons play an orchestrating role in gamma oscillation induction and it has been shown recently that gamma oscillations can be induced in an anesthetized animal using optogenetic techniques. We use a knock-in mouse model together with optogenetics and in vivo electrophysiology to study the effects of acute cocaine on PFC gamma oscillation as a step toward understanding the cortical changes that may underlie continuous use of stimulants. Our results show that acute cocaine administration increases entrainment of the gamma oscillation to the optogentically induced driving frequency. Our results also suggest that this modulation of gamma oscillations is driven trough activation of DAD1 receptors. The acute cocaine-mediated changes in mPFC may underlie the enhancement of attention and awareness commonly reported by cocaine users and may contribute to the further use and abuse of psychostimulants.

  19. Demand curves for hypothetical cocaine in cocaine-dependent individuals.

    Science.gov (United States)

    Bruner, Natalie R; Johnson, Matthew W

    2014-03-01

    Drug purchasing tasks have been successfully used to examine demand for hypothetical consumption of abused drugs including heroin, nicotine, and alcohol. In these tasks, drug users make hypothetical choices whether to buy drugs, and if so, at what quantity, at various potential prices. These tasks allow for behavioral economic assessment of that drug's intensity of demand (preferred level of consumption at extremely low prices) and demand elasticity (sensitivity of consumption to price), among other metrics. However, a purchasing task for cocaine in cocaine-dependent individuals has not been investigated. This study examined a novel Cocaine Purchasing Task and the relation between resulting demand metrics and self-reported cocaine use data. Participants completed a questionnaire assessing hypothetical purchases of cocaine units at prices ranging from $0.01 to $1,000. Demand curves were generated from responses on the Cocaine Purchasing Task. Correlations compared metrics from the demand curve to measures of real-world cocaine use. Group and individual data were well modeled by a demand curve function. The validity of the Cocaine Purchasing Task was supported by a significant correlation between the demand curve metrics of demand intensity and O max (determined from Cocaine Purchasing Task data) and self-reported measures of cocaine use. Partial correlations revealed that after controlling for demand intensity, demand elasticity and the related measure, P max, were significantly correlated with real-world cocaine use. Results indicate that the Cocaine Purchasing Task produces orderly demand curve data, and that these data relate to real-world measures of cocaine use.

  20. Cocaine and Pregnancy

    Science.gov (United States)

    ... babies. They are also more likely to have life-long disabilities, including learning, visual, and hearing problems. Since cocaine can lower the supply of food and oxygen to the developing baby, even full- term newborns ... with serious health problems, especially breathing difficulties. These ...

  1. Mind Over Matter: Cocaine

    Science.gov (United States)

    ... of chocolate or a good time with friends. Research suggests that long-term cocaine use may reduce the amount of dopamine or number of dopamine receptors in the brain. When this happens, nerve cells need more dopamine to function normally—or more drug to be able to ...

  2. Binge-pattern cocaine administration causes long-lasting behavioral hyperarousal but does not enhance vulnerability to single prolonged stress in rats.

    Science.gov (United States)

    Lisieski, Michael J; Perrine, Shane A

    2017-11-01

    Cocaine use disorder and post-traumatic stress disorder (PTSD) commonly co-occur. This could be due to vulnerability to post-traumatic symptoms conferred by previous exposure to cocaine. Therefore, we combined chronic binge-pattern cocaine with a model of psychological trauma (single prolonged stress) to determine whether the behavioral effects of psychological trauma are enhanced in cocaine-sensitized individuals. Adult male Sprague Dawley rats received 14 days of cocaine (15mg/kg/injection) or saline in a binge pattern (3 injections per day, 1h apart). Seven days after the last injection animals were exposed to traumatic stress or a control procedure. Seven days after stress, activity and anxiety-like behaviors were measured. Binge-pattern cocaine increased locomotor activity in the open field and elevated plus maze, and both cocaine and SPS exposure increased the rapidity with which rats moved through grooming sequences. Neither binge-pattern cocaine nor SPS increased anxiety-like behaviors, and no interactions were found between binge-pattern cocaine exposure and SPS exposure. A behavioral phenotype categorization approach demonstrated that cocaine-exposed groups expressed a high incidence of hyperactivity-like symptoms. These results suggest that binge-pattern cocaine exposure causes a long-lasting hyper-exploratory phenotype but does not make individuals more vulnerable to a later traumatic stress exposure. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Chronic repeated exposure to weather-related stimuli elicits few symptoms of chronic stress in captive molting and non-molting European starlings (Sturnus vulgaris).

    Science.gov (United States)

    de Bruijn, Robert; Reed, J Michael; Romero, L Michael

    2017-10-01

    Repeated exposure to acute stressors causes dramatic changes in an animal's stress physiology and the cumulative effects are often called chronic stress. Recently we showed that short-term exposure to weather-related stimuli, such as temperature change, artificial precipitation, and food restriction, cause acute responses in captive European starlings (Sturnus vulgaris). Here, we examined the effect of repeated exposure to weather-related stressors on heart rate and corticosterone (CORT) of captive non-molting and molting European starlings. Four times every day for 3 weeks, birds were exposed to either 30 min of a subtle (3°C) decrease in temperature, a short bout of simulated rain, or 2 hr of food removal. The order and time of presentation were randomly assigned on each day. We found no differences in heart rate or heart rate variability. Furthermore, there were no changes in baseline CORT levels, CORT negative feedback efficacy, or maximal adrenal capacity. Mass increased across the experimental period only in molting birds. CORT responses to restraint were decreased in both groups following treatment, suggesting the birds had downregulated their responses to acute stress. Molting birds showed evidence of suppression of the HPA axis compared with non-molting birds, which is consistent with previous research. Overall, our data show that repeated exposure to weather-related stressors does not elicit most of the symptoms normally associated with chronic stress. © 2018 Wiley Periodicals, Inc.

  4. Repeated exposure to two stressors in sequence demonstrates that corticosterone and paraventricular nucleus of the hypothalamus interleukin-1β responses habituate independently.

    Science.gov (United States)

    Lovelock, D F; Deak, T

    2017-09-01

    A wide range of stress-related pathologies such as post-traumatic stress disorder are considered to arise from aberrant or maladaptive forms of stress adaptation. The hypothalamic-pituitary-adrenal (HPA) axis readily adapts to repeated stressor exposure, yet little is known about adaptation in neuroimmune responses to repeated or sequential stress challenges. In Experiment 1, rats were exposed to 10 days of restraint alone (60 minutes daily), forced swim alone (30 minutes daily) or daily sequential exposure to restraint (60 minutes) followed immediately by forced swim (30 minutes), termed sequential stress exposure. Habituation of the corticosterone (CORT) response occurred to restraint by 5 days and swim at 10 days, whereas rats exposed to sequential stress exposure failed to display habituation to the combined challenge. Experiment 2 compared 1 or 5 days of forced swim with sequential stress exposure and examined how each affected expression of several neuroimmune and cellular activation genes in the paraventricular nucleus of the hypothalamus (PVN), prefrontal cortex (PFC) and hippocampus (HPC). Sequential exposure to restraint and swim increased interleukin (IL)-1β in the PVN, an effect that was attenuated after 5 days. Sequential stress exposure also elicited IL-6 and tumour necrosis factor-α responses in the HPC and PFC, respectively, which did not habituate after 5 days. Experiment 3 tested whether prior habituation to restraint (5 days) would alter the IL-1β response evoked by swim exposure imposed immediately after the sixth day of restraint. Surprisingly, a history of repeated exposure to restraint attenuated the PVN IL-1β response after swim in comparison to acutely-exposed subjects despite an equivalent CORT response. Overall, these findings suggest that habituation of neuroimmune responses to stress proceeds: (i) independent of HPA axis habituation; (ii) likely requires more daily sessions of stress to develop; and (iii) IL-1β displays

  5. Moderate and severe perinatal asphyxia induces differential effects on cocaine sensitization in adult rats.

    Science.gov (United States)

    Galeano, Pablo; Romero, Juan Ignacio; Luque-Rojas, María Jesús; Suárez, Juan; Holubiec, Mariana Inés; Bisagno, Verónica; Santín, Luis Javier; De Fonseca, Fernando Rodríguez; Capani, Francisco; Blanco, Eduardo

    2013-09-01

    Perinatal asphyxia (PA) increases the likelihood of suffering from dopamine-related disorders, such as ADHD and schizophrenia. Since dopaminergic transmission plays a major role in cocaine sensitization, the purpose of this study was to determine whether PA could be associated with altered behavioral sensitization to cocaine. To this end, adult rats born vaginally (CTL), by caesarean section (C+), or by C+ with 15 min (PA15, moderate PA) or 19 min (PA19, severe PA) of global anoxia were repeatedly administered with cocaine (i.p., 15 mg/kg) and then challenged with cocaine (i.p., 15 mg/kg) after a 5-day withdrawal period. In addition, c-Fos, FosB/ΔFosB, DAT, and TH expression were assessed in dorsal (CPu) and ventral (NAcc) striatum. Results indicated that PA15 rats exhibited an increased locomotor sensitization to cocaine, while PA19 rats displayed an abnormal acquisition of locomotor sensitization and did not express a sensitized response to cocaine. c-Fos expression in NAcc, but not in CPu, was associated with these alterations in cocaine sensitization. FosB/ΔFosB expression was increased in all groups and regions after repeated cocaine administration, although it reached lower expression levels in PA19 rats. In CTL, C+, and PA15, but not in PA19 rats, the expression of TH in NAcc was reduced in groups repeatedly treated with cocaine, independently of the challenge test. Furthermore, this reduction was more pronounced in PA15 rats. DAT expression remained unaltered in all groups and regions studied. These results suggest that moderate PA may increase the vulnerability to drug abuse and in particular to cocaine addiction. Copyright © 2013 Wiley Periodicals, Inc.

  6. Enhanced Choice for Viewing Cocaine Pictures in Cocaine Addiction

    International Nuclear Information System (INIS)

    Moeller, S.J.; Goldstein, R.; Moeller, S.J.; Maloney, T.; Parvaz, M.A.; Dunning, J.P.; Alia-Klein, N.; Woicik, P.A.; Hajcak, G.; Telang, F.; Wang, G.-J.; Volkow, N.D.; Goldstein, R.Z.

    2009-01-01

    Individuals with cocaine use disorder (CUD) chose cocaine over nondrug rewards. In two newly designed laboratory tasks with pictures, we document this modified choice outside of a cocaine administration paradigm. Choice for viewing cocaine, pleasant, unpleasant, or neutral pictures-under explicit contingencies (choice made between two fully visible side-by-side images) and under more implicit contingencies (selections made between pictures hidden under flipped-over cards)-was examined in 20 CUD and 20 matched healthy control subjects. Subjects also provided self-reported ratings of each picture's pleasantness and arousal. Under both contingencies, CUD subjects chose to view more cocaine pictures than control subjects, group differences that were not fully explained by the self-reported picture ratings. Furthermore, whereas CUD subjects choice for viewing cocaine pictures exceeded choice for viewing unpleasant pictures (but did not exceed choice for viewing pleasant pictures, in contrast to their self-reported ratings), healthy control subjects avoided viewing cocaine pictures as frequently as, or even more than, unpleasant pictures. Finally, CUD subjects with the most cocaine viewing selections, even when directly compared with selections of the pleasant pictures, also reported the most frequent recent cocaine use. Enhanced drug-related choice in cocaine addiction can be demonstrated even for nonpharmacologic (pictorial) stimuli. This choice, which is modulated by alternative stimuli, partly transcends self-reports (possibly indicative of a disconnect in cocaine addiction between self-reports and objective behavior) to provide an objective marker of addiction severity. Neuroimaging studies are needed to establish the neural underpinnings of such enhanced cocaine-related choice.

  7. Enhanced Choice for Viewing Cocaine Pictures in Cocaine Addiction

    Energy Technology Data Exchange (ETDEWEB)

    Moeller, S.J.; Goldstein, R.; Moeller, S.J.; Maloney, T. Parvaz, M.A.; Dunning, J.P.; Alia-Klein, N.; Woicik, P.A.; Hajcak, G.; Telang, F.; Wang, G.-J.; Volkow, N.D.; Goldstein, R.Z.

    2009-02-01

    Individuals with cocaine use disorder (CUD) chose cocaine over nondrug rewards. In two newly designed laboratory tasks with pictures, we document this modified choice outside of a cocaine administration paradigm. Choice for viewing cocaine, pleasant, unpleasant, or neutral pictures-under explicit contingencies (choice made between two fully visible side-by-side images) and under more implicit contingencies (selections made between pictures hidden under flipped-over cards)-was examined in 20 CUD and 20 matched healthy control subjects. Subjects also provided self-reported ratings of each picture's pleasantness and arousal. Under both contingencies, CUD subjects chose to view more cocaine pictures than control subjects, group differences that were not fully explained by the self-reported picture ratings. Furthermore, whereas CUD subjects choice for viewing cocaine pictures exceeded choice for viewing unpleasant pictures (but did not exceed choice for viewing pleasant pictures, in contrast to their self-reported ratings), healthy control subjects avoided viewing cocaine pictures as frequently as, or even more than, unpleasant pictures. Finally, CUD subjects with the most cocaine viewing selections, even when directly compared with selections of the pleasant pictures, also reported the most frequent recent cocaine use. Enhanced drug-related choice in cocaine addiction can be demonstrated even for nonpharmacologic (pictorial) stimuli. This choice, which is modulated by alternative stimuli, partly transcends self-reports (possibly indicative of a disconnect in cocaine addiction between self-reports and objective behavior) to provide an objective marker of addiction severity. Neuroimaging studies are needed to establish the neural underpinnings of such enhanced cocaine-related choice.

  8. Repeated Exposure to the “Spice” Cannabinoid JWH-018 Induces Tolerance and Enhances Responsiveness to 5-HT1A Receptor Stimulation in Male Rats

    Directory of Open Access Journals (Sweden)

    Joshua S. Elmore

    2018-02-01

    Full Text Available Naphthalen-1-yl-(1-pentylindol-3-ylmethanone (JWH-018 is a synthetic compound found in psychoactive “spice” products that activates cannabinoid receptors. Preclinical evidence suggests that exposure to synthetic cannabinoids increases 5-HT2A/2C receptor function in the brain, an effect which might contribute to psychotic symptoms. Here, we hypothesized that repeated exposures to JWH-018 would enhance behavioral responsiveness to the 5-HT2A/2C receptor agonist DOI. Male Sprague-Dawley rats fitted with subcutaneously (sc temperature transponders received daily injections of JWH-018 (1.0 mg/kg, sc or its vehicle for seven consecutive days. Body temperature and catalepsy scores were determined at 1, 2, and 4 h post-injection each day. At 1 and 7 days after the final repeated treatment, rats received a challenge injection of either DOI (0.1 mg/kg, sc or the 5-HT1A receptor agonist 8-OH-DPAT (0.3 mg/kg, sc, then temperature and behavioral responses were assessed. Behaviors induced by DOI included wet dog shakes and back muscle contractions (i.e., skin jerks, while behaviors induced by 8-OH-DPAT included ambulation, forepaw treading, and flat body posture. On the first day of repeated treatment, JWH-018 produced robust hypothermia and catalepsy which lasted up to 4 h, and these effects were significantly blunted by day 7 of treatment. Repeated exposure to JWH-018 did not affect behaviors induced by DOI, but behavioral and hypothermic responses induced by 8-OH-DPAT were significantly augmented 1 day after cessation of JWH-018 treatment. Collectively, our findings show that repeated treatment with JWH-018 produces tolerance to its hypothermic and cataleptic effects, which is accompanied by transient enhancement of 5-HT1A receptor sensitivity in vivo.

  9. 'Just a pinch of salt'. An experimental comparison of the effect of repeated exposure and flavor-flavor learning with salt or spice on vegetable acceptance in toddlers.

    Science.gov (United States)

    Bouhlal, Sofia; Issanchou, Sylvie; Chabanet, Claire; Nicklaus, Sophie

    2014-12-01

    Children's vegetable intake is below the recommended amounts. No studies to date have tested the relevance of using salt or spices to increase children's vegetable acceptance. Our objective was to compare the effect of repeated exposure (RE) and of flavor-flavor learning (FFL) on toddlers' acceptance of a non-familiar vegetable. Two unconditioned stimuli were used: salt and a salt-associated spice. Toddlers attending six nurseries were assigned to 3 groups in a between subject design. Groups were exposed 8 times to a basic salsify puree (0.2% salt w/w; RE group; n = 47), a salty salsify puree (0.5% salt w/w; FFL-Salt group; n = 54) or a spiced salsify puree (0.2% salt and 0.02% nutmeg w/w; FFL-Nutmeg group; n = 50). Acceptance (intake and liking) of the target vegetable (basic salsify puree) and of a control vegetable (carrot puree) was evaluated at pre-exposure, at each exposure of the learning period, at post-exposure, and at 1, 3 and 6 months after exposure. In all groups, intake of the target vegetable increased from pre- to post-exposure. This increase was significantly higher in the RE group (64 ± 11 g) than in the FFL-Salt group (23 ± 11 g) and marginally higher than in the FFL-Nutmeg group (36 ± 11 g). No difference between groups was observed on the increase in liking of the target vegetable from pre- to post-exposure. The increase of the target vegetable intake was still observed after 6 months for all groups. Thus, repeated exposure appears to be the simplest choice to increase vegetable intake on the short and long term in toddlers. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Repeated exposure to high-frequency spanking and child externalizing behavior across the first decade: a moderating role for cumulative risk.

    Science.gov (United States)

    MacKenzie, Michael J; Nicklas, Eric; Brooks-Gunn, Jeanne; Waldfogel, Jane

    2014-12-01

    This study used the Fragile Families and Child Well-Being Study to examine the effects of repeated exposure to harsh parenting on child externalizing behavior across the first decade of life, and a moderating role for cumulative ecological risk. Maternal report of harsh parenting, defined as high frequency spanking, was assessed at age 1, 3, 5, and 9, along with child externalizing at age 9 (N=2,768). Controlling for gender, race, maternal nativity, and city of residence, we found a cumulative risk index to significantly moderate the effects of repeated harsh parenting on child behavior, with the effects of repeated high-frequency spanking being amplified for those experiencing greater levels of cumulative risk. Harsh parenting, in the form of high frequency spanking, remains a too common experience for children, and results demonstrate that the effects of repeated exposure to harsh parenting across the first decade are amplified for those children already facing the most burden. Copyright © 2014. Published by Elsevier Ltd.

  11. A bacterial cocaine esterase protects against cocaine-induced epileptogenic activity and lethality.

    Science.gov (United States)

    Jutkiewicz, Emily M; Baladi, Michelle G; Cooper, Ziva D; Narasimhan, Diwahar; Sunahara, Roger K; Woods, James H

    2009-09-01

    Cocaine toxicity results in cardiovascular complications, seizures, and death and accounts for approximately 20% of drug-related emergency department visits every year. Presently, there are no treatments to eliminate the toxic effects of cocaine. The present study hypothesizes that a bacterial cocaine esterase with high catalytic efficiency would provide rapid and robust protection from cocaine-induced convulsions, epileptogenic activity, and lethality. Cocaine-induced paroxysmal activity and convulsions were evaluated in rats surgically implanted with radiotelemetry devices (N=6 per treatment group). Cocaine esterase was administered 1 minute after a lethal dose of cocaine or after cocaine-induced convulsions to determine the ability of the enzyme to prevent or reverse, respectively, the effects of cocaine. The cocaine esterase prevented all cocaine-induced electroencephalographic changes and lethality. This effect was specific for cocaine because the esterase did not prevent convulsions and death induced by a cocaine analog, (-)-2beta-carbomethoxy-3beta-phenyltropane. The esterase prevented lethality even after cocaine-induced convulsions occurred. In contrast, the short-acting benzodiazepine, midazolam, prevented cocaine-induced convulsions but not the lethal effects of cocaine. The data showed that cocaine esterase successfully degraded circulating cocaine to prevent lethality and that cocaine-induced convulsions alone are not responsible for the lethal effects of cocaine in this model. Therefore, further investigation into the use of cocaine esterase for treating cocaine overdose and its toxic effects is warranted.

  12. Repeated exposure to cat urine induces complex behavioral, hormonal, and c-fos mRNA responses in Norway rats ( Rattus norvegicus)

    Science.gov (United States)

    Yin, Baofa; Gu, Chen; Lu, Yi; Hegab, Ibrahim M.; Yang, Shengmei; Wang, Aiqin; Wei, Wanhong

    2017-08-01

    Prey species show specific adaptations that allow recognition, avoidance, and defense against predators. This study was undertaken to investigate the processing of a chronic, life-threatening stimulus to Norway rats ( Rattus norvegicus). One hundred forty-four Norway rats were tested by repeated presentation of cat urine for 1 h at different days in a defensive withdrawal apparatus. Rats exposed to urine for short periods showed significantly larger defensive behavioral and medial hypothalamic c-fos messenger RNA (mRNA) responses than other groups. These defensive responses habituated shortly after the presentation of cat urine. Serum levels of adrenocorticotropic hormone and corticosterone increased significantly when animals were repeatedly exposed to cat urine. However, the hormonal responses took longer to habituate than the behavioral and molecular responses did. We conclude that the behavioral and c-fos mRNA responses are "primed" for habituation to repeated exposures to cat urine, while the hormonal responses show "resistance." The results support our hypothesis that the strongest anti-predator responses at three levels would occur during short-term exposure to cat urine and that these responses would subsequently disappear on prolonged exposure. This study assists understanding the way in which the different levels of defensive responses are integrated and react during chronic stress.

  13. Glycogen synthase kinase 3β in the basolateral amygdala is critical for the reconsolidation of cocaine reward memory.

    Science.gov (United States)

    Wu, Ping; Xue, Yan-Xue; Ding, Zeng-Bo; Xue, Li-Fen; Xu, Chun-Mei; Lu, Lin

    2011-07-01

    Exposure to cocaine-associated conditioned stimuli elicits craving and increases the probability of cocaine relapse in cocaine users even after extended periods of abstinence. Recent evidence indicates that cocaine seeking can be inhibited by disrupting the reconsolidation of the cocaine cue memories and that basolateral amygdala (BLA) neuronal activity plays a role in this effect. Previous studies demonstrated that glycogen synthase kinase 3β (GSK-3β) plays a role in the reconsolidation of fear memory. Here, we used a conditioned place preference procedure to examine the role of GSK-3β in the BLA in the reconsolidation of cocaine cue memories. GSK-3β activity in the BLA, but not central amygdala (CeA), in rats that acquired cocaine (10 mg/kg)-induced conditioned place preference increased after re-exposure to a previously cocaine-paired chamber (i.e., a memory reactivation procedure). Systemic injections of the GSK-3β inhibitor lithium chloride after memory reactivation impaired the reconsolidation of cocaine cue memories and inhibited subsequent cue-induced GSK-3β activity in the BLA. Basolateral amygdala, but not central amygdala, injections of SB216763, a selective inhibitor of GSK-3β, immediately after the reactivation of cocaine cue memories also disrupted cocaine cue memory reconsolidation and prevented cue-induced increases in GSK-3β activity in the BLA. The effect of SB216763 on the reconsolidation of cocaine cue memories lasted at least 2 weeks and was not recovered by a cocaine priming injection. These results indicate that GSK-3β activity in the BLA mediates the reconsolidation of cocaine cue memories. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

  14. Preventive Strength of Dyadic Social Interaction against Reacquisition/Reexpression of Cocaine Conditioned Place Preference.

    Science.gov (United States)

    Bregolin, Tanja; Pinheiro, Barbara S; El Rawas, Rana; Zernig, Gerald

    2017-01-01

    The reorientation away from drugs of abuse and toward social interaction is a highly desirable but as yet elusive goal in the therapy of substance dependence. We could previously show that cocaine preferring Sprague-Dawley rats which engaged in only four 15 min episodes of dyadic social interaction (DSI) did not reacquire and reexpress cocaine conditioned place preference (CPP) after a single cocaine exposure. In the present study, we investigated how strong this preventive effect of DSI is. In corroboration of our previous findings in rats, four 15 min DSI episodes prevented the reacquisition/reexpression of cocaine CPP in mice. However, this effect was only observed if only one cocaine conditioning session (15 min) was used. If mice were counterconditioned with a total of four cocaine sessions, the cocaine CPP reemerged. Interestingly, the opposite also held true: in mice that had acquired/expressed cocaine CPP, one conditioning session with DSI did not prevent the persistence of cocaine CPP, whereas four DSI conditioning sessions reversed CPP for 15 mg/kg intraperitoneal cocaine. Of note, this cocaine dose was a strong reward in C57BL/6J mice, causing CPP in all tested animals. Our findings suggest that both the reversal (reconditioning) of CPP from cocaine to DSI as well as that from DSI to cocaine requires four conditioning sessions. As previously shown in C57BL/6 mice from the NIH substrain, mice from the Jackson substrain also showed a greater relative preference for 15 mg/kg intraperitoneal cocaine over DSI, whereas Sprague-Dawley rats were equally attracted to contextual stimuli associated with this cocaine dose and DSI. Also in corroboration of previous findings, both C57BL/6J mice and experimenters several generations removed from the original ones produced CPP for DSI to a lesser degree than Sprague-Dawley rats. Our findings demonstrate the robustness of our experimental model across several subject- and experimenter generations in two rodent genus (i

  15. Preventive Strength of Dyadic Social Interaction against Reacquisition/Reexpression of Cocaine Conditioned Place Preference

    Directory of Open Access Journals (Sweden)

    Tanja Bregolin

    2017-11-01

    Full Text Available The reorientation away from drugs of abuse and toward social interaction is a highly desirable but as yet elusive goal in the therapy of substance dependence. We could previously show that cocaine preferring Sprague-Dawley rats which engaged in only four 15 min episodes of dyadic social interaction (DSI did not reacquire and reexpress cocaine conditioned place preference (CPP after a single cocaine exposure. In the present study, we investigated how strong this preventive effect of DSI is. In corroboration of our previous findings in rats, four 15 min DSI episodes prevented the reacquisition/reexpression of cocaine CPP in mice. However, this effect was only observed if only one cocaine conditioning session (15 min was used. If mice were counterconditioned with a total of four cocaine sessions, the cocaine CPP reemerged. Interestingly, the opposite also held true: in mice that had acquired/expressed cocaine CPP, one conditioning session with DSI did not prevent the persistence of cocaine CPP, whereas four DSI conditioning sessions reversed CPP for 15 mg/kg intraperitoneal cocaine. Of note, this cocaine dose was a strong reward in C57BL/6J mice, causing CPP in all tested animals. Our findings suggest that both the reversal (reconditioning of CPP from cocaine to DSI as well as that from DSI to cocaine requires four conditioning sessions. As previously shown in C57BL/6 mice from the NIH substrain, mice from the Jackson substrain also showed a greater relative preference for 15 mg/kg intraperitoneal cocaine over DSI, whereas Sprague-Dawley rats were equally attracted to contextual stimuli associated with this cocaine dose and DSI. Also in corroboration of previous findings, both C57BL/6J mice and experimenters several generations removed from the original ones produced CPP for DSI to a lesser degree than Sprague-Dawley rats. Our findings demonstrate the robustness of our experimental model across several subject- and experimenter generations in two

  16. The development of a preference for cocaine over food identifies individual rats with addiction-like behaviors.

    Science.gov (United States)

    Perry, Adam N; Westenbroek, Christel; Becker, Jill B

    2013-01-01

    Cocaine dependence is characterized by compulsive drug taking that supercedes other recreational, occupational or social pursuits. We hypothesized that rats vulnerable to addiction could be identified within the larger population based on their preference for cocaine over palatable food rewards. To validate the choice self-administration paradigm as a preclinical model of addiction, we examined changes in motivation for cocaine and recidivism to drug seeking in cocaine-preferring and pellet-preferring rats. We also examined behavior in males and females to identify sex differences in this "addicted" phenotype. Preferences were identified during self-administration on a fixed-ratio schedule with cocaine-only, pellet-only and choice sessions. Motivation for each reward was probed early and late during self-administration using a progressive-ratio schedule. Reinstatement of cocaine- and pellet-seeking was examined following exposure to their cues and non-contingent delivery of each reward. Cocaine preferring rats increased their drug intake at the expense of pellets, displayed increased motivation for cocaine, attenuated motivation for pellets and greater cocaine and cue-induced reinstatement of drug seeking. Females were more likely to develop cocaine preferences and recidivism of cocaine- and pellet-seeking was sexually dimorphic. The choice self-administration paradigm is a valid preclinical model of addiction. The unbiased selection criteria also revealed sex-specific vulnerability factors that could be differentiated from generalized sex differences in behavior, which has implications for the neurobiology of addiction and effective treatments in each sex.

  17. Effects of Single and Repeated Exposure to a 50-Hz 2-mT Electromagnetic Field on Primary Cultured Hippocampal Neurons.

    Science.gov (United States)

    Zeng, Ying; Shen, Yunyun; Hong, Ling; Chen, Yanfeng; Shi, Xiaofang; Zeng, Qunli; Yu, Peilin

    2017-06-01

    The prevalence of domestic and industrial electrical appliances has raised concerns about the health risk of extremely low-frequency magnetic fields (ELF-MFs). At present, the effects of ELF-MFs on the central nervous system are still highly controversial, and few studies have investigated its effects on cultured neurons. Here, we evaluated the biological effects of different patterns of ELF-MF exposure on primary cultured hippocampal neurons in terms of viability, apoptosis, genomic instability, and oxidative stress. The results showed that repeated exposure to 50-Hz 2-mT ELF-MF for 8 h per day after different times in culture decreased the viability and increased the production of intracellular reactive oxidative species in hippocampal neurons. The mechanism was potentially related to the up-regulation of Nox2 expression. Moreover, none of the repeated exposure patterns had significant effects on DNA damage, apoptosis, or autophagy, which suggested that ELF-MF exposure has no severe biological consequences in cultured hippocampal neurons.

  18. Irritancy of antiseptics tested by repeated open exposures on the human skin, evaluated by non-invasive methods

    NARCIS (Netherlands)

    Tupker, RA; Schuur, J; Coenraads, PJ

    1997-01-01

    The aim of the study was to test the irritancy of 6 antiseptics in an open exposure model. The following agents were tested in their normal use concentrations using open exposures, 2x daily for 4 days in 20 subjects: chlorhexidine 4% (CH), chlorhexidine 0.5% in ethanol 70% (CE), ethanol 70% (ET),

  19. Effects of single and repeated exposure to biocidal active substances on the barrier function of the skin in vitro

    NARCIS (Netherlands)

    Buist, H.E.; Sandt, J.J.M. van de; Burgsteden, J.A. van; Heer, C. de

    2005-01-01

    The dermal route of exposure is important in worker exposure to biocidal products. Many biocidal active substances which are used on a daily basis may decrease the barrier function of the skin to a larger extent than current risk assessment practice addresses, due to possible skin effects of

  20. Effect of exposure to evening light on sleep initiation in the elderly: a longitudinal analysis for repeated measurements in home settings.

    Science.gov (United States)

    Obayashi, Kenji; Saeki, Keigo; Iwamoto, Junko; Okamoto, Nozomi; Tomioka, Kimiko; Nezu, Satoko; Ikada, Yoshito; Kurumatani, Norio

    2014-05-01

    Epidemiologic data have demonstrated associations of sleep-onset insomnia with a variety of diseases, including depression, dementia, diabetes and cardiovascular diseases. Sleep initiation is controlled by the suprachiasmatic nucleus of the hypothalamus and endogenous melatonin, both of which are influenced by environmental light. Exposure to evening light is hypothesized to cause circadian phase delay and melatonin suppression before bedtime, resulting in circadian misalignment and sleep-onset insomnia; however, whether exposure to evening light disturbs sleep initiation in home settings remains unclear. In this longitudinal analysis of 192 elderly individuals (mean age: 69.9 years), we measured evening light exposure and sleep-onset latency for 4 days using a wrist actigraph incorporating a light meter and an accelerometer. Mixed-effect linear regression analysis for repeated measurements was used to evaluate the effect of evening light exposure on subsequent sleep-onset latency. The median intensity of evening light exposure and the median sleep-onset latency were 27.3 lux (interquartile range, 17.9-43.4) and 17 min (interquartile range, 7-33), respectively. Univariate models showed significant associations between sleep-onset latency and age, gender, daytime physical activity, in-bed time, day length and average intensity of evening and nighttime light exposures. In a multivariate model, log-transformed average intensity of evening light exposure was significantly associated with log-transformed sleep-onset latency independent of the former potential confounding factors (regression coefficient, 0.133; 95% CI, 0.020-0.247; p = 0.021). Day length and nighttime light exposure were also significantly associated with log-transformed sleep-onset latency (p = 0.001 and p < 0.001, respectively). In conclusion, exposure to evening light in home setting prolongs subsequent sleep-onset latency in the elderly.

  1. The effects of prenatal cocaine, post-weaning housing and sex on conditioned place preference in adolescent rats.

    Science.gov (United States)

    Dow-Edwards, Diana; Iijima, Maiko; Stephenson, Stacy; Jackson, April; Weedon, Jeremy

    2014-04-01

    Gestational exposure to cocaine now affects several million people including adolescents and young adults. Whether prenatal drug exposures alter an individual's tendency to take and/or abuse drugs is still a matter of debate. This study sought to answer the question "Does prenatal exposure to cocaine, in a dose-response fashion, alter the rewarding effects of cocaine using a conditioned place preference (CPP) procedure during adolescence in the rat?" Further, we wanted to assess the possible sex differences and the role of being raised in an enriched versus impoverished environment. Virgin female Sprague-Dawley rats were dosed daily with cocaine at 30 mg/kg (C30), 60 mg/kg (C60), or vehicle intragastrically prior to mating and throughout gestation. Pups were culled, fostered and, on postnatal day (PND) 23, placed into isolation cages or enriched cages with three same-sex littermates and stimulus objects. On PND43-47, CPP was determined across a range of cocaine doses. C30 exposure increased sensitivity to the rewarding effects of cocaine in adolescent males, and being raised in an enriched environment further enhanced this effect. Rats exposed to C60 resembled the controls in cocaine CPP. Overall, females were modestly affected by prenatal cocaine and enrichment. These data support the unique sensitivity of males to the effects of gestational cocaine, that moderate prenatal cocaine doses produce greater effects on developing reward circuits than high doses and that housing condition interacts with prenatal treatment and sex such that enrichment increases cocaine CPP mostly in adolescent males prenatally exposed to moderate cocaine doses.

  2. Dopaminergic mechanisms of cocaine use

    NARCIS (Netherlands)

    Veeneman - Rijkens, M.M.J.

    2011-01-01

    Cocaine addiction is an enormous medical problem for which there is currently no effective pharmacotherapy. In order to develop treatments for this disorder, it is essential to understand the neurobiological underpinnings of cocaine addiction. One of the behavioral characteristics of addiction is an

  3. Electrophysiological and neurochemical changes in the rat hippocampus after in vitro and in vivo treatments with cocaine

    International Nuclear Information System (INIS)

    Yasuda, R.P.

    1986-01-01

    The in vitro and in vivo effects of cocaine in the noradrenergic pathway in the rat hippocampus were examined. Although the blockade of [ 3 H]-norepinephrine-uptake by cocaine has been well-characterized in both the central and peripheral nervous systems, investigations characterizing the electrophysiological effects of cocaine in the central nervous system have been limited. The first part of this thesis examines the relationship between the ability of cocaine to potentiate the electrophysiological response to norepinephrine (NE) and the ability of cocaine to block noradrenergic high affinity uptake in rat hippocampal slices. The second part of this thesis examines the effects of the repeated administration of cocaine on noradrenergic pre- and postsynaptic function and receptors of the rat hippocampus. These studies demonstrate that after repeated administration of cocaine (10 mg/kg/day) for 8 and 14 days there is a 50% decrease in NE high affinity uptake in the rat hippocampus. This was accompanied by a 40% increase in a binding site for NE uptake inhibitors at 14 days. In contrast to these effects, there was no effect on β-adrenergic receptor number or the isoproterenol induced electrophysiological responsiveness in the rat hippocampus. The conclusion of these studies is that the repeated administration of cocaine has a greater effect on presynaptic targets in the noradrenergic system than on postsynaptic neurons

  4. Cocaine in the UK--1991.

    Science.gov (United States)

    Strang, J; Johns, A; Caan, W

    1993-01-01

    More than 100 years after Freud's original endorsement of the drug, the use of cocaine is a problem for both users and for society, which struggles to organise effective responses to the epidemic of the last decade. During the 1980s the rapid spread of smokeable cocaine (including 'crack') was seen in the Americas (particularly the US). The initial simple predictions of an identical European epidemic were mistaken. The available data on the extent of cocaine use and of cocaine problems in the UK are examined. New forms of cocaine have been developed by black-market entrepreneurs ('freebase' and 'crack'), and new technologies have emerged for their use; with these new technologies have come new effects and new problems. The general psychiatrist now needs a knowledge of directly and indirectly related psychopathology which has an increasing relevance to the diagnosis and management of the younger patient.

  5. Cocaine- and amphetamine-regulated transcript peptide in the nucleus accumbens shell inhibits cocaine-induced locomotor sensitization to transient over-expression of α-Ca2+ /calmodulin-dependent protein kinase II.

    Science.gov (United States)

    Xiong, Lixia; Meng, Qing; Sun, Xi; Lu, Xiangtong; Fu, Qiang; Peng, Qinghua; Yang, Jianhua; Oh, Ki-Wan; Hu, Zhenzhen

    2018-01-04

    Cocaine- and amphetamine-regulated transcript (CART) peptide is a widely distributed neurotransmitter that attenuates cocaine-induced locomotor activity when injected into the nucleus accumbens (NAc). Our previous work first confirmed that the inhibitory mechanism of the CART peptide on cocaine-induced locomotor activity is related to a reduction in cocaine-enhanced phosphorylated Ca 2+ /calmodulin-dependent protein kinaseIIα (pCaMKIIα) and the enhancement of cocaine-induced D3R function. This study investigated whether CART peptide inhibited cocaine-induced locomotor activity via inhibition of interactions between pCaMKIIα and the D3 dopamine receptor (D3R). We demonstrated that lentivirus-mediated gene transfer transiently increased pCaMKIIα expression, which peaked at 10 days after microinjection into the rat NAc shell, and induced a significant increase in Ca 2+ influx along with greater behavioral sensitivity in the open field test after intraperitoneal injections of cocaine (15 mg/kg). However, western blot analysis and coimmunoprecipitation demonstrated that CART peptide treatment in lentivirus-transfected CaMKIIα-over-expressing NAc rat tissues or cells prior to cocaine administration inhibited the cocaine-induced Ca 2+ influx and attenuated the cocaine-increased pCaMKIIα expression in lentivirus-transfected CaMKIIα-over-expressing cells. CART peptide decreased the cocaine-enhanced phosphorylated cAMP response element binding protein (pCREB) expression via inhibition of the pCaMKIIα-D3R interaction, which may account for the prolonged locomotor sensitization induced by repeated cocaine treatment in lentivirus-transfected CaMKIIα-over-expressing cells. These results provide strong evidence for the inhibitory modulation of CART peptide in cocaine-induced locomotor sensitization. © 2018 International Society for Neurochemistry.

  6. The effects of chronic cadmium exposure on repeat swimming performance and anaerobic metabolism in brown trout (Salmo trutta) and lake whitefish (Coregonus clupeaformis)

    Energy Technology Data Exchange (ETDEWEB)

    Cunningham, Jessie L.; McGeer, James C., E-mail: jmcgeer@wlu.ca

    2016-04-15

    Highlights: • Exposure to 18 nM waterborne Cd induced plasma Ca loss that recovered by day 30 for lake whitefish but not brown trout. • Ucrit measured after an initial swim to 85% of Ucrit and a 30 min rest period was reduced in 18 nM Cd exposed fish compared to controls. • Swimming to 85% of Ucrit resulted in decreased muscle glycogen and increased lactate that was not recovered in the 30 min recovery period. • Second swim impairment is not related to metabolic processes in white muscle. - Abstract: This study investigates the effect of chronic Cd exposure on the ability to perform repeat swim challenges in brown trout (Salmo trutta) and lake whitefish (Coregonus clupeaformis). Fish were exposed to waterborne Cd (18 nM) in moderately hard water (120 mg L{sup −1} CaCO{sub 3}) for 30 days. This level of exposure has been shown to cause sublethal physiological disruption and acclimation responses but no impairment of sustained swimming capacity (U{sub crit}) in single swim challenges. Swim trials were done over the course of the exposure and each one consisted of an initial swim to 85% of the U{sub crit} of control fish, a 30 min recovery period and finally a second swim challenge to determine U{sub crit}. Plasma and tissue samples were collected before and after each of the swim periods. As expected from previous studies, Cd exposure resulted in significant accumulation of Cd in gills, liver and kidney but not in white muscle. Exposure also induced a loss of plasma Ca followed by subsequent recovery (in lake whitefish but not brown trout) with few mortalities (100% survival for lake whitefish and 93% for brown trout). Both control and exposed fish swam to 85% of the single swim U{sub crit} and no differences in performance were seen. The Ucrit of unexposed controls in the second swim challenges were not different from the single swim Ucrit. However, second swim performance was significantly reduced in Cd exposed fish, particularly after a week of exposure

  7. The effects of chronic cadmium exposure on repeat swimming performance and anaerobic metabolism in brown trout (Salmo trutta) and lake whitefish (Coregonus clupeaformis)

    International Nuclear Information System (INIS)

    Cunningham, Jessie L.; McGeer, James C.

    2016-01-01

    Highlights: • Exposure to 18 nM waterborne Cd induced plasma Ca loss that recovered by day 30 for lake whitefish but not brown trout. • Ucrit measured after an initial swim to 85% of Ucrit and a 30 min rest period was reduced in 18 nM Cd exposed fish compared to controls. • Swimming to 85% of Ucrit resulted in decreased muscle glycogen and increased lactate that was not recovered in the 30 min recovery period. • Second swim impairment is not related to metabolic processes in white muscle. - Abstract: This study investigates the effect of chronic Cd exposure on the ability to perform repeat swim challenges in brown trout (Salmo trutta) and lake whitefish (Coregonus clupeaformis). Fish were exposed to waterborne Cd (18 nM) in moderately hard water (120 mg L"−"1 CaCO_3) for 30 days. This level of exposure has been shown to cause sublethal physiological disruption and acclimation responses but no impairment of sustained swimming capacity (U_c_r_i_t) in single swim challenges. Swim trials were done over the course of the exposure and each one consisted of an initial swim to 85% of the U_c_r_i_t of control fish, a 30 min recovery period and finally a second swim challenge to determine U_c_r_i_t. Plasma and tissue samples were collected before and after each of the swim periods. As expected from previous studies, Cd exposure resulted in significant accumulation of Cd in gills, liver and kidney but not in white muscle. Exposure also induced a loss of plasma Ca followed by subsequent recovery (in lake whitefish but not brown trout) with few mortalities (100% survival for lake whitefish and 93% for brown trout). Both control and exposed fish swam to 85% of the single swim U_c_r_i_t and no differences in performance were seen. The Ucrit of unexposed controls in the second swim challenges were not different from the single swim Ucrit. However, second swim performance was significantly reduced in Cd exposed fish, particularly after a week of exposure where 31% and 38

  8. Vulnerability for cocaine dependence / Involvement of µ-opioid receptors

    NARCIS (Netherlands)

    Lesscher, Heidi Maria Bonifacio

    2004-01-01

    Drug dependence is a major health issue worldwide, which is characterised by its persistence and high rates of relapse. Individual differences exist in the vulnerability for drug dependence after first exposure to drugs of abuse like cocaine. A likely risk factor for drug dependence is the

  9. Cocaine – Characteristics and addiction

    Directory of Open Access Journals (Sweden)

    Katarzyna Girczys-Połedniok

    2016-08-01

    Full Text Available Cocaine use leads to health, social and legal problems. The aim of this paper is to discuss cocaine action, addicts characteristics, use patterns and consequences, as well as addiction treatment methods. A literature review was based on the Medline, PubMed, Polish Medical Bibliography databases and the Silesian Library resources. The Police and Central Statistical Office statistics, as well as the World Health Organization, the European Monitoring Centre for Drugs and Drug Addiction and the National Office for Combating Drug Addiction reports were used. Cocaine leads to mood improvement, appetite decrease, physical and intellectual activity enhancement, euphoria, inflated self-esteem, social networking ease and increased sexual desire. Cocaine hydrochloride is mainly used intranasaly, but also as intravenous and subcutaneous injections. Cocaine use and first addiction treatment fall in later age compared to other psychoactive substances. There is a high men to women ratio among addicts. There is a relationship between cocaine addiction, the presence of other disorders and genetic predisposition to addiction development. Polish reports indicate higher popularity of cocaine among people with a high economic and social status. Although Poland is a country with the low percentage of cocaine use, its popularity is growing. The consequences of cocaine use concern somatic and mental health problems, socioeconomic and legal conditions. The drug plays a role in crimes and traffic accidents. Because of the risks associated with cocaine use, it has been listed in a register of drugs attached to the Act on Counteracting Drug Addiction. Addiction treatment includes psychological, pharmacological and harm reduction strategies. Med Pr 2016;67(4:537–544

  10. Short-term exposure to repeated chasing stress does not induce habituation in Senegalese sole, Solea senegalensis

    DEFF Research Database (Denmark)

    Conde-Sieira, Marta; Valente, Luisa M.P.; Hernandez-Perez, Juan

    2018-01-01

    Animals can habituate to certain repeated stressors and reduce the physiological response that such stressor evoked initially. Studies related to stress habituation in fish are scarce and the available data differ depending on the species and on the type, duration and severity of the stressor...... no significant changes in serotonergic activity. However, incremented serotonergic activity was detected in fish previously trained. Furthermore, dopaminergic activity decreased in diurnal trained and nocturnal trained groups with respect to ST/naïve fish. Crh expression in hypothalamus was higher in ST...... for the animals to habituate, indicating that repeated chasing within short periods should be avoided when manipulating fish in order to keep proper welfare conditions in this species....

  11. High levels of wheel running protect against behavioral sensitization to cocaine.

    Science.gov (United States)

    Renteria Diaz, Laura; Siontas, Dora; Mendoza, Jose; Arvanitogiannis, Andreas

    2013-01-15

    Although there is no doubt that the direct action of stimulant drugs on the brain is necessary for sensitization to their behavioral stimulating effects, several experiments indicate that drug action is often not sufficient to produce sensitization. There is considerable evidence that many individual characteristics and experiential variables can modulate the behavioral and neural changes that are seen following repeated exposure to stimulant drugs. In the work presented here, we examined whether chronic wheel running would modulate behavioral sensitization to cocaine, and whether any such influence was contingent on individual differences in wheel running. We found that a 5- or 10-week experience with wheel running protects against behavioral sensitization to cocaine but only in animals with a natural tendency to run the most. Understanding the mechanism underlying the modulating effect of wheel running on behavioral sensitization may have important implications for future studies on the link between drug-induced behavioral and neural adaptations. Copyright © 2012 Elsevier B.V. All rights reserved.

  12. The effect of sensory-nutrient congruency on food intake after repeated exposure: do texture and/or energy density matter?

    Science.gov (United States)

    Hogenkamp, P S

    2014-09-01

    Sensory properties guide the amount that people eat. In particular, food texture plays an important role in a food's 'expected satiation', which in turn affects the food-related decision making process. One hypothesis is that incongruent pairing of a textural cue with a post-ingestive outcome compromises this process, leading to poor energy compensation. Several studies examined the effect of both energy density and sensory characteristics (i.e. increased creaminess and thickness) on expectations, subjective appetite and food intake. To add to this literature, a re-analysis of data assessed whether the effect of sensory-nutrient pairings on energy intake compensation persisted after repeated exposure to a food. In this cross-over design, 27 participants consumed two preloads with 'congruent' (low-energy/liquid; high-energy/semi-solid) and two preloads with 'incongruent' (low-energy/semi-solid; high-energy/liquid) texture-nutrient combinations for nine subsequent meals, during which ad libitum intake was measured. Intake at first exposure did not differ between the low-energy (280±150kcal) and high-energy preloads (292±183kcal) in the incongruent conditions. By contrast, it was greater after the low-energy (332±203kcal) than after the high-energy (236±132kcal) preload in the congruent conditions (energy∗incongruent/congruent, p=0.04). Post-exposure, this pattern changed: intake depended on the energy density of the preloads in all conditions, and was greater after low-energy preloads (day∗energy∗incongruent/congruent-interaction for breakfast: p=0.02). Thus, manipulating the sensory properties of a food influenced energy compensation and meal size, but only at initial exposure. Repeated exposure 'corrected' the initial lack of compensation observed in conditions with incongruent sensory-nutrient pairings. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Narrative exposure therapy for posttraumatic stress disorder associated with repeated interpersonal trauma in patients with severe mental illness: a mixed methods design

    Directory of Open Access Journals (Sweden)

    Maria W. Mauritz

    2016-09-01

    Full Text Available Background: In the Netherlands, most patients with severe mental illness (SMI receive flexible assertive community treatment (FACT provided by multidisciplinary community mental health teams. SMI patients with comorbid posttraumatic stress disorder (PTSD are sometimes offered evidence-based trauma-focused treatment like eye movement desensitization reprocessing or prolonged exposure. There is a large amount of evidence for the effectiveness of narrative exposure therapy (NET within various vulnerable patient groups with repeated interpersonal trauma. Some FACT-teams provide NET for patients with comorbid PTSD, which is promising, but has not been specifically studied in SMI patients. Objectives: The primary aim is to evaluate NET in SMI patients with comorbid PTSD associated with repeated interpersonal trauma to get insight into whether (1 PTSD and dissociative symptoms changes and (2 changes occur in the present SMI symptoms, care needs, quality of life, global functioning, and care consumption. The second aim is to gain insight into patients’ experiences with NET and to identify influencing factors on treatment results. Methods: This study will have a mixed methods convergent design consisting of quantitative repeated measures and qualitative semi-structured in-depth interviews based on Grounded Theory. The study population will include adult SMI outpatients (n=25 with comorbid PTSD and receiving NET. The quantitative study parameters will be existence and severity of PTSD, dissociative, and SMI symptoms; care needs; quality of life; global functioning; and care consumption. In a longitudinal analysis, outcomes will be analyzed using mixed models to estimate the difference in means between baseline and repeated measurements. The qualitative study parameters will be experiences with NET and perceived factors for success or failure. Integration of quantitative and qualitative results will be focused on interpreting how qualitative results

  14. Unique Behavioral and Neurochemical Effects Induced by Repeated Adolescent Consumption of Caffeine-Mixed Alcohol in C57BL/6 Mice.

    Directory of Open Access Journals (Sweden)

    Meridith T Robins

    Full Text Available The number of highly caffeinated products has increased dramatically in the past few years. Among these products, highly caffeinated energy drinks are the most heavily advertised and purchased, which has resulted in increased incidences of co-consumption of energy drinks with alcohol. Despite the growing number of adolescents and young adults reporting caffeine-mixed alcohol use, knowledge of the potential consequences associated with co-consumption has been limited to survey-based results and in-laboratory human behavioral testing. Here, we investigate the effect of repeated adolescent (post-natal days P35-61 exposure to caffeine-mixed alcohol in C57BL/6 mice on common drug-related behaviors such as locomotor sensitivity, drug reward and cross-sensitivity, and natural reward. To determine changes in neurological activity resulting from adolescent exposure, we monitored changes in expression of the transcription factor ΔFosB in the dopaminergic reward pathway as a sign of long-term increases in neuronal activity. Repeated adolescent exposure to caffeine-mixed alcohol exposure induced significant locomotor sensitization, desensitized cocaine conditioned place preference, decreased cocaine locomotor cross-sensitivity, and increased natural reward consumption. We also observed increased accumulation of ΔFosB in the nucleus accumbens following repeated adolescent caffeine-mixed alcohol exposure compared to alcohol or caffeine alone. Using our exposure model, we found that repeated exposure to caffeine-mixed alcohol during adolescence causes unique behavioral and neurochemical effects not observed in mice exposed to caffeine or alcohol alone. Based on similar findings for different substances of abuse, it is possible that repeated exposure to caffeine-mixed alcohol during adolescence could potentially alter or escalate future substance abuse as means to compensate for these behavioral and neurochemical alterations.

  15. Intracellular mechanisms of cocaine-memory reconsolidation in the basolateral amygdala and dorsal hippocampus

    Science.gov (United States)

    Wells, Audrey Marie

    The ability of cocaine-associated environmental contexts to promote relapse in abstinent humans and reinstatement of cocaine-seeking behavior in laboratory animals depends on the formation and maintenance of maladaptive context-response-cocaine associative memories, the latter of which can be disrupted by manipulations that interfere with memory reconsolidation. Memory reconsolidation refers to a protein synthesis-dependent phenomenon whereby memory traces are reincorporated back into long-term memory storage following their retrieval and subsequent destabilization. To elucidate the distinctive roles of the basolateral amygdala (BLA) and dorsal hippocampus (DH) in the reconsolidation of context-response-cocaine memories, Experiments 1-3 evaluated novel molecular mechanisms within each structure that control this phenomenon. Experiment 1 tested the hypothesis that activation of the extracellular signal-regulated kinase (ERK) in the BLA and nucleus accumbens core (NACc - a substrate for Pavlovian cocaine-memory reconsolidation) would critically control instrumental cocaine-memory reconsolidation. To determine this, rats were re-exposed to a context that had previously been used for cocaine self-administration (i.e., cocaine memory-reactivation) and immediately thereafter received bilateral intra-BLA or intra-NACc microinfusions of the ERK inhibitor U0126 or vehicle (VEH) and were subsequently tested for drug context-induced cocaine-seeking behavior (non-reinforced lever responding) ~72 h later. Re-exposure to the cocaine-paired context at test fully reinstated cocaine-seeking behavior, relative to responding in an alternate, extinction context, and post-reactivation U0126 treatment in the BLA, but not the NACc, impaired cocaine-seeking behavior, relative to VEH. This effect was associated with a temporary increase in ERK2, but not ERK1, phosphorylation in the BLA and required explicit reactivation of the target memory trace (i.e., did not similarly manifest when U

  16. The effects of chronic cadmium exposure on repeat swimming performance and anaerobic metabolism in brown trout (Salmo trutta) and lake whitefish (Coregonus clupeaformis).

    Science.gov (United States)

    Cunningham, Jessie L; McGeer, James C

    2016-04-01

    This study investigates the effect of chronic Cd exposure on the ability to perform repeat swim challenges in brown trout (Salmo trutta) and lake whitefish (Coregonus clupeaformis). Fish were exposed to waterborne Cd (18nM) in moderately hard water (120mgL(-1) CaCO3) for 30 days. This level of exposure has been shown to cause sublethal physiological disruption and acclimation responses but no impairment of sustained swimming capacity (Ucrit) in single swim challenges. Swim trials were done over the course of the exposure and each one consisted of an initial swim to 85% of the Ucrit of control fish, a 30min recovery period and finally a second swim challenge to determine Ucrit. Plasma and tissue samples were collected before and after each of the swim periods. As expected from previous studies, Cd exposure resulted in significant accumulation of Cd in gills, liver and kidney but not in white muscle. Exposure also induced a loss of plasma Ca followed by subsequent recovery (in lake whitefish but not brown trout) with few mortalities (100% survival for lake whitefish and 93% for brown trout). Both control and exposed fish swam to 85% of the single swim Ucrit and no differences in performance were seen. The Ucrit of unexposed controls in the second swim challenges were not different from the single swim Ucrit. However, second swim performance was significantly reduced in Cd exposed fish, particularly after a week of exposure where 31% and 38% reductions were observed for brown trout and lake whitefish respectively. Swimming to 85% Ucrit resulted in metabolic expenditure with little recovery after 30min. Few differences were observed between control and Cd exposed fish with the exception of a reduction in resting white muscle ATP stores of Cd exposed fish after 1 week of exposure. The results show that chronic sublethal Cd exposure results in an impairment of swimming ability in repeat swim challenges but this impairment is generally not related to metabolic processes

  17. Repeated sublethal exposures to the sea lice pesticide Salmosan® (azamethiphos) on adult male lobsters (Homarus americanus) causes neuromuscular dysfunction, hypoxia, metabolic disturbances and mortality.

    Science.gov (United States)

    Dounia, Daoud; Andrea, Battison; Lefort, Natalie; Van Geest, Jordana Lynne

    2016-12-01

    In Atlantic Canada and other salmon-growing regions, treatment of sea lice infestations in salmon aquaculture is necessary to protect fish health. The product Salmosan®, which contains the organophosphate azamethiphos as the active ingredient, is a pesticide presently used for treatment against sea lice. It is applied as a bath treatment and then released into the surrounding seawater. The potential for lethality to non-target species following acute and chronic exposures to Salmosan® has been studied over the past decade, however, the potential for sublethal effects on lobsters remains a concern. Adult male lobsters were exposed to 0.06, 0.5, and 5µgL -1 azamethiphos for one hour, repeated five times, over 48h. Lobsters were assessed immediately after exposure and over six days of recovery. Inhibition of muscle cholinesterase activity was detected in lobsters exposed to 0.5 and 5µgL -1 azamethiphos. The 5µgL -1 dose was considered lethal (93% cumulative mortality). Significant changes in hemolymph plasma biochemistry were most apparent in the 5µgL -1 exposure group in the immediate post-exposure samples. Citrate synthase activity was significantly lower in muscles of the 0.5µgL -1 exposure group compared to control lobsters. Mean electron transport system and standard metabolic rates tended to be lower in muscle tissue of the 0.5µgL -1 exposure group than control group lobsters. These results suggest that sublethal effects on lobster energetics may occur under laboratory exposure conditions (i.e., concentrations and duration) considered environmentally relevant, which could result in impairment under natural conditions. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. The Effects of Exposure to Repeated Minor Pain During the Neonatal Period on Formalin Pain Behavior and Thermal Withdrawal Latencies

    Directory of Open Access Journals (Sweden)

    C Celeste Johnston

    2003-01-01

    Full Text Available Preterm infants undergoing untreated, repeated painful procedures as part of their early experience are more likely to behave differently to pain as they mature than infants who were born at term and did not experience excessive exogenous pain. The neonatal rat model was used to investigate the short- and long-term effects of repeated pain in infancy on later development of pain responses. Newborn rat pups were randomly assigned by litter to be left unhandled (UH, handled by being removed from the dam for 15 min four times daily (H, and being handled and receiving pain from a paw prick with a 26G needle four times daily (Pon postnatal days (PD 2 through 8 (PD2-PD8. Maternal behaviour and grooming of pups on their return to the nest were recorded at PD6 for H and P pups. At PD15, PD36 and PD65, animals were first tested for latency to thermal stimulation threshold using the Hargreaves test and then for inflammatory pain using the formalin test. Pups in the HP group received significantly more grooming from their mothers (359 s than pups in the H group (295 s, P<0.0001. When accounting for differences in maternal grooming, a decreased thermal threshold in the P group compared with the H group (6.04 s versus 5.3 s, P<0.05 was found, although the correlations were not significant between maternal grooming and thermal thresholds. No group differences were seen with the formalin test. Interestingly, age was a significant factor in both tests, with younger animals showing fewer pain behaviours regardless of group or maternal grooming of the pup. Sex was significant at one age only in latency to thermal stimulation testing. The results suggest that changes in maternal care may be an important factor mediating the long-term effects of repeated neonatal experiences of pain.

  19. Effects of acute and repeated oral exposure to the organophosphate insecticide chlorpyrifos on open-field activity in chicks.

    Science.gov (United States)

    Al-Badrany, Y M A; Mohammad, F K

    2007-11-01

    The effects of the organophosphate insecticide chlorpyrifos on 5min open-field activity were examined in a 7-15 days old chick model. Chlorpyrifos was acutely administered taking into account cholinesterase inhibition and determination of the acute (24h) median lethal dose (LD50). The oral LD50 value of chlorpyrifos in chicks was 18.14mg/kg, with cholinergic toxicosis observed on intoxicated chicks. Chlorpyrifos at the dose rates of 5,10 and 20mg/kg orally produced within 2h signs of cholinergic toxicosis in the chicks and significantly inhibited plasma (40-70%), whole brain (43-69%) and liver (31-46%) cholinesterase activities in a dose-dependent manner. Chlorpyrifos at 2 and 4mg/kg, orally did not produce overt signs of cholinergic toxicosis, but decreased (30, 60 and 90min after dosing) the general locomotor activity of the chicks as seen by a significant increase in the latency to move from the central square of the open-field arena, decreases in the numbers of lines crossed and vocalization score. Repeated daily chlorpyrifos treatments (2 and 4mg/kg, orally) for seven consecutive days also caused hypoactivity in chicks in the open-field behavioral paradigm. Only the high dose of chlorpyrifos (4mg/kg, orally) given repeatedly for 7 days caused significant cholinesterase inhibition in the whole brain (37%) and the liver (22%). In conclusion, chlorpyrifos at single or short-term repeated doses-induced behavioral changes in 7-15 days old chicks, in a model that could be used for further neurobehavioral studies involving subtle effects of organophosphates on chicks.

  20. Regional Differences in Striatal Neuronal Ensemble Excitability Following Cocaine and Extinction Memory Retrieval in Fos-GFP Mice.

    Science.gov (United States)

    Ziminski, Joseph J; Sieburg, Meike C; Margetts-Smith, Gabriella; Crombag, Hans S; Koya, Eisuke

    2018-03-01

    Learned associations between drugs of abuse and the drug administration environment have an important role in addiction. In rodents, exposure to a drug-associated environment elicits conditioned psychomotor activation, which may be weakened following extinction (EXT) learning. Although widespread drug-induced changes in neuronal excitability have been observed, little is known about specific changes within neuronal ensembles activated during the recall of drug-environment associations. Using a cocaine-conditioned locomotion (CL) procedure, the present study assessed the excitability of neuronal ensembles in the nucleus accumbens core and shell (NAc core and NAc shell ), and dorsal striatum (DS) following cocaine conditioning and EXT in Fos-GFP mice that express green fluorescent protein (GFP) in activated neurons (GFP+). During conditioning, mice received repeated cocaine injections (20 mg/kg) paired with a locomotor activity chamber (Paired) or home cage (Unpaired). Seven to 13 days later, both groups were re-exposed to the activity chamber under drug-free conditions and Paired, but not Unpaired, mice exhibited CL. In a separate group of mice, CL was extinguished by repeatedly exposing mice to the activity chamber under drug-free conditions. Following the expression and EXT of CL, GFP+ neurons in the NAc core (but not NAc shell and DS) displayed greater firing capacity compared to surrounding GFP- neurons. This difference in excitability was due to a generalized decrease in GFP- excitability following CL and a selective increase in GFP+ excitability following its EXT. These results suggest a role for both widespread and ensemble-specific changes in neuronal excitability following recall of drug-environment associations.

  1. Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment.

    Science.gov (United States)

    Chaudhari, Umesh; Nemade, Harshal; Wagh, Vilas; Gaspar, John Antonydas; Ellis, James K; Srinivasan, Sureshkumar Perumal; Spitkovski, Dimitry; Nguemo, Filomain; Louisse, Jochem; Bremer, Susanne; Hescheler, Jürgen; Keun, Hector C; Hengstler, Jan G; Sachinidis, Agapios

    2016-11-01

    The currently available techniques for the safety evaluation of candidate drugs are usually cost-intensive and time-consuming and are often insufficient to predict human relevant cardiotoxicity. The purpose of this study was to develop an in vitro repeated exposure toxicity methodology allowing the identification of predictive genomics biomarkers of functional relevance for drug-induced cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The hiPSC-CMs were incubated with 156 nM doxorubicin, which is a well-characterized cardiotoxicant, for 2 or 6 days followed by washout of the test compound and further incubation in compound-free culture medium until day 14 after the onset of exposure. An xCELLigence Real-Time Cell Analyser was used to monitor doxorubicin-induced cytotoxicity while also monitoring functional alterations of cardiomyocytes by counting of the beating frequency of cardiomyocytes. Unlike single exposure, repeated doxorubicin exposure resulted in long-term arrhythmic beating in hiPSC-CMs accompanied by significant cytotoxicity. Global gene expression changes were studied using microarrays and bioinformatics tools. Analysis of the transcriptomic data revealed early expression signatures of genes involved in formation of sarcomeric structures, regulation of ion homeostasis and induction of apoptosis. Eighty-four significantly deregulated genes related to cardiac functions, stress and apoptosis were validated using real-time PCR. The expression of the 84 genes was further studied by real-time PCR in hiPSC-CMs incubated with daunorubicin and mitoxantrone, further anthracycline family members that are also known to induce cardiotoxicity. A panel of 35 genes was deregulated by all three anthracycline family members and can therefore be expected to predict the cardiotoxicity of compounds acting by similar mechanisms as doxorubicin, daunorubicin or mitoxantrone. The identified gene panel can be applied in the safety

  2. The in vitro biokinetics of chlorpromazine and diazepam in aggregating rat brain cell cultures after repeated exposure

    NARCIS (Netherlands)

    Broeders, Jessica J W; Hermens, Joop L M; Blaauboer, Bas J; Zurich, Marie-Gabrielle

    2015-01-01

    Neurotoxic effects of compounds can be tested in vitro using cell systems. One example is aggregating rat brain cell cultures. For the extrapolation of in vitro data to the in vivo situation, it is important to take the biokinetics of the test compound into account. In addition, the exposure in vivo

  3. Repeated exposure to intra-amniotic LPS partially protects against adverse effects of intravenous LPS in preterm lambs.

    Science.gov (United States)

    Gisslen, Tate; Hillman, Noah H; Musk, Gabrielle C; Kemp, Matthew W; Kramer, Boris W; Senthamaraikannan, Paranthaman; Newnham, John P; Jobe, Alan H; Kallapur, Suhas G

    2014-02-01

    Histologic chorioamnionitis, frequently associated with preterm births and adverse outcomes, results in prolonged exposure of preterm fetuses to infectious agents and pro-inflammatory mediators, such as LPS. Endotoxin tolerance-type effects were demonstrated in fetal sheep following repetitive systemic or intra-amniotic (i.a.) exposures to LPS, suggesting that i.a. LPS exposure would cause endotoxin tolerance to a postnatal systemic dose of LPS in preterm sheep. In this study, randomized pregnant ewes received either two i.a. injections of LPS or saline prior to preterm delivery. Following operative delivery, the lambs were treated with surfactant, ventilated, and randomized to receive either i.v. LPS or saline at 30  min of age. Physiologic variables and indicators of systemic and lung inflammation were measured. Intravenous LPS decreased blood neutrophils and platelets values following i.a. saline compared to that after i.a. LPS. Intra-amniotic LPS prevented blood pressure from decreasing following the i.v. LPS, but also caused an increased oxygen index. Intra-amniotic LPS did not cause endotoxin tolerance as assessed by cytokine expression in the liver, lung or plasma, but increased myeloperoxidase-positive cells in the lung. The different compartments of exposure to LPS (i.a. vs i.v.) are unique to the fetal to newborn transition. Intra-amniotic LPS incompletely tolerized fetal lambs to postnatal i.v. LPS.

  4. Intake during repeated exposure to low- and high-energy-dense yogurts by different means of consumption

    NARCIS (Netherlands)

    Hogenkamp, P.S.; Mars, M.; Stafleu, A.; Graaf, C.de

    2010-01-01

    Background: An important question in the regulation of energy intake is whether dietary learning of energy content depends on the food's characteristics, such as texture. Texture might affect the duration of sensory exposure and eating rate. Objective: The objective was to investigate whether a long

  5. Androgen receptor gene CAG repeat length as modifier of the association between Persistent Organohalogen Pollutant exposure markers and semen characteristics

    DEFF Research Database (Denmark)

    Giwercman, Aleksander; Rylander, Lars; Rignell-Hydbom, Anna

    2007-01-01

    OBJECTIVES: Exposure to persistent organohalogen pollutants was suggested to impair male reproductive function. A gene-environment interaction has been proposed. No genes modifying the effect of persistent organohalogen pollutants on reproductive organs have yet been identified. We aimed to inves...

  6. Cocaine addiction: the hidden dimension.

    Science.gov (United States)

    Oswald, L M

    1989-06-01

    There is growing awareness within the nursing profession that nurses need to expand their knowledge about addiction and develop expertise in providing care for substance abusing clients. This report presents a discussion about cocaine abuse that is focused on evolving knowledge about the physiology of addiction. Researchers have recently described cocaine-induced neurochemical changes in the brain that may form the underpinnings for the behavioral manifestations and symptomatology that have been associated with cocaine addiction. These neurochemical alterations are described at the cellular level, and treatment implications for nurses are presented.

  7. Deletion of Type 2 Metabotropic Glutamate Receptor Decreases Sensitivity to Cocaine Reward in Rats.

    Science.gov (United States)

    Yang, Hong-Ju; Zhang, Hai-Ying; Bi, Guo-Hua; He, Yi; Gao, Jun-Tao; Xi, Zheng-Xiong

    2017-07-11

    Cocaine users show reduced expression of the metabotropic glutamate receptor (mGluR2), but it is not clear whether this is a predisposing trait for addiction or a consequence of drug exposure. In this study, we found that a nonsense mutation at the mGluR2 gene decreased mGluR2 expression and altered the seeking and taking of cocaine. mGluR2 mutant rats show reduced sensitivity to cocaine reward, requiring more cocaine to reach satiation when it was freely available and ceasing their drug-seeking behavior sooner than controls when the response requirement was increased. mGluR2 mutant rats also show a lower propensity to relapse after a period of cocaine abstinence, an effect associated with reduced cocaine-induced dopamine and glutamate overflow in the nucleus accumbens. These findings suggest that mGluR2 polymorphisms or reduced availability of mGluR2 might be risk factors for the initial development of cocaine use but could actually protect against addiction by reducing sensitivity to cocaine reward. Published by Elsevier Inc.

  8. A broad-spectrum sunscreen prevents cumulative damage from repeated exposure to sub-erythemal solar ultraviolet radiation representative of temperate latitudes.

    Science.gov (United States)

    Seité, S; Christiaens, F; Bredoux, C; Compan, D; Zucchi, H; Lombard, D; Fourtanier, A; Young, A R

    2010-02-01

    We have previously shown the detrimental effects of 19 sub-erythemal exposures to daily ultraviolet radiation (DUVR, which mimics non-extreme exposure conditions), delivered over 4 weeks to volunteers. This source had UVA (320-400 nm) to UVB (290-320 nm) irradiance ratio of 25, instead of that close to 10 that is typically the case with solar-simulated radiation (SSR) that represents summer global sunlight with a clear sky and quasi-zenith solar irradiance. Here, we report on an extension of this previous study, in which we evaluated the photoprotection afforded by a broad-spectrum daily-care product with a low-sun protection factor (SPF 8, UVA-PF 7 and 3* rated UVA protection). We assessed cellular and molecular markers of photodamage that are relevant to skin cancer and photoageing. This study shows that biological effects of repeated exposure to DUVR can be prevented by a broad-spectrum daily-care product and that the level of protection afforded varies with the studied endpoint. Efficient daily UVR protection, as provided by a broad-spectrum daily-care product, is necessary to prevent the 'silent' sub-erythemal cumulative effects of UVR from inadvertent sun exposure.

  9. Association between secondhand smoke exposure at home and cigarette gifting and sharing in Zhejiang, China: a repeat cross-sectional study.

    Science.gov (United States)

    Xu, Yue; Xu, ShuiYang; Wu, QingQing; Guo, YuJie

    2016-03-03

    The aims of the current study were to assess the prevalence of household cigarette gifting and sharing, and to evaluate the relationship between secondhand smoke (SHS) exposure, and cigarette gifting and sharing, in Zhejiang, China. A repeat cross-sectional design. 10 sites in 5 cities in Zhejiang, China. Two surveys were conducted with adults in Zhejiang, China, in 2010 (N=2112) and 2012 (N=2279), respectively. At both waves, the same questionnaire was used; respondents were asked questions on residence, number of family smokers, indoor smoking rules, household income and cigarette gifting and sharing. The findings revealed that more than half of respondents' families (54.50% in 2010, 52.79% in 2012) reported exposure to SHS. Many families (54.73% in 2010, 47.04% in 2012) shared cigarettes with others, and a minority (14.91% in 2010, 14.17% in 2012) reported their family giving cigarettes as a gift. There was a significant decrease in cigarette sharing from 2010 to 2012, irrespective of household with SHS exposure status; and the cigarette gifting was significantly decreased in household without SHS exposure. Compared to households without SHS exposure, the prevalence of cigarette gifting and sharing in households with SHS exposure was more obvious. Encouraging and promoting a smoke-free household environment is necessary to change public smoking customs in Zhejiang, China. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  10. Mood and autonomic responses to repeated exposure to the Trier Social Stress Test for Groups (TSST-G).

    Science.gov (United States)

    Boesch, Maria; Sefidan, Sandra; Ehlert, Ulrike; Annen, Hubert; Wyss, Thomas; Steptoe, Andrew; La Marca, Roberto

    2014-05-01

    A group version of the Trier Social Stress Test (TSST-G) was introduced as a standardized, economic and efficient tool to induce a psychobiological stress response simultaneously in a group of subjects. The aim of the present study was to examine the efficacy of the TSST-G to repeatedly induce an affective and autonomic stress response while comparing two alternative protocols for the second examination. Healthy young male recruits participated twice in the TSST-G 10 weeks apart. In the first examination, the TSST-G consisted of a combination of mental arithmetic and a fake job interview (TSST-G-1st; n=294). For the second examination, mental arithmetic was combined with either (a) a defensive speech in response to a false shoplifting accusation (TSST-G-2nd-defence; n=105), or (b) a speech on a more neutral topic selected by the investigators (TSST-G-2nd-presentation; n=100). Affect ratings and salivary alpha-amylase (sAA) were determined immediately before and after the stress test, while heart rate (HR) and heart rate variability (HRV) were measured continuously. TSST-G-1st resulted in a significant increase of negative affect, HR, and sAA, and a significant decrease in positive affect and HRV. TSST-G-2nd, overall, resulted in a significant increase of HR and sAA (the latter only in response to TSST-G-2nd-defence) and a decrease in HRV, while no significant affect alterations were found. When comparing both, TSST-G-2nd-defence and -2nd-presentation, the former resulted in a stronger stress response with regard to HR and HRV. The findings reveal that the TSST-G is a useful protocol to repeatedly evoke an affective and autonomic stress response, while repetition leads to affective but not necessarily autonomic habituation. When interested in examining repeated psychosocial stress reactivity, a task that requires an ego-involving effort, such as a defensive speech, seems to be significantly superior to a task using an impersonal speech. Copyright © 2014 Elsevier

  11. In utero exposure to nanosized carbon black (Printex90) does not induce tandem repeat mutations in female murine germ cells

    DEFF Research Database (Denmark)

    Boisen, Anne Mette Zenner; Shipley, Thomas; Jackson, Petra

    2013-01-01

    Inhalation of particles has been shown to induce mutations in the male germline in mice following both prenatal and adult exposures in several experiments. In contrast, the effects of particles on female germ cell mutagenesis are not well established. Germline mutations are induced during active...... cell division, which occurs during fetal development in females. We investigated the effects of prenatal exposure to carbon black nanoparticles (CB) on induction of mutations in the female mouse germline during fetal development, spanning the critical developmental stages of oogenesis. Pregnant C57BL/6...... mutation rates in the resulting F2 generation were determined from full pedigrees (mother, father, offspring) of F1 female mice (178 CB-exposed and 258 control F2 offspring). ESTR mutation rates in CB-exposed F2 female offspring were not statistically different from those of F2 female control offspring....

  12. Eosinophilia and biotoxin exposure in bottlenose dolphins (Tursiops truncatus) from a coastal area impacted by repeated mortality events

    International Nuclear Information System (INIS)

    Schwacke, Lori H.; Twiner, Michael J.; De Guise, Sylvain; Balmer, Brian C.; Wells, Randall S.; Townsend, Forrest I.; Rotstein, David C.; Varela, Rene A.; Hansen, Larry J.; Zolman, Eric S.; Spradlin, Trevor R.

    2010-01-01

    Bottlenose dolphins (Tursiops truncatus) inhabiting coastal waters in the northern Gulf of Mexico have been impacted by recurrent unusual mortality events over the past few decades. Several of these mortality events along the Florida panhandle have been tentatively attributed to poisoning from brevetoxin produced by the dinoflagellate Karenia brevis. While dolphins in other regions of the Florida coast are often exposed to K. brevis blooms, large-scale dolphin mortality events are relatively rare and the frequency and magnitude of die-offs along the Panhandle raise concern for the apparent vulnerability of dolphins in this region. We report results from dolphin health assessments conducted near St. Joseph Bay, Florida, an area impacted by 3 unusual die-offs within a 7-year time span. An eosinophilia syndrome, manifested as an elevated blood eosinophil count without obvious cause, was observed in 23% of sampled dolphins. Elevated eosinophil counts were associated with decreased T-lymphocyte proliferation and increased neutrophil phagocytosis. In addition, indication of chronic low-level exposure to another algal toxin, domoic acid produced by the diatom Pseudo-nitzschia spp., was determined. Previous studies of other marine mammal populations exposed recurrently to Pseudo-nitzschia blooms have suggested a possible link between the eosinophilia and domoic acid exposure. While the chronic eosinophilia syndrome could over the long-term produce organ damage and alter immunological status and thereby increase vulnerability to other challenges, the significance of the high prevalence of the syndrome to the observed mortality events in the St. Joseph Bay area is unclear. Nonetheless, the unusual immunological findings and concurrent evidence of domoic acid exposure in this sentinel marine species suggest a need for further investigation to elucidate potential links between chronic, low-level exposure to algal toxins and immune health.

  13. Eosinophilia and biotoxin exposure in bottlenose dolphins (Tursiops truncatus) from a coastal area impacted by repeated mortality events

    Energy Technology Data Exchange (ETDEWEB)

    Schwacke, Lori H., E-mail: Lori.Schwacke@noaa.gov [National Oceanic and Atmospheric Administration, National Ocean Service, Center for Human Health Risks, 331 Fort Johnson Road, Charleston, SC 29412 (United States); Twiner, Michael J. [National Oceanic and Atmospheric Administration, National Ocean Service, Center for Coastal Environmental Health and Biomolecular Research, 219 Fort Johnson Road, Charleston, SC 29412 (United States); De Guise, Sylvain [University of Connecticut, Department of Pathobiology and Veterinary Science, 61 North Eagleville Road, U-89, Storrs, CT 06269 (United States); Balmer, Brian C.; Wells, Randall S. [Chicago Zoological Society, c/o Mote Marine Laboratory, 1600 Ken Thompson Parkway, Sarasota, FL 34236 (United States); Townsend, Forrest I. [Bayside Hospital for Animals, 251 N.E. Racetrack Road, Fort Walton Beach, FL 32547 (United States); Rotstein, David C. [National Oceanic and Atmospheric Administration, National Marine Fisheries Service, Office of Protected Resources, Marine Mammal Health and Stranding Response Program, 1315 East West Highway, Silver Spring, MD 20910 (United States); Varela, Rene A. [Ocean Embassy Inc, 6433 Pinecastle Blvd, Ste 2, Orlando, FL 32809 (United States); Hansen, Larry J. [National Oceanic and Atmospheric Administration, National Marine Fisheries Service Southeast Fisheries Science Center,101 Pivers Island Road, Beaufort, NC 28516 (United States); Zolman, Eric S. [National Oceanic and Atmospheric Administration, National Ocean Service, Center for Coastal Environmental Health and Biomolecular Research, 219 Fort Johnson Road, Charleston, SC 29412 (United States); Spradlin, Trevor R. [National Oceanic and Atmospheric Administration, National Marine Fisheries Service, Office of Protected Resources, Marine Mammal Health and Stranding Response Program, 1315 East West Highway, Silver Spring, MD 20910 (United States); and others

    2010-08-15

    Bottlenose dolphins (Tursiops truncatus) inhabiting coastal waters in the northern Gulf of Mexico have been impacted by recurrent unusual mortality events over the past few decades. Several of these mortality events along the Florida panhandle have been tentatively attributed to poisoning from brevetoxin produced by the dinoflagellate Karenia brevis. While dolphins in other regions of the Florida coast are often exposed to K. brevis blooms, large-scale dolphin mortality events are relatively rare and the frequency and magnitude of die-offs along the Panhandle raise concern for the apparent vulnerability of dolphins in this region. We report results from dolphin health assessments conducted near St. Joseph Bay, Florida, an area impacted by 3 unusual die-offs within a 7-year time span. An eosinophilia syndrome, manifested as an elevated blood eosinophil count without obvious cause, was observed in 23% of sampled dolphins. Elevated eosinophil counts were associated with decreased T-lymphocyte proliferation and increased neutrophil phagocytosis. In addition, indication of chronic low-level exposure to another algal toxin, domoic acid produced by the diatom Pseudo-nitzschia spp., was determined. Previous studies of other marine mammal populations exposed recurrently to Pseudo-nitzschia blooms have suggested a possible link between the eosinophilia and domoic acid exposure. While the chronic eosinophilia syndrome could over the long-term produce organ damage and alter immunological status and thereby increase vulnerability to other challenges, the significance of the high prevalence of the syndrome to the observed mortality events in the St. Joseph Bay area is unclear. Nonetheless, the unusual immunological findings and concurrent evidence of domoic acid exposure in this sentinel marine species suggest a need for further investigation to elucidate potential links between chronic, low-level exposure to algal toxins and immune health.

  14. Repeated exposure to methamphetamine induces sex-dependent hypersensitivity to ischemic injury in the adult rat heart.

    Directory of Open Access Journals (Sweden)

    Boyd R Rorabaugh

    Full Text Available We previously reported that adult female, but not male rats that were prenatally exposed to methamphetamine exhibit myocardial hypersensitivity to ischemic injury. However, it is unknown whether hypersensitivity to ischemic injury develops when rats are exposed to methamphetamine during adulthood. The goal of this study was to determine whether methamphetamine exposure during adulthood sensitizes the heart to ischemic injury.Adult male and female rats received daily injections of methamphetamine (5 mg/kg or saline for 10 days. Their hearts were isolated on day 11 and subjected to a 20 min ischemic insult on a Langendorff isolated heart apparatus. Cardiac contractile function was measured by an intraventricular balloon, and infarct size was measured by triphenyltetrazolium chloride staining.Hearts from methamphetamine-treated females exhibited significantly larger infarcts and suppressed postischemic recovery of contractile function compared to hearts from saline-treated females. In contrast, methamphetamine had no effect on infarct size or contractile recovery in male hearts. Subsequent experiments demonstrated that hypersensitivity to ischemic injury persisted in female hearts following a 1 month period of abstinence from methamphetamine. Myocardial protein kinase C-ε expression, Akt phosphorylation, and ERK phosphorylation were unaffected by adult exposure to methamphetamine.Exposure of adult rats to methamphetamine sex-dependently increases the extent of myocardial injury following an ischemic insult. These data suggest that women who have a heart attack might be at risk of more extensive myocardial injury if they have a recent history of methamphetamine abuse.

  15. Repeated exposure to methamphetamine induces sex-dependent hypersensitivity to ischemic injury in the adult rat heart

    Science.gov (United States)

    Seeley, Sarah L.; Stoops, Thorne S.; D’Souza, Manoranjan S.

    2017-01-01

    Background We previously reported that adult female, but not male rats that were prenatally exposed to methamphetamine exhibit myocardial hypersensitivity to ischemic injury. However, it is unknown whether hypersensitivity to ischemic injury develops when rats are exposed to methamphetamine during adulthood. The goal of this study was to determine whether methamphetamine exposure during adulthood sensitizes the heart to ischemic injury. Methods Adult male and female rats received daily injections of methamphetamine (5 mg/kg) or saline for 10 days. Their hearts were isolated on day 11 and subjected to a 20 min ischemic insult on a Langendorff isolated heart apparatus. Cardiac contractile function was measured by an intraventricular balloon, and infarct size was measured by triphenyltetrazolium chloride staining. Results Hearts from methamphetamine-treated females exhibited significantly larger infarcts and suppressed postischemic recovery of contractile function compared to hearts from saline-treated females. In contrast, methamphetamine had no effect on infarct size or contractile recovery in male hearts. Subsequent experiments demonstrated that hypersensitivity to ischemic injury persisted in female hearts following a 1 month period of abstinence from methamphetamine. Myocardial protein kinase C-ε expression, Akt phosphorylation, and ERK phosphorylation were unaffected by adult exposure to methamphetamine. Conclusions Exposure of adult rats to methamphetamine sex-dependently increases the extent of myocardial injury following an ischemic insult. These data suggest that women who have a heart attack might be at risk of more extensive myocardial injury if they have a recent history of methamphetamine abuse. PMID:28575091

  16. The Neuropsychology of Cocaine Addiction: Recent Cocaine Use Masks Impairment

    Science.gov (United States)

    Woicik, Patricia A; Moeller, Scott J; Alia-Klein, Nelly; Maloney, Thomas; Lukasik, Tanya M; Yeliosof, Olga; Wang, Gene-Jack; Volkow, Nora D; Goldstein, Rita Z

    2009-01-01

    Individuals with current cocaine use disorders (CUD) form a heterogeneous group, making sensitive neuropsychological (NP) comparisons with healthy individuals difficult. The current study examined the effects on NP functioning of four factors that commonly vary among CUD: urine status for cocaine (positive vs negative on study day), cigarette smoking, alcohol consumption, and dysphoria. Sixty-four cocaine abusers were matched to healthy comparison subjects on gender and race; the groups also did not differ in measures of general intellectual functioning. All subjects were administered an extensive NP battery measuring attention, executive function, memory, facial and emotion recognition, and motor function. Compared with healthy control subjects, CUD exhibited performance deficits on tasks of attention, executive function, and verbal memory (within one standard deviation of controls). Although CUD with positive urine status, who had higher frequency and more recent cocaine use, reported greater symptoms of dysphoria, these cognitive deficits were most pronounced in the CUD with negative urine status. Cigarette smoking, frequency of alcohol consumption, and dysphoria did not alter these results. The current findings replicate a previously reported statistically significant, but relatively mild NP impairment in CUD as compared with matched healthy control individuals and further suggest that frequent/recent cocaine may mask underlying cognitive (but not mood) disturbances. These results call for development of pharmacological agents targeted to enhance cognition, without negatively impacting mood in individuals addicted to cocaine. PMID:18496524

  17. Potential for the development of tolerance by Aspergillus amstelodami, A. repens and A. ruber after repeated exposure to potassium sorbate.

    Science.gov (United States)

    Viñas, I; Morlans, I; Sanchis, V

    1990-01-01

    Three strains of A. amstelodami, A. repens and A. ruber were exposed to various levels of potassium sorbate, and the MICs were determined. Selected strains of the molds were then repeatedly exposed to subinhibitory levels of the compound to determine whether increased tolerance might develop. The MIC of sorbate (pH 5.5 or 6.5) for 3 species of Aspergillus was 0.07%. Increasing levels of sorbate resulted in increasing growth suppression of the molds. The 3 Aspergillus species were tested for increased tolerance to potassium sorbate, and none was found. They developed a slight increase in tolerance dependent upon pH and the mold strain by subculturing at low levels of sorbate.

  18. Comparative study of the pharmacokinetics of carbon tetrachloride in the rat following repeated inhalation exposures of 8 and 11.5 hr/day

    International Nuclear Information System (INIS)

    Paustenbach, D.J.; Carlson, G.P.; Christian, J.E.; Born, G.S.

    1986-01-01

    To evaluate whether exposure to inhaled vapors for periods longer than 8 hr/day could affect the rates and routes of elimination, male Sprague-Dawley rats were repeatedly exposed to 100 ppm of radiolabeled carbon tetrachloride ( 14 CCl 4 ) in a closed-loop chamber. One group was exposed for 8 hr/day for 5 days and another group for 11.5 hr/day for 4 days. Two other groups were exposed for either 8 hr/day for 10 of 12 consecutive days or 11.5 hr/day for 7 of 10 days. The elimination of 14 C activity was measured in the expired air, urine, and feces for up to 100 hr following exposure and the pharmacokinetic parameters were determined. Following 2 weeks of exposure to the 8-hr/day schedule, 14 CCl 4 in the breath and 14 C activity in the feces comprised 45 and 48% of the total 14 C excreted, respectively. Following 2 weeks of exposure to the 11.5-hr/day schedule, the values were 32 and 62%, respectively, indicating that repeated exposure to the longer schedule altered the route of elimination of CCl 4 . Regardless of the period of exposure, less than 8% of the inhaled 14 CCl 4 was excreted in the urine and less than 2% was exhaled in the breath as the 14 CO 2 metabolite. Approximately 97-98% of the 14 C activity in the expired air was 14 CCl 4 . The quantities of 14 C noted in the feces and urine suggest that more than 60% of the inhaled CCl 4 was metabolized. Elimination of 14 CCl 4 and 14 CO 2 in the breath followed a two-compartment, first-order pharmacokinetic model (r2 = 0.98). For rats exposed 8 hr/day and 11.5 hr/day for 2 weeks, the average half-lives for elimination of 14 CCl 4 in the breath for the fast (alpha) and slow (beta) phases averaged 96 and 455 min, and 89 and 568 min, respectively. The average alpha and beta half-lives for elimination of 14 CO 2 in the breath

  19. Performance of bias-correction methods for exposure measurement error using repeated measurements with and without missing data.

    Science.gov (United States)

    Batistatou, Evridiki; McNamee, Roseanne

    2012-12-10

    It is known that measurement error leads to bias in assessing exposure effects, which can however, be corrected if independent replicates are available. For expensive replicates, two-stage (2S) studies that produce data 'missing by design', may be preferred over a single-stage (1S) study, because in the second stage, measurement of replicates is restricted to a sample of first-stage subjects. Motivated by an occupational study on the acute effect of carbon black exposure on respiratory morbidity, we compare the performance of several bias-correction methods for both designs in a simulation study: an instrumental variable method (EVROS IV) based on grouping strategies, which had been recommended especially when measurement error is large, the regression calibration and the simulation extrapolation methods. For the 2S design, either the problem of 'missing' data was ignored or the 'missing' data were imputed using multiple imputations. Both in 1S and 2S designs, in the case of small or moderate measurement error, regression calibration was shown to be the preferred approach in terms of root mean square error. For 2S designs, regression calibration as implemented by Stata software is not recommended in contrast to our implementation of this method; the 'problematic' implementation of regression calibration although substantially improved with use of multiple imputations. The EVROS IV method, under a good/fairly good grouping, outperforms the regression calibration approach in both design scenarios when exposure mismeasurement is severe. Both in 1S and 2S designs with moderate or large measurement error, simulation extrapolation severely failed to correct for bias. Copyright © 2012 John Wiley & Sons, Ltd.

  20. Decreased extracellular adenosine levels lead to loss of hypoxia-induced neuroprotection after repeated episodes of exposure to hypoxia.

    Directory of Open Access Journals (Sweden)

    Mei Cui

    Full Text Available Achieving a prolonged neuroprotective state following transient ischemic attacks (TIAs is likely to effectively reduce the brain damage and neurological dysfunction associated with recurrent stroke. HPC is a phenomenon in which advanced exposure to mild hypoxia reduces the stroke volume produced by a subsequent TIA. However, this neuroprotection is not long-lasting, with the effects reaching a peak after 3 days. Therefore, in this study, we investigated the use of multiple episodes of hypoxic exposure at different time intervals to induce longer-term protection in a mouse stroke model. C57BL/6 mice were subjected to different hypoxic preconditioning protocols: a single episode of HPC or five identical episodes at intervals of 3 days (E3d HPC or 6 days (E6d HPC. Three days after the last hypoxic exposure, temporary middle cerebral artery occlusion (MCAO was induced. The effects of these HPC protocols on hypoxia-inducible factor (HIF regulated gene mRNA expression were measured by quantitative PCR. Changes in extracellular adenosine concentrations, known to exert neuroprotective effects, were also measured using in vivo microdialysis and high pressure liquid chromatography (HPLC. Neuroprotection was provided by E6d HPC but not E3d HPC. HIF-regulated target gene expression increased significantly following all HPC protocols. However, E3d HPC significantly decreased extracellular adenosine and reduced cerebral blood flow in the ischemic region with upregulated expression of the adenosine transporter, equilibrative nucleoside transporter 1 (ENT1. An ENT1 inhibitor, propentofylline increased the cerebral blood flow and re-established neuroprotection in E3d HPC. Adenosine receptor specific antagonists showed that adenosine mainly through A1 receptor mediates HPC induced neuroprotection. Our data indicate that cooperation of HIF-regulated genes and extracellular adenosine is necessary for HPC-induced neuroprotection.

  1. Biochemical and histopathological changes in the kidney and adrenal gland of rats following repeated exposure to lambda-cyhalothrin

    OpenAIRE

    Hassina Khaldoun Oularbi

    2014-01-01

    Lambda-cyhalothrin (LCT) is a type II pyrethroid insecticide widely used in pest management. This study was undertaken to evaluate the toxic effects of LCT on the kidneys and adrenal glands of rats after subacute exposure. Twenty-eight 6-week-old male albino Rattus norvegicus rats were randomly assigned to four groups. Group 1 was the control group, which received distilled water. The experimental groups 2, 3 and 4 received 20.4, 30.6 and 61.2 mg/kg body weight, respectively, of LCT, administ...

  2. Prevention of diabetes in NOD mice by repeated exposures to a contact allergen inducing a sub-clinical dermatitis

    DEFF Research Database (Denmark)

    Engkilde, Kaare; Buschard, Karsten; Hansen, Axel Jacob Kornerup

    2010-01-01

    Type 1 diabetes is an autoimmune disease, while allergic contact dermatitis although immune mediated, is considered an exposure driven disease that develops due to epicutaneous contact with reactive low-molecular chemicals. The objective of the present study was to experimentally study the effect...... of contact allergens on the development of diabetes in NOD mice. As the link between contact allergy and diabetes is yet unexplained we also examined the effect of provocation with allergens on Natural Killer T (NKT) cells, since involvement of NKT cells could suggest an innate connection between the two...

  3. Repeated exposure to media messages encouraging parent-child communication about sex: differential trajectories for mothers and fathers.

    Science.gov (United States)

    Blitstein, Jonathan L; Evans, W Douglas; Davis, Kevin C; Kamyab, Kian

    2012-01-01

    To examine changes in parent-child communication related to sexual behavior after exposure to public health messages. Randomized, controlled trial that was part of precampaign message testing. Exposure occurred online or through DVDs mailed to participants and viewed on their personal computers. Data collection occurred via a secure Web site. Participants included parents (n  =  1969) living with a child age 10 to 14 years drawn from a nationally representative sample of U.S. households. Treatment participants were exposed to video, audio, and print advertisements that promoted the benefits of speaking to their children early and often about delaying initiation of sexual activity; messages also directed parents to an informational Web site. The dependent variable assessed frequency of parent-child communication related to sexual behavior. The primary independent variable was treatment assignment. Longitudinal growth modeling that included five waves of data. The trajectory of growth over time differed between fathers in the treatment group and fathers in the control group (F[1, 2357]  =  4.15; p groups. This study demonstrates that father-child and mother-child communication patterns differ over time in response to public health messages. Findings have implication for researchers developing health marketing campaigns.

  4. Tratamento de exposição a estímulos e treinamento de habilidades como coadjuvantes no manejo do craving em um dependente de crack Cue exposure treatment and coping skills training as adjuvant therapies in the management of craving in a crack cocaine addict

    Directory of Open Access Journals (Sweden)

    Renata Brasil Araujo

    2011-01-01

    Full Text Available OBJETIVO: Tem-se observado um aumento da prevalência de dependentes de crack em amostras clínicas, o que torna necessária a realização de pesquisas quanto a estratégias de tratamento direcionadas a essa clientela. O objetivo deste estudo foi descrever o caso de um dependente de crack internado no qual foram utilizados o tratamento de exposição a estímulos (TEE e o treinamento de habilidades (TH como coadjuvantes ao tratamento tradicional. DESCRIÇÃO DO CASO: O paciente é do sexo masculino, 29 anos de idade, solteiro, ensino médio completo. Era dependente de crack e de maconha e fazia uso nocivo de álcool. O paciente já estava internado havia 2 semanas e tinha passado por um protocolo de quatro sessões com entrevista motivacional e prevenção à recaída. Foram feitas seis sessões, ao longo de 2 semanas, de TEE e TH, nas quais o paciente foi exposto in vivo e pela imaginação a estímulos evocadores de fissura, como cachimbo de crack, isqueiro, pedras simuladas, lembranças de locais e amigos associados ao uso da droga. Ele também foi treinado para utilizar estratégias de manejo da fissura. Após 3 meses da alta hospitalar, foi realizado screening toxicológico para avaliar a manutenção de abstinência. O paciente avaliou o uso das técnicas como importante para a manutenção da abstinência após 3 meses da alta e para sua baixa média de fissura pelo crack. COMENTÁRIOS: Talvez o TEE e o TH para manejo da fissura possam ser úteis como coadjuvantes no tratamento de dependentes de crack. Tal uso deve ser avaliado em ensaios clínicos para demonstrar seu real benefício.OBJECTIVE: An increased prevalence of crack cocaine users has been observed in clinical samples over the past years, underscoring the need for conducting research and developing treatment strategies aimed at this population. The objective of this study was to describe the case of a crack cocaine addict (inpatient submitted to cue exposure treatment (CET and

  5. Changes in expression of c-Fos protein following cocaine-cue extinction learning.

    Science.gov (United States)

    Nic Dhonnchadha, B Á; Lovascio, B F; Shrestha, N; Lin, A; Leite-Morris, K A; Man, H Y; Kaplan, G B; Kantak, K M

    2012-09-01

    Extinguishing abnormally strengthened learned responses to cues associated with drugs of abuse remains a key tactic for alleviating addiction. To assist in developing pharmacotherapies to augment exposure therapy for relapse prevention, investigation into neurobiological underpinnings of drug-cue extinction learning is needed. We used regional analyses of c-Fos and GluR2 protein expression to delineate neural activity and plasticity that may be associated with cocaine-cue extinction learning. Rats were trained to self-administer cocaine paired with a light cue, and later underwent a single 2h extinction session for which cocaine was withheld but response-contingent cues were presented (cocaine-cue extinction). Control groups consisted of rats yoked to animals self-administering cocaine and receiving saline non-contingently followed by an extinction session, or rats trained to self-administer cocaine followed by a no-extinction session for which levers were retracted, and cocaine and cues were withheld. Among 11 brain sites examined, extinction training increased c-Fos expression in basolateral amygdala and prelimbic prefrontal cortex of cocaine-cue extinguished rats relative to both control conditions. In dorsal subiculum and infralimbic prefrontal cortex, extinction training increased c-Fos expression in both cocaine-cue and saline-cue extinguished rats relative to the no-extinction control condition. GluR2 protein expression was not altered in any site examined after extinction or control training. Findings suggest that basolateral amygdala and prelimbic prefrontal cortex neurons are activated during acquisition of cocaine-cue extinction learning, a process that is independent of changes in GluR2 abundance. Other sites are implicated in processing the significance of cues that are present early in extinction training. Copyright © 2012 Elsevier B.V. All rights reserved.

  6. Reduction of extinction and reinstatement of cocaine seeking by wheel running in female rats.

    Science.gov (United States)

    Zlebnik, Natalie E; Anker, Justin J; Gliddon, Luke A; Carroll, Marilyn E

    2010-03-01

    Previous work has shown that wheel running reduced the maintenance of cocaine self-administration in rats. In the present study, the effect of wheel running on extinction and reinstatement of cocaine seeking was examined. Female rats were trained to run in a wheel during 6-h sessions, and they were then catheterized and placed in an operant conditioning chamber where they did not have access to the wheel but were allowed to self-administer iv cocaine. Subsequently, rats were divided into four groups and were tested on the extinction and reinstatement of cocaine seeking while they had varying access to a wheel in an adjoining compartment. The four groups were assigned to the following wheel access conditions: (1) wheel running during extinction and reinstatement (WER), (2) wheel running during extinction and a locked wheel during reinstatement (WE), (3) locked wheel during extinction and wheel running during reinstatement (WR), and (4) locked wheel during extinction and reinstatement (WL). WE and WR were retested later to examine the effect of one session of wheel access on cocaine-primed reinstatement. There were no group differences in wheel revolutions, in rate of acquisition of cocaine self-administration, or in responding during maintenance when there was no wheel access. However, during extinction, WE and WER responded less than WR and WL. WR and WER had lower cocaine-primed reinstatement than WE and WL. One session of wheel exposure in WE also suppressed cocaine-primed reinstatement. Wheel running immediately and effectively reduced cocaine-seeking behavior, but concurrent access to running was necessary. Thus, exercise is a useful and self-sustaining intervention to reduce cocaine-seeking behavior.

  7. Toxicological evaluation of silver nanoparticles and silver nitrate in rats following 28 days of repeated oral exposure.

    Science.gov (United States)

    Qin, Guangqiu; Tang, Song; Li, Shibin; Lu, Haoliang; Wang, Yanwu; Zhao, Peng; Li, Bin; Zhang, Jiehong; Peng, Liang

    2017-02-01

    The increasing application of silver nanoparticles (AgNPs) has been raising concerns about their potential adverse effects to human and the environment. However, the knowledge on the systemic toxicity of AgNPs in mammalian systems is still limited. The present study investigated the toxicity of PVP-coated AgNPs in rats treated with repeated oral administration, and compared that with equivalent dose of AgNO 3 . Specifically, one hundred male and female rats were orally administrated with particulate or ionic forms of silver (Ag) separately at doses of 0.5 and 1 mg kg -1 body weight daily for 28 days. The results reveal no significant toxic effects of AgNPs and AgNO 3 up to 1 mg kg -1 body weight, with respect to the body weight, organ weight, food intake, and histopathological examination. Ag distribution pattern in organs of rats treated with AgNPs was similar to that of AgNO 3 treated rats, showing liver and kidneys are the main target organs followed by testis and spleen. The total Ag contents in organs were significantly lower in the AgNPs treated rats than those in the AgNO 3 treated rats. However, the comparisons between AgNPs and AgNO 3 treatments further indicated more potent of AgNPs in biochemical and hematological parameters in rats, including red blood cell count (RBC), platelet count (PLT), white blood cell count (WBC) and aspartate transaminase (AST). Results of this study suggested that particulate Ag at least partially contributed to the observed toxicity of AgNPs, and both ionic and particulate Ag should be taken into consideration in toxicological evaluation of AgNPs. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 609-618, 2017. © 2016 Wiley Periodicals, Inc.

  8. The Naturally Occurring Compound Garcinia Indica Selectively Impairs the Reconsolidation of a Cocaine-Associated Memory

    OpenAIRE

    Monsey, Melissa S; Sanchez, Hayde; Taylor, Jane R

    2016-01-01

    Sustained abstinence from cocaine use is frequently compromised by exposure to environmental stimuli that have previously been strongly associated with drug taking. Such cues trigger memories of the effects of the drug, leading to craving and potential relapse. Our work has demonstrated that manipulating cocaine-cue memories by destabilizing them through interfering with the reconsolidation process is one potential therapeutic tool by which to prolong abstinence. Here, we examine the use of t...

  9. Development of immunity against viral and bacterial antigens after repeated exposures to suberythemal doses of ultraviolet light

    Directory of Open Access Journals (Sweden)

    S. A. Snopov

    2012-01-01

    Full Text Available The effects of ultraviolet (UV radiation on human infectious immunity are not well studied. On the one hand, solar and artificial UU sources have been shown to change cytokine levels in human skin, lymphocyte subpopulation counts in parepheral blood, lymphocyte DNA synthesis and prolifarative response to mitogens. On the other hand, there are just only one or two observations suggesting an influence of UV radiation on human infection course. For instance, UV irradiations have been reported to induce a reccurence of orofacial vesicular lesions caused by herpes siplex virus. Moreover, there is a lack of data concerning immune effects of suberythtemal doses of UV in spite of a long history of using them by Russian prophylactic medicine. In this work we questioned whether such suberythemal UV exposures can affect the immune responses of children to infectious conjunctivitis, to simultaneous measles and polio vaccinations and to simultaneous polio and diphtheria-tetanus vaccinations. In peripheral blood of vaccinated children we examined leukocyte counts (monocytes, neutrophils, eosinophils, lymphocytes, percentages of lymphocyte subpopulations (CD3+, CD20+, CD4+, CD8+, CD25+, HLADR+, concentrations of cytokines (IL-1 beta, TNF-alpha, IFN- amma и IL-10, DNA-synthetic activity of lymphocytes and titres of antibodies against measles and diphtheria toxin. We observed no local or systemic reactions to the vaccines in the UV-group while a moderate rise in body temperature occured in several children from unexposed group. In the blood of childeren from UV-group we found increases in CD25+ и HLADR+ cell percentages, IL- 1 beta and IL-10 concentrations, PWMinduced DNA synthesis in mononuclears, and no decreases in formation of antibodies against measles and diphreria. We concluded that suberythemal UV exposures of children modulated their further responses to imminisations perhaps through the activation of a T helper 2-like

  10. Cocaine enhances the conditioned rewarding effects of MDMA in adolescent mice.

    Science.gov (United States)

    Aguilar, M A; Roger-Sánchez, C; Rodríguez-Arias, M; Miñarro, J

    2015-04-01

    Although the consumption of cocaine is frequent in young users of MDMA (3,4-methylenedioxymethamphetamine), the influence of exposure to cocaine on the rewarding effects of MDMA in adolescents has not been studied. The purpose of the present work was to evaluate the effect of co-administration of cocaine (1 and 10 mg/kg) and a sub-threshold dose of MDMA (1.25 mg/kg) on the acquisition of conditioned place preference (CPP) (experiment 1). In addition, the effect of pre-treatment with cocaine on MDMA-induced CPP was evaluated (experiment 2). Levels of monoamines in striatum, hippocampus and cortex were measured in both experiments. Our hypotheses were that cocaine co-administration or pre-treatment would increase the rewarding effects of MDMA, and that these effects would be related with changes in brain monoamine levels. Our results showed that cocaine potentiated the rewarding effects of MDMA, since a sub-threshold dose of MDMA, which did not induce CPP by itself, induced a significant CPP in adolescent mice when administered along with cocaine during conditioning (experiment 1). Moreover, pre-treatment with cocaine several days before conditioning also increased the rewarding effects of MDMA (experiment 2). No significant changes in the levels of biogenic amines, which correlated with these behavioural effects, were observed. Our results confirm the involvement of the dopaminergic system in MDMA-induced CPP in adolescent mice and suggest that combined consumption with or pre-exposure to cocaine increases the conditioned rewarding effects of MDMA, which may enhance the capacity of MDMA to induce dependence. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. The rate of repeating X-rays in the medical centers of Jenin District/Palestine and how to reduce patient exposure to radiation

    Science.gov (United States)

    Assi, Abed Al Nasser

    2018-03-01

    Reduction of the patient's received radiation dose to as low as reasonably achievable (ALARA) is based on recommendations of radiation protection organizations such as the International Commission on Radiological Protection (ICRP) and the National Radiological Protection Board (NRPB). The aim of this study was to explore the frequency and characteristics of rejected / repeated radiographic films in governmental and private centers in Jenin city. The radiological centers were chosen based on their high volume of radiographic studies. The evaluation was carried out over a period of four months. The collected data were compiled at the end of each week and entered into a computer for analysis at the end of study. Overall 5000 films (images) were performed in four months, The average repeat rate of radiographic images was 10% (500 films). Repetition rate was the same for both thoracic and abdominal images (42%). The main reason for repeating imaging was inadequate imaging quality (58.2%) and poor film processing (38%). Human error was the most likely reason necessitating the repetition of the radiographs (48 %). Infant and children groups comprised 85% of the patient population that required repetition of the radiographic studies. In conclusion, we have a higher repetition rate of imaging studies compared to the international standards (10% vs. 4-6%, respectively). This is especially noticeable in infants and children, and mainly attributed to human error in obtaining and processing images. This is an important issue that needs to be addressed on a national level due to the ill effects associated with excessive exposure to radiation especially in children, and to reduce cost of the care delivered.

  12. Disposition of Lead (Pb) in Saliva and Blood of Sprague-Dawley Rats Following a Single or Repeated Oral Exposure to Pb-Acetate

    Energy Technology Data Exchange (ETDEWEB)

    Timchalk, Chuck; Lin, Yuehe; Weitz, Karl K.; Wu, Hong; Gies, Richard A.; Moore, Dean A.; Yantasee, Wassana

    2006-05-01

    Biological monitoring for lead (Pb) is usually based upon a determination of blood Pb concentration; however, saliva has been suggested as a non-invasive biological matrix for assessing exposure. To further evaluate the potential utility of saliva for biomonitoring, the disposition of Pb was evaluated in whole blood (WB), red blood cells (RBC), plasma, parotid gland, bone, and saliva following either a single oral dose of 100 mg Pb-acetate/kg body weight in rats or {approx}1-week after 5 sequential daily oral gavage doses of 1, 10, or 100 mg Pb-acetate/kg/day. Saliva volume, pH, total saliva protein, and ?-amylase activity were also determined. At specified times post-dosing groups of animals were anethetized and administered pilocarpine to induce salivation. Saliva was collected, the animals were humanely sacrificed, and tissue samples were likewise collected, weighed, and processed for Pb analysis. Following a single dose exposure to PB-acetate, Pb was detectable in all samples by 30 min post-dosing. For both the single and repeated dose treatments the concentration of Pb was highest in WB and RBC relative to plasma and saliva. However, the Pb rapidly redistributed (within 5-days post-treatment) from the blood into the bone compartment based on the substantial decrease in WB and RBC Pb concentration, and the concurrent increase in bone Pb following repeated exposure at all dose levels. Although there is clear variability in the observed Pb concentrations in plasma and saliva, there was a reasonable correlation (r2=0.922) between the average Pb concentrations in these biological matrices which was consistent with previous observations. The single oral dose of Pb-acetate resulted in a decrease in salivary pH which recovered by 24 hr post-dosing and a decrease in ?-amylase enzyme activity which did recover within 5-days of ceasing exposure. It is currently unclear what impact these slight functional changes may or may not have on Pb salivary clearance rates. These

  13. Pyrolysis and volatilization of cocaine

    International Nuclear Information System (INIS)

    Martin, B.R.; Lue, L.P.; Boni, J.P.

    1989-01-01

    The increasing popularity of inhaling cocaine vapor prompted the present study, to determine cocaine's fate during this process. The free base of [3H]cocaine (1 microCi/50 mg) was added to a glass pipe, which was then heated in a furnace to simulate freebasing. Negative pressure was used to draw the vapor through a series of glass wool, ethanol, acidic, and basic traps. Air flow rate and temperature were found to have profound effects on the volatilization and pyrolysis of cocaine. At a temperature of 260 degrees C and a flow rate of 400 mL/min, 37% of the radioactivity remained in the pipe, 39% was found in the glass wool trap, and less than 1% in the remainder of the volatilization apparatus after a 10-min volatilization. Reducing the air flow rate to 100 mL/min reduced the amount of radioactivity collected in the glass wool trap to less than 10% of the starting material and increased the amount that remained in the pipe to 58%. GC/MS analysis of the contents of the glass wool trap after volatilization at 260 degrees C and a flow rate of 400 mL/min revealed that 60% of the cocaine remained intact, while approximately 6 and 2% of the starting material was recovered as benzoic acid and methylecgonidine, respectively. As the temperature was increased to 650 degrees C, benzoic acid and methylecgonidine accounted for 83 and 89% of the starting material, respectively, whereas only 2% of the cocaine remained intact. Quantitation of cocaine in the vapor during the course of volatilization revealed high concentrations during the first two min and low concentrations for the remaining time

  14. Comparative electrophysiological evaluation of hippocampal function following repeated inhalation exposures to JP-8, Jet A, JP-5, and the synthetic Fischer Tropsch fuel.

    Science.gov (United States)

    Rohan, Joyce G; McInturf, Shawn M; Miklasevich, Molly K; Gut, Chester P; Grimm, Michael D; Reboulet, James E; Howard, William R; Mumy, Karen L

    2018-01-01

    Exposure to fuels continues to be a concern in both military and general populations. The aim of this study was to examine effects of in vivo rat repeated exposures to different types of jet fuel utilizing microelectrode arrays for comparative electrophysiological (EP) measurements in hippocampal slices. Animals were exposed to increasing concentrations of four jet fuels, Jet Propellant (JP)-8, Jet A, JP-5, or synthetic Fischer Tropsch (FT) fuel via whole-body inhalation for 20 d (6 hr/d, 5 d/week for 28 d) and synaptic transmission as well as behavioral performance were assessed. Our behavioral studies indicated no significant changes in behavioral performance in animals exposed to JP-8, Jet A, or JP-5. A significant deviation in learning pattern during the Morris water maze task was observed in rats exposed to the highest concentration of FT (2000 mg/m 3 ). There were also significant differences in the EP profile of hippocampal neurons from animals exposed to JP-8, Jet A, JP-5, or FT compared to control air. However, these differences were not consistent across fuels or dose dependent. As expected, patterns of EP alterations in brain slices from JP-8 and Jet A exposures were more similar compared to those from JP-5 and FT. Further longitudinal investigations are needed to determine if these EP effects are transient or persistent. Such studies may dictate if and how one may use EP measurements to indicate potential susceptibility to neurological impairments, particularly those that result from inhalation exposure to chemicals or mixtures.

  15. Biochemical and histopathological changes in the kidney and adrenal gland of rats following repeated exposure to lambda-cyhalothrin

    Directory of Open Access Journals (Sweden)

    Hassina Khaldoun Oularbi

    2014-04-01

    Full Text Available Lambda-cyhalothrin (LCT is a type II pyrethroid insecticide widely used in pest management. This study was undertaken to evaluate the toxic effects of LCT on the kidneys and adrenal glands of rats after subacute exposure. Twenty-eight 6-week-old male albino Rattus norvegicus rats were randomly assigned to four groups. Group 1 was the control group, which received distilled water. The experimental groups 2, 3 and 4 received 20.4, 30.6 and 61.2 mg/kg body weight, respectively, of LCT, administered orally over 28 days. The effects of the insecticide on various biochemical parameters were evaluated at 14 and 28 days. Histopathological studies were carried out in the kidneys and adrenal glands at the end of the experiment. Lambda-cyhalothrin, as a pyrethroid insecticide, induced significant increases (P≤0.05 in plasma urea, creatinine, uric acid and glucose concentrations, and alanine aminotransferase and aspartate aminotransferase activities after 14 and 28 days. In the rat plasma samples after 28 days, residual concentrations of LCT 1R, cis,

  16. Gene x Disease Interaction on Orbitofrontal Gray Matter in Cocaine Addiction

    International Nuclear Information System (INIS)

    Alia-Klein, N.; Parvaz, M.A.; Woicik, P.A.; Konova, A.B.; Maloney, T.; Shumay, E.; Wang, R.; Telang, F.; Biegon, A.; Wang, G.-J.; Fowler, J.S.; Tomasi, D.; Volkow, N.D.; Goldstein, R.Z.

    2011-01-01

    Long-term cocaine use has been associated with structural deficits in brain regions having dopamine-receptive neurons. However, the concomitant use of other drugs and common genetic variability in monoamine regulation present additional structural variability. The objective is to examine variations in gray matter volume (GMV) as a function of lifetime drug use and the genotype of the monoamine oxidase A gene, MAOA, in men with cocaine use disorders (CUD) and healthy male controls. Forty individuals with CUD and 42 controls who underwent magnetic resonance imaging to assess GMV and were genotyped for the MAOA polymorphism (categorized as high- and low-repeat alleles). The impact of cocaine addiction on GMV, tested by (1) comparing the CUD group with controls, (2) testing diagnosis x MAOA interactions, and (3) correlating GMV with lifetime cocaine, alcohol, and cigarette smoking, and testing their unique contribution to GMV beyond other factors. The results are: (1) Individuals with CUD had reductions in GMV in the orbitofrontal, dorsolateral prefrontal, and temporal cortex and the hippocampus compared with controls; (2) The orbitofrontal cortex reductions were uniquely driven by CUD with low- MAOA genotype and by lifetime cocaine use; and (3) The GMV in the dorsolateral prefrontal cortex and hippocampus was driven by lifetime alcohol use beyond the genotype and other pertinent variables. Long-term cocaine users with the low-repeat MAOA allele have enhanced sensitivity to gray matter loss, specifically in the orbitofrontal cortex, indicating that this genotype may exacerbate the deleterious effects of cocaine in the brain. In addition, long-term alcohol use is a major contributor to gray matter loss in the dorsolateral prefrontal cortex and hippocampus, and is likely to further impair executive function and learning in cocaine addiction.

  17. Gene x Disease Interaction on Orbitofrontal Gray Matter in Cocaine Addiction

    Energy Technology Data Exchange (ETDEWEB)

    Alia-Klein, N.; Alia-Klein, N.; Parvaz, M.A.; Woicik, P.A.; Konova, A.B.; Maloney, T.; Shumay, E.; Wang, R.; Telang, F.; Biegon, A.; Wang, G.-J.; Fowler, J.S.; Tomasi, D.; Volkow, N.D.; Goldstein, R.Z.

    2011-03-07

    Long-term cocaine use has been associated with structural deficits in brain regions having dopamine-receptive neurons. However, the concomitant use of other drugs and common genetic variability in monoamine regulation present additional structural variability. The objective is to examine variations in gray matter volume (GMV) as a function of lifetime drug use and the genotype of the monoamine oxidase A gene, MAOA, in men with cocaine use disorders (CUD) and healthy male controls. Forty individuals with CUD and 42 controls who underwent magnetic resonance imaging to assess GMV and were genotyped for the MAOA polymorphism (categorized as high- and low-repeat alleles). The impact of cocaine addiction on GMV, tested by (1) comparing the CUD group with controls, (2) testing diagnosis x MAOA interactions, and (3) correlating GMV with lifetime cocaine, alcohol, and cigarette smoking, and testing their unique contribution to GMV beyond other factors. The results are: (1) Individuals with CUD had reductions in GMV in the orbitofrontal, dorsolateral prefrontal, and temporal cortex and the hippocampus compared with controls; (2) The orbitofrontal cortex reductions were uniquely driven by CUD with low- MAOA genotype and by lifetime cocaine use; and (3) The GMV in the dorsolateral prefrontal cortex and hippocampus was driven by lifetime alcohol use beyond the genotype and other pertinent variables. Long-term cocaine users with the low-repeat MAOA allele have enhanced sensitivity to gray matter loss, specifically in the orbitofrontal cortex, indicating that this genotype may exacerbate the deleterious effects of cocaine in the brain. In addition, long-term alcohol use is a major contributor to gray matter loss in the dorsolateral prefrontal cortex and hippocampus, and is likely to further impair executive function and learning in cocaine addiction.

  18. Analgesia induced by repeated exposure to low dose X-rays in mice, and involvement of the accessory olfactory system in modulation of the radiation effects

    International Nuclear Information System (INIS)

    Miyachi, Yukihisa; Yamada, Takeshi

    1997-01-01

    The effects of low-dose X-rays on mouse nociceptive behavior were examined using a formalin injected test which rated the amount of time the animals spent licking the injected hind-paw. Male ICR White Swiss mice showed a marked suppression of licking behavior after repeated low-dose X-irradiation (5 cGy/day, 6 consecutive days). The most profound effect was observed on the day 30 after irradiation. The decline of licking behavior, however, was not observed at all following olfactory bulbectomy or vomeronasal tract cut. The analgesic effects could be observed in writhing animals administered acetic-acid intraperitoneally. Moreover, analgesia was totally blocked by the administration of N-nitro-L-arginine, a nitric oxide synthase inhibitor, to accessory olfactory bulbs prior to the exposure. The present results indicate that the olfactory system plays an important role in modulation of radiation-induced analgesia, and a possible involvement of nitric oxide in the formation of recognition memory subjected to repeated X-rays. Relatively higher doses (5 cGy x 9 days, 5 cGy x 12 days), however, did not induce such effects, namely, the decline of nociceptive response was limited to the animals irradiated with the smaller dose. (author)

  19. Stress Alters the Discriminative Stimulus and Response Rate Effects of Cocaine Differentially in Lewis and Fischer Inbred Rats

    Directory of Open Access Journals (Sweden)

    Therese A. Kosten

    2012-03-01

    Full Text Available Stress enhances the behavioral effects of cocaine, perhaps via hypothalamic-pituitary-adrenal (HPA axis activity. Yet, compared to Fischer 344 (F344 rats, Lewis rats have hyporesponsive HPA axis function and more readily acquire cocaine self-administration. We hypothesized that stress would differentially affect cocaine behaviors in these strains. The effects of three stressors on the discriminative stimulus and response rate effects of cocaine were investigated. Rats of both strains were trained to discriminate cocaine (10 mg/kg from saline using a two-lever, food-reinforced (FR10 procedure. Immediately prior to cumulative dose (1, 3, 10 mg/kg cocaine test sessions, rats were restrained for 15-min, had 15-min of footshock in a distinct context, or were placed in the shock-paired context. Another set of F344 and Lewis rats were tested similarly except they received vehicle injections to test if stress substituted for cocaine. Most vehicle-tested rats failed to respond after stressor exposures. Among cocaine-tested rats, restraint stress enhanced cocaine’s discriminative stimulus effects in F344 rats. Shock and shock-context increased response rates in Lewis rats. Stress-induced increases in corticosterone levels showed strain differences but did not correlate with behavior. These data suggest that the behavioral effects of cocaine can be differentially affected by stress in a strain-selective manner.

  20. Corrigendum to "Acute and repeated exposure to social stress reduces gut microbiota diversity in Syrian hamsters" [Behav. Brain Res. 345 (2018) 39-48].

    Science.gov (United States)

    Partrick, Katherine A; Chassaing, Benoit; Beach, Linda Q; McCann, Katharine E; Gewirtz, Andrew T; Huhman, Kim L

    2018-08-01

    Social stress can promote a variety of neuropsychiatric illnesses, many of which have a high co-morbidity with gastrointestinal disorders. Recent data indicate that gastrointestinal microbiota can affect their host's brain and behavior. Syrian hamsters are ideal subjects for social stress research because they are territorial, aggressive, and rapidly form dominant/subordinate relationships. The purpose of this study was to determine if exposure to social stress in hamsters alters gut microbiota in dominants and subordinates after an agonistic encounter and if pre-stress gut microbiota composition is correlated with the outcome of such a conflict. Microbiota composition was assessed via 16S mRNA Illumina sequencing on fecal samples. One agonistic encounter caused a decrease in alpha diversity in both dominant and subordinate animals with a more pronounced decrease after repeated encounters. PERMANOVA analysis of the unweighted unifrac distance revealed a distinct change in beta diversity after one and nine encounters in both dominants and subordinates. Linear discriminant analysis (LEfSE) showed bacteria from the order Lactobacillales were significantly reduced following social stress in both dominants and subordinates, and both groups exhibited increases in phyla Bacteroidetes and decreases in phyla Firmicutes following repeated encounters. LEfSE analysis on samples collected prior to social interaction revealed that some microbial taxa were correlated with a hamster achieving dominant or subordinate status. These data suggest that even an acute exposure to social stress can impact gastrointestinal microbiota and that the state of the microbial community before social stress may predict dominant/subordinate status following a subsequent agonistic encounter. Copyright © 2018.

  1. Twenty-three generations of mice bidirectionally selected for open-field thigmotaxis: selection response and repeated exposure to the open field.

    Science.gov (United States)

    Leppänen, Pia K; Ravaja, N; Ewalds-Kvist, S B M

    2006-03-01

    We examined: (a) the response to bidirectional selection for open-field (OF) thigmotaxis in mice for 23 generations and (b) the effects of repeated exposure (during 5 days) on different OF behaviors in the selectively bred high OF thigmotaxis (HOFT) and low OF thigmotaxis (LOFT) mice. A total of 2049 mice were used in the study. Prior to the testing in the selection experiment, the mice were exposed to the OF apparatus for approximately 2 min on each of 4 consecutive days. Thus, the selection was based on the scores registered on the 5th day after the four habituation periods. The HOFT mice were more thigmotactic than the LOFT mice in almost each generation. The HOFT mice also tended to rear less than the LOFT mice, which was explained by the inverse relationship between emotionality and exploratory tendencies. The lines did not generally differ in ambulation. Sex differences were found in thigmotaxis, ambulation, and rearing. In the repeated exposure experiment, the development of nine different OF behaviors across the 5 days of testing was addressed. Both lines ambulated, explored, and reared most on the 1st, 4th, and 5th days. Grooming and radial latency decreased and thigmotaxis increased linearly across the testing days. Line differences were found in ambulation, exploration, grooming, and rearing, while sex differences were manifested in ambulation and exploration. The line difference in thigmotaxis was evident only on the 5th day. Temporal changes were partially at variance with the general assumptions. OF thigmotaxis was found to be a powerful characteristic for producing two diverging lines of mice.

  2. Repeated exposure to Lutzomyia intermedia sand fly saliva induces local expression of interferon-inducible genes both at the site of injection in mice and in human blood.

    Science.gov (United States)

    Weinkopff, Tiffany; de Oliveira, Camila I; de Carvalho, Augusto M; Hauyon-La Torre, Yazmin; Muniz, Aline C; Miranda, Jose Carlos; Barral, Aldina; Tacchini-Cottier, Fabienne

    2014-01-01

    During a blood meal, Lutzomyia intermedia sand flies transmit Leishmania braziliensis, a parasite causing tegumentary leishmaniasis. In experimental leishmaniasis, pre-exposure to saliva of most blood-feeding sand flies results in parasite establishment in absence of any skin damages in mice challenged with dermotropic Leishmania species together with saliva. In contrast, pre-immunization with Lu. intermedia salivary gland sonicate (SGS) results in enhanced skin inflammatory exacerbation upon co-inoculation of Lu. intermedia SGS and L. braziliensis. These data highlight potential unique features of both L. braziliensis and Lu. intermedia. In this study, we investigated the genes modulated by Lu. intermedia SGS immunization to understand their potential impact on the subsequent cutaneous immune response following inoculation of both SGS and L. braziliensis. The cellular recruitment and global gene expression profile was analyzed in mice repeatedly inoculated or not with Lu. intermedia. Microarray gene analysis revealed the upregulation of a distinct set of IFN-inducible genes, an immune signature not seen to the same extent in control animals. Of note this INF-inducible gene set was not induced in SGS pre-immunized mice subsequently co-inoculated with SGS and L. braziliensis. These data suggest the parasite prevented the upregulation of this Lu. intermedia saliva-related immune signature. The presence of these IFN-inducible genes was further analyzed in peripheral blood mononuclear cells (PBMCs) sampled from uninfected human individuals living in a L. braziliensis-endemic region of Brazil thus regularly exposed to Lu. intermedia bites. PBMCs were cultured in presence or absence of Lu. intermedia SGS. Using qRT-PCR we established that the IFN-inducible genes induced in the skin of SGS pre-immunized mice, were also upregulated by SGS in PBMCs from human individuals regularly exposed to Lu. intermedia bites, but not in PBMCs of control subjects. These data demonstrate

  3. Repeated stressor exposure enhances contextual fear memory in a beta-adrenergic receptor-dependent process and increases impulsivity in a non-beta receptor-dependent fashion.

    Science.gov (United States)

    Camp, Robert M; Johnson, John D

    2015-10-15

    Memory formation is promoted by stress via the release of norepinephrine and stimulation of beta-adrenergic receptors (β-ARs). Previous data demonstrate that repeated stressor exposure increases norepinephrine turnover and β-AR signaling within the amygdala, which led to the hypothesis that some stress-induced behavioral changes are likely due to facilitated associative learning. To test this, Fischer rats were exposed to chronic mild stress for four days. On day 5, subjects (including non-stressed controls) were injected with the beta-blocker propranolol or vehicle prior to conditioning in an operant box (animals receive two mild foot shocks) or passive avoidance apparatus (animals received a foot shock upon entry into the dark chamber). Twenty-four hours later, subjects were returned to the operant box for measurement of freezing or returned to the passive avoidance apparatus for measurement of latency to enter the dark chamber. Subjects were also tested in an open field to assess context-independent anxiety-like behavior. Animals exposed to chronic stress showed significantly more freezing behavior in the operant box than did controls, and this exaggerated freezing was blocked by propranolol during the conditioning trial. There was no effect of stress on behavior in the open field. Unexpectedly, retention latency was significantly reduced in subjects exposed to chronic stress. These results indicate that chronic exposure to stress results in complex behavioral changes. While repeated stress appears to enhance the formation of fearful memories, it also results in behavioral responses that resemble impulsive behaviors that result in poor decision-making. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Strain-dependent sex differences in the effects of alcohol on cocaine-induced taste aversions.

    Science.gov (United States)

    Jones, Jermaine D; Busse, Gregory D; Riley, Anthony L

    2006-04-01

    Research using the conditioned taste aversion procedure has reported that a cocaine/alcohol combination induces a significantly stronger taste aversion than either cocaine or alcohol alone. These findings suggest that the co-administration of alcohol intensifies the aversive effects of cocaine. Although the behavioral interaction of cocaine and alcohol is well established, little is known about how the effects of this drug combination might be modulated by a variety of subject variables. The current investigation addressed this by assessing if the ability of alcohol to potentiate cocaine-induced taste aversions is dependent upon the strain and/or sex of the subject. In this series of studies, male and female rats of Long-Evans (Experiment 1) and Sprague-Dawley (Experiment 2) descent were given limited access to a novel saccharin solution to drink and were then injected with either vehicle, cocaine (20 mg/kg), alcohol (0.56 g/kg) or the alcohol/cocaine combination. This procedure was repeated every fourth day for a total of four conditioning trials. All subjects were then compared on an Aversion Test that followed the fourth conditioning cycle. In three of the groups tested (male Long-Evans; male and female Sprague-Dawley), cocaine induced a significant taste aversion that was unaffected by the co-administration of alcohol. However, in female Long-Evans subjects, the addition of alcohol significantly strengthened the avoidance of the saccharin solution. Although the effects of alcohol on cocaine-induced taste aversions are dependent upon an interaction of sex and strain, the basis for this SexxStrain interaction is not known. That such an interaction is evident suggests that attention to such factors in assessing the effects of drug combinations is important to understanding the likelihood of the use and abuse of such drugs.

  5. Cocaine Conditioned Behavior: A Cocaine Memory Trace or an Anti-Habituation Effect

    OpenAIRE

    Carey, Robert J.; Damianopoulos, Ernest N.; Shanahan, Arielle B.

    2008-01-01

    Whether cocaine locomotor conditioning represents a cocaine positive effect; i.e., a Pavlovian cocaine conditioned response; or, a cocaine negative effect; i.e., interference with habituation to the test environment, is a subject of some controversy. Three separate experiments were conducted to compare the behavior (locomotion and grooming) of separate groups of rats given 1, 9 or 14 cocaine (10 mg/kg) treatments paired/unpaired with placement into an open-field arena. The behavior of the coc...

  6. Prenatal IV Cocaine: Alterations in Auditory Information Processing

    Directory of Open Access Journals (Sweden)

    Charles F. Mactutus

    2011-06-01

    Full Text Available One clue regarding the basis of cocaine-induced deficits in attentional processing is provided by the clinical findings of changes in the infants’ startle response; observations buttressed by neurophysiological evidence of alterations in brainstem transmission time. Using the IV route of administration and doses that mimic the peak arterial levels of cocaine use in humans, the present study examined the effects of prenatal cocaine on auditory information processing via tests of the acoustic startle response (ASR, habituation, and prepulse inhibition (PPI in the offspring. Nulliparous Long-Evans female rats, implanted with an IV access port prior to breeding, were administered saline, 0.5, 1.0, or 3.0 mg/kg/injection of cocaine HCL (COC from gestation day (GD8-20 (1x/day-GD8-14, 2x/day-GD15-20. COC had no significant effects on maternal/litter parameters or growth of the offspring. At 18-20 days of age, one male and one female, randomly selected from each litter displayed an increased ASR (>30% for males at 1.0 mg/kg and >30% for females at 3.0 mg/kg. When reassessed in adulthood (D90-100, a linear dose-response increase was noted on response amplitude. At both test ages, within-session habituation was retarded by prenatal cocaine treatment. Testing the females in diestrus vs. estrus did not alter the results. Prenatal cocaine altered the PPI response function across interstimulus interval (ISI and induced significant sex-dependent changes in response latency. Idazoxan, an alpha2-adrenergic receptor antagonist, significantly enhanced the ASR, but less enhancement was noted with increasing doses of prenatal cocaine. Thus, in utero exposure to cocaine, when delivered via a protocol designed to capture prominent features of recreational usage, causes persistent, if not permanent, alterations in auditory information processing, and suggests dysfunction of the central noradrenergic circuitry modulating, if not mediating, these responses.

  7. Signs of Cocaine Abuse and Addiction

    Science.gov (United States)

    ... Used Drugs in the Past Drug Use Prevention Phone Numbers and Websites Search Share You are here Home » Drugs That People Abuse » Cocaine (Coke, Crack) Facts » Signs of Cocaine Use and Addiction Signs of Cocaine Use and Addiction Listen ©istock. ...

  8. Cerebral vasculitis associated with cocaine abuse

    International Nuclear Information System (INIS)

    Kaye, B.R.; Fainstat, M.

    1987-01-01

    A case of cerebral vasculitis in a previously healthy 22-year-old man with a history of cocaine abuse is described. Cerebral angiograms showed evidence of vasculitis. A search for possible causes other than cocaine produced no results. The authors include cocaine with methamphetamines, heroin, and ephedrine as illicit drugs that can cause cerebral vasculitis

  9. Characterization of a high affinity cocaine binding site in rat brain

    International Nuclear Information System (INIS)

    Calligaro, D.; Eldefrawi, M.

    1986-01-01

    Binding of [ 3 H]cocaine to synaptic membranes from whole rat brain was reversible and saturable. Nonlinear regression analysis of binding isotherms indicated two binding affinities: one with k/sub d/ = 16 nM, B/sub max/ = 0.65 pmoles/mg protein and the other with K/sub d/ = 660 nM, B/sub max/ = 5.1 pmoles/mg protein. The high-affinity binding of [ 3 H]cocaine was sensitive to the actions of trypsin and chymotrypsin but not carboxypeptidase, and was eliminated by exposure of the membranes to 95 0 C for 5 min. Specific binding at 2 nM was higher at pH 8.8 than at pH 7.0. Binding of [ 3 H]cocaine (15 nM) was inhibited by increasing concentrations of Na + ions. Several cocaine analogues, neurotransmitter uptake inhibitors and local anesthetics displaced specific [ 3 H]cocaine binding at 2 nM with various potencies. The cocaine analogue (-)-norcocaine was the most potent (IC 50 = 10 nM), while the local anesthetic tetracaine was the least potent in inhibiting [ 3 H]cocaine binding. Several biogenic amine uptake inhibitors, including tricyclic antidepressants and phencyclidine, had IC 50 values below μM concentrations

  10. Food acceptability in field studies with US army men and women: relationship with food intake and food choice after repeated exposures.

    Science.gov (United States)

    de Graaf, Cees; Kramer, F Matthew; Meiselman, Herbert L; Lesher, Larry L; Baker-Fulco, Carol; Hirsch, Edward S; Warber, John

    2005-02-01

    Laboratory data with single exposures showed that palatability has a positive relationship with food intake. The question addressed in this study is whether this relationship also holds over repeated exposures in non-laboratory contexts in more natural environments. The data were collected in four field studies, lasting 4-11 days with 307 US Army men and 119 Army women, and comprised 5791 main meals and 8831 snacks in total. Acceptability was rated on the nine point hedonic scale, and intake was registered in units of 1/4, 1/2, 3/4, or 1 or more times of the provided portion size. Correlation coefficients between individual acceptability ratings and intakes varied from 0.22 to 0.62 for the main meals (n=193-2267), and between 0.13 and 0.56 for the snacks (n=304-2967). The likelihood of choosing a meal for the second time was positively related to the acceptability rating of the meal when it was consumed for the first time. The results reinforce the importance of liking in food choice and food intake/choice behavior. However, the magnitude of the correlation coefficients between acceptability ratings and food intake suggest that environmental factors also have an important role in determining intake and choice.

  11. INFLUENCE OF MORINGA OLEIFERA (DRUM-STICK FRUIT EXTRACT ON HAEMATOLOGICAL PROFILE FOLLOWING REPEATED EXPOSURE TO LOW LEVELS OF ARSENIC THROUGH FEED ON RATS

    Directory of Open Access Journals (Sweden)

    Vaibhav R. Pachade

    2012-01-01

    Full Text Available Effect of Moringa oleifera fruits hot methanolic extract (MFE, if any, in minimizing the adverse reactions of repeated exposure to arsenic trioxide (AT in feed was investigated in Wistar rats with reference to haematological profile. Three groups of rats each containing 10 (5male+5female were used. The group I served as negative control. Rats of group II were fed arsenic trioxide (AT alone @ 100 ppm in feed while those of group III simultaneously received AT (@100 ppm and MFE (50 mg/kg/day for 28 days. Blood samples were collected from retroorbital plexus for estimation of hematological parameters (haemoglobin, PCV, TEC, MCH, MCHC, MCV of different groups on 0 day, 15th day and 29th day respectively. Exposure to AT through feed in group II resulted in significant (P<0.05 decrease in haemoglobin, TEC and MCHC, accompanied by increased MCV, with no significant alteration of PCV or MCH of the rats. While rats of group III treated with AT (@100 ppm and MFE (50 mg/kg/day also resulted in same consequences as it was in group II but it was slightly less than that of group II suggesting of mild non significant protective effect.

  12. The context dependency of extinction negates the effectiveness of cognitive enhancement to reduce cocaine-primed reinstatement.

    Science.gov (United States)

    Hammond, Sherri; Wagner, John J

    2013-09-01

    With respect to the treatment of addiction, the objective of extinction training is to decrease drug-seeking behavior by repeatedly exposing the patient to cues in the absence of unconditioned reinforcement. Such exposure therapy typically takes place in a novel (clinical) environment. This is potentially problematic, as the effects of extinction training include a context dependent component and therefore diminished efficacy is expected upon the patient's return to former drug-seeking/taking environments. We have reported that treatment with the NMDAR coagonist d-serine is effective in facilitating the effects of extinction to reduce cocaine-primed reinstatement. The present study assesses d-serine's effectiveness in reducing drug-primed reinstatement under conditions in which extinction training occurs in a novel environment. After 22 days of cocaine self-administration (0.5 mg/kg) in context "A", animals underwent 5 extinction training sessions in context "B". Immediately after each extinction session in "B", animals received either saline or d-serine (60 mg/kg) treatment. Our results indicate that d-serine treatment following extinction in "B" had no effect on either IV or IP cocaine-primed reinstatement conducted in "A". These results stand in contrast to our previous findings where extinction occurred in "A", indicating that d-serine's effectiveness in facilitating extinction training to reduce drug-primed reinstatement is not transferable to a novel extinction environment. This inability of d-serine treatment to reduce the context specificity of extinction training may explain the inconsistent effects observed in clinical studies published to date in which adjunctive cognitive enhancement treatment has been combined with behavioral therapy without significant benefit. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. Stress responses in juvenile pacu (Piaractus mesopotamicus submitted to repeated air exposure - DOI: 10.4025/actascianimsci.v30i1.3618 Stress responses in juvenile pacu (Piaractus mesopotamicus submitted to repeated air exposure - DOI: 10.4025/actascianimsci.v30i1.3618

    Directory of Open Access Journals (Sweden)

    Leonardo Susumu Takahashi

    2008-06-01

    Full Text Available Juvenis de pacu (5,2 Pacu juveniles (5.2 ± 1.5 g were submitted to two one-minute air exposures in a 24 h interval, and sampled before the exposure (control and 5, 15, 30 and 60 min, 24 and 48 h afterwards for whole-body cortisol, sodium, potassium and calcium ion concentrations. For the first air exposure, there was a trend of increased cortisol concentration after 15 min, whereas in the second air exposure, the cortisol concentration increased significantly within 5 min after stress was induced. Sodium ion concentration increased significantly 24 h after both air exposures. Potassium concentration presented fluctuations over the experimental period. Calcium ion concentration increased progressively from 5 to 30 min, in both air exposures. The repeated air exposures exacerbated the cortisol response, but they did not affect the recovery ability of pacu over the experimental period. Additionally, the whole-body cortisol measurement might be a reliable indicator of stress, when sampled fish are smaller and blood volumes are very low, making samples inadequate for analysis1,5 g foram submetidos a duas exposições aéreas de um minuto, em intervalo de 24 horas, e amostrados antes da exposição (controle e 5, 15, 30 e 60 min, 24 e 48 horas depois para análise da concentração corporal de cortisol e dos íons sódio, potássio e cálcio. Na primeira exposição, os peixes apresentaram concentrações de cortisol aumentadas a partir de 15 min, embora não diferissem estatisticamente do controle. Na segunda exposição, a concentração de cortisol aumentou significativamente aos 5 min, retornando às concentrações equivalentes às dos peixes-controle em 30 min. A concentração do íon sódio aumentou significativamente 24 horas depois das duas exposições aéreas. A concentração do íon potássio apresentou flutuações durante o experimento, enquanto a do cálcio apresentou-se reduzida aos 5 min, aumentando gradativamente até os 30 min

  14. Effects of Trace Amine-associated Receptor 1 Agonists on the Expression, Reconsolidation, and Extinction of Cocaine Reward Memory.

    Science.gov (United States)

    Liu, Jian-Feng; Thorn, David A; Zhang, Yanan; Li, Jun-Xu

    2016-07-01

    As a modulator of dopaminergic system, trace amine-associated receptor 1 has been shown to play a critical role in regulating the rewarding properties of additive drugs. It has been demonstrated that activation of trace amine-associated receptor 1 decreased the abuse-related behaviors of cocaine in rats. However, the role of trace amine-associated receptor 1 in specific stages of cocaine reward memory is still unclear. Here, using a cocaine-induced conditioned place preference model, we tested the effects of a selective trace amine-associated receptor 1 agonist RO5166017 on the expression, reconsolidation, and extinction of cocaine reward memory. We found that RO5166017 inhibited the expression but not retention of cocaine-induced conditioned place preference. RO5166017 had no effect on the reconsolidation of cocaine reward memory. Pretreatment with RO5166017 before extinction hindered the formation of extinction long-term memory. RO5166017 did not affect the movement during the conditioned place preference test, indicating the inhibitory effect of RO5166017 on the expression of cocaine-induced conditioned place preference was not caused by locomotion inhibition. Using a cocaine i.v. self-administration model, we found that the combined trace amine-associated receptor 1 partial agonist RO5263397 with extinction had no effect on the following cue- and drug-induced reinstatement of cocaine-seeking behavior. Repeated administration of the trace amine-associated receptor 1 agonist during extinction showed a continually inhibitory effect on the expression of cocaine reward memory both in cocaine-induced conditioned place preference and cocaine self-administration models. Taken together, these results indicate that activation of trace amine-associated receptor 1 specifically inhibited the expression of cocaine reward memory. The inhibitory effect of trace amine-associated receptor 1 agonists on cocaine reward memory suggests that trace amine-associated receptor 1

  15. Drug smuggling using clothing impregnated with cocaine.

    Science.gov (United States)

    McDermott, Seán D; Power, John D

    2005-11-01

    A case study is presented where a woman travelling from South America to the Republic of Ireland was detained at Dublin Airport and articles of clothing she had in her luggage were found to be impregnated with cocaine. The study shows that the amount of powder recovered from the garments was approximately 14% of the total weight of the garments. The cocaine was in the form of cocaine hydrochloride and the purity was approximately 80%. An examination of the garments under filtered light highlighted the areas exposed to cocaine and indicated that the method of impregnation was by pouring liquid containing cocaine onto the clothing.

  16. Multiple Gastrointestinal Complications of Crack Cocaine Abuse

    Directory of Open Access Journals (Sweden)

    Neal Carlin

    2014-01-01

    Full Text Available Cocaine and its alkaloid free base “crack-cocaine” have long since been substances of abuse. Drug abuse of cocaine via oral, inhalation, intravenous, and intranasal intake has famously been associated with a number of medical complications. Intestinal ischemia and perforation remain the most common manifestations of cocaine associated gastrointestinal disease and have historically been associated with oral intake of cocaine. Here we find a rare case of two relatively uncommon gastrointestinal complications of hemorrhage and pancreatitis presenting within a single admission in a chronic crack cocaine abuser.

  17. WITHDRAWN: Carbamazepine for cocaine dependence.

    Science.gov (United States)

    Lima Reisser, Anelise A R L; Silva de Lima, Mauricio; Soares, Bernardo Garcia de Oliveira; Farrell, Michael

    2009-01-21

    Cocaine dependence has become a public health problem, developing a significant number of medical, psychological and social problems. Although there is no consensus regarding how to treat cocaine dependence, effective pharmacotherapy has a potentially major role to play as part of a broader treatment milieu. The anti-convulsant carbamazepine, a tricyclic medication that is widely used to treat a variety of neurological and psychiatric disorders, has been used for treatment of cocaine dependence, although its effectiveness has not been established. To determine whether carbamazepine is effective for the treatment of cocaine dependence. We searched: Cochrane Controlled Trials Register (Cochrane Library issue 1, 1999), MEDLINE (f1966 - October 1997), EMBASE (1980 - October 1997), PsycLIT (1974 - July 1997), Biological Abstracts and LILACS (1982 - 1997); scan of reference list of relevant articles; personal communication; conference abstracts; unpublished trials from pharmaceutical industry; book chapters on treatment of cocaine dependence. The specialised register of trials of Cochrane Group on Drugs and Alcohol until February 2003. All randomised controlled trials focused on the use of carbamazepine versus placebo on the treatment of cocaine dependence. Trials including patients with additional diagnosis such as opiate dependence were also eligible. The reviewers extracted the data independently, Odds Ratios, weighted mean difference and number needed to treat were estimated. Qualitative assessments of the methodology of eligible studies were carried out using validated checklists. The reviewers assumed that people who died or dropped out had no improvement and tested the sensitivity of the final results to this assumption. Where possible analysis was carried out according to the "intention to treat" principles. 5 studies were included (455 participants). No differences regarding positive urine sample for cocaine metabolites. Scores on Spielberg State Anxiety

  18. Cocaine-induced renal infarction: report of a case and review of the literature

    Directory of Open Access Journals (Sweden)

    Nosrati Saeid M

    2005-09-01

    Full Text Available Abstract Background Cocaine abuse has been known to have detrimental effects on the cardiovascular system. Its toxicity has been associated with myocardial ischemia, cerebrovascular accidents and mesenteric ischemia. The pathophysiology of cocaine-related renal injury is multifactorial and involves renal hemodynamic changes, alterations in glomerular matrix synthesis, degradation and oxidative stress, and possibly induction of renal atherogenesis. Renal infarction as a result of cocaine exposure, however, is rarely reported in the literature. Case presentation A 48 year-old male presented with a four-day history of severe right flank pain following cocaine use. On presentation, he was tachycardic, febrile and had severe right costovertebral angle tenderness. He had significant proteinuria, leukocytosis and elevated serum creatinine and lactate dehydrogenase. Radiographic imaging studies as well as other screening tests for thromboembolic events, hypercoagulability states, collagen vascular diseases and lipid disorders were suggestive of Cocaine-Induced Renal Infarction (CIRI by exclusion. Conclusion In a patient with a history of cocaine abuse presenting with fevers and flank pain suggestive of urinary tract infection or nephrolithiasis, cocaine-induced renal infarction must be considered in the differential diagnosis. In this article, we discuss the prior reported cases of CIRI and thoroughly review the literature available on this disorder. This is important for several reasons. First, it will allow us to discuss and elaborate on the mechanism of renal injury caused by cocaine. In addition, this review will demonstrate the importance of considering the diagnosis of CIRI in a patient with documented cocaine use and an atypical presentation of acute renal injury. Finally, we will emphasize the need for a consensus on optimal treatment of this disease, for which therapy is not yet standardized.

  19. Cocaine Hoppers : The Nigerian Involvement in the Global Cocaine Trade

    NARCIS (Netherlands)

    Oboh, Jude Roys

    2016-01-01

    In recent decades, Nigerian criminal drug ‘barons’ and ‘gangs’ have come to dominate international cocaine trafficking via West Africa to destination countries globally, a trend that presents a serious security threat to Africa and the world. This work provides empirical evidence to define and

  20. Adverse effects of levamisole in cocaine users: a review and risk assessment.

    Science.gov (United States)

    Brunt, Tibor Markus; van den Berg, Jorrit; Pennings, Ed; Venhuis, Bastiaan

    2017-06-01

    The immunomodulatory adjuvant and antihelminth levamisole is increasingly used as an adulterant in cocaine worldwide. An accumulating body of clinical and toxicological literature has appeared since 2010 describing neutropenia, agranulocytosis, leukoencephalopathy and vasculitis in cases associated with levamisole-adulterated cocaine. Mostly, neutropenia and agranulocytosis were reported, characterized by a decimation of neutrophils. A large proportion of cases also involved vasculopathy, characterized by pronounced black and purple skin purpura with cutaneous necrosis. Females are more susceptible for both agranulocytosis and vasculitis. Another complication reported with levamisole-adulterated cocaine is leukoencephalopathy, a disabling and potentially fatal neurological disorder caused by cerebral demyelination. In this review, all adverse effects associated with therapeutic levamisole and levamisole-adulterated cocaine are described. In addition, this review provides an update of the pharmacology of levamisole, its metabolism, including toxic metabolites and metabolites that are relevant for levamisole's addition to cocaine. Special emphasis is put on the immunopathology and the dose-effect relationship of chronic levamisole exposure. Finally, a risk assessment is provided based on the current level of levamisole adulteration in street cocaine, the dose range calculated per gram and the pattern of chronic exposure in heavy or dependent users.

  1. Cocaine/levamisole-associated autoimmune syndrome: a disease of neutrophil-mediated autoimmunity.

    Science.gov (United States)

    Cascio, Michael J; Jen, Kuang-Yu

    2018-01-01

    Levamisole was previously used for its immunomodulatory properties to treat rheumatoid arthritis and some cancers. However, because of serious side-effects, it was taken off the market in the United States. Recently, levamisole has reemerged as a popular cocaine adulterant. Some individuals who consume levamisole-adulterated cocaine can develop a life-threatening autoimmune syndrome. In this review, the medical consequences of levamisole exposure and postulated mechanisms by which levamisole induces these adverse effects are discussed. Although agranulocytosis and cutaneous vasculitis are the major findings in patients who develop cocaine/levamisole-associated autoimmune syndrome (CLAAS), more recent experience indicates that other organ systems can be involved as well. Current studies point to neutrophil activation and neutrophil extracellular trap formation with subsequent antineutrophil cytoplasmic antibody-mediated tissue injury as a possible mechanism of CLAAS. In the past decade, the detrimental effects of levamisole have reemerged because of its popularity as a cocaine adulterant. Although infrequent, some individuals develop a systemic autoimmune syndrome characterized by immune-mediated agranulocytosis and antineutrophil cytoplasmic antibody-mediated vasculitis. Mechanistically, neutrophil antigens appear to be a major player in inducing CLAAS. Prompt cessation of levamisole exposure is key to treatment, although relapses are frequent because of the addictive effects of cocaine and the high prevalence of levamisole within the cocaine supply.

  2. Addiction-Related Effects of DOV 216,303 and Cocaine

    DEFF Research Database (Denmark)

    Sørensen, Gunnar; Husum, Henriette; Brennum, Lise T

    2014-01-01

    DOV 216,303, an inhibitor of serotonin, noradrenaline and dopamine reuptake, belongs to a new line of drugs called 'triple reuptake inhibitors' that have been proposed for treatment of depression. The addictive drug cocaine has similar mechanism of action and exerts rewarding effects by blocking...... of DOV 216,303, we conducted a comparative study of addiction-related effects of DOV 216,303 and cocaine in mice using acute self-administration, conditioned place preference (CPP) and drug-induced hyperlocomotion. Effects on accumbal extracellular dopamine levels were determined using microdialysis......, and we measured monoamine receptor occupancy as well as brain and plasma exposure. DOV 216,303 was self-administered acutely in the same dose range as cocaine. However, in the CPP model, DOV 216,303 did not induce place preference at doses where cocaine caused place preference. Higher doses of DOV 216...

  3. Responses to Novelty and Vulnerability to Cocaine Addiction: Contribution of a Multi-Symptomatic Animal Model

    Science.gov (United States)

    Belin, David; Deroche-Gamonet, Véronique

    2012-01-01

    Epidemiological studies have revealed striking associations between several distinct behavioral/personality traits and drug addiction, with a large emphasis on the sensation-seeking trait and the associated impulsive dimension of personality. However, in human studies, it is difficult to identify whether personality/behavioral traits actually contribute to increased vulnerability to drug addiction or reflect psychobiological adaptations to chronic drug exposure. Here we show how animal models, including the first multi-symptomatic model of addiction in the rat, have contributed to a better understanding of the relationships between different subdimensions of the sensation-seeking trait and different stages of the development of cocaine addiction, from vulnerability to initiation of cocaine self-administration to the transition to compulsive drug intake. We argue that sensation seeking predicts vulnerability to use cocaine, whereas novelty seeking, akin to high impulsivity, predicts instead vulnerability to shift from controlled to compulsive cocaine use, that is, addiction. PMID:23125204

  4. The Effects of a Single Whole-Body Cryotherapy Exposure on Physiological, Performance, and Perceptual Responses of Professional Academy Soccer Players After Repeated Sprint Exercise.

    Science.gov (United States)

    Russell, Mark; Birch, Jack; Love, Thomas; Cook, Christian J; Bracken, Richard M; Taylor, Tom; Swift, Eamon; Cockburn, Emma; Finn, Charlie; Cunningham, Daniel; Wilson, Laura; Kilduff, Liam P

    2017-02-01

    Russell, M, Birch, J, Love, T, Cook, CJ, Bracken, RM, Taylor, T, Swift, E, Cockburn, E, Finn, C, Cunningham, D, Wilson, L, and Kilduff, LP. The effects of a single whole-body cryotherapy exposure on physiological, performance, and perceptual responses of professional academy soccer players after repeated sprint exercise. J Strength Cond Res 31(2): 415-421, 2017-In professional youth soccer players, the physiological, performance, and perceptual effects of a single whole-body cryotherapy (WBC) session performed shortly after repeated sprint exercise were investigated. In a randomized, counterbalanced, and crossover design, 14 habituated English Premier League academy soccer players performed 15 × 30 m sprints (each followed by a 10 m forced deceleration) on 2 occasions. Within 20 minutes of exercise cessation, players entered a WBC chamber (Cryo: 30 seconds at -60° C, 120 seconds at -135° C) or remained seated (Con) indoors in temperate conditions (∼25° C). Blood and saliva samples, peak power output (countermovement jump), and perceptual indices of recovery and soreness were assessed pre-exercise and immediately, 2-hour and 24-hour postexercise. When compared with Con, a greater testosterone response was observed at 2-hour (+32.5 ± 32.3 pg·ml, +21%) and 24-hour (+50.4 ± 48.9 pg·ml, +28%) postexercise (both P = 0.002) in Cryo (trial × treatment interaction: P = 0.001). No between-trial differences were observed for other salivary (cortisol and testosterone/cortisol ratio), blood (lactate and creatine kinase), performance (peak power output), or perceptual (recovery or soreness) markers (all trial × treatment interactions: P > 0.05); all of which were influenced by exercise (time effects: all P ≤ 0.05). A single session of WBC performed within 20 minutes of repeated sprint exercise elevated testosterone concentrations for 24 hours but did not affect any other performance, physiological, or perceptual measurements taken. Although unclear, WBC may be

  5. Repeated Gestational Exposure of Mice to Chlorpyrifos Oxon Is Associated with Paraoxonase 1 (PON1) Modulated Effects in Maternal and Fetal Tissues

    Science.gov (United States)

    Co, Aila L.; Hay, Ariel M.; MacDonald, James W.; Bammler, Theo K.; Farin, Federico M.; Costa, Lucio G.; Furlong, Clement E.

    2014-01-01

    Chlorpyrifos oxon (CPO), the toxic metabolite of the organophosphorus (OP) insecticide chlorpyrifos, causes developmental neurotoxicity in humans and rodents. CPO is hydrolyzed by paraoxonase-1 (PON1), with protection determined by PON1 levels and the human Q192R polymorphism. To examine how the Q192R polymorphism influences fetal toxicity associated with gestational CPO exposure, we measured enzyme inhibition and fetal-brain gene expression in wild-type (PON1+/+), PON1-knockout (PON1−/−), and tgHuPON1R192 and tgHuPON1Q192 transgenic mice. Pregnant mice exposed dermally to 0, 0.50, 0.75, or 0.85 mg/kg/d CPO from gestational day (GD) 6 through 17 were sacrificed on GD18. Biomarkers of CPO exposure inhibited in maternal tissues included brain acetylcholinesterase (AChE), red blood cell acylpeptide hydrolase (APH), and plasma butyrylcholinesterase (BChE) and carboxylesterase (CES). Fetal plasma BChE was inhibited in PON1−/− and tgHuPON1Q192, but not PON1+/+ or tgHuPON1R192 mice. Fetal brain AChE and plasma CES were inhibited in PON1−/− mice, but not in other genotypes. Weighted gene co-expression network analysis identified five gene modules based on clustering of the correlations among their fetal-brain expression values, allowing for correlation of module membership with the phenotypic data on enzyme inhibition. One module that correlated highly with maternal brain AChE activity had a large representation of homeobox genes. Gene set enrichment analysis revealed multiple gene sets affected by gestational CPO exposure in tgHuPON1Q192 but not tgHuPON1R192 mice, including gene sets involved in protein export, lipid metabolism, and neurotransmission. These data indicate that maternal PON1 status modulates the effects of repeated gestational CPO exposure on fetal-brain gene expression and on inhibition of both maternal and fetal biomarker enzymes. PMID:25070982

  6. The development of a preference for cocaine over food identifies individual rats with addiction-like behaviors.

    Directory of Open Access Journals (Sweden)

    Adam N Perry

    Full Text Available Cocaine dependence is characterized by compulsive drug taking that supercedes other recreational, occupational or social pursuits. We hypothesized that rats vulnerable to addiction could be identified within the larger population based on their preference for cocaine over palatable food rewards.To validate the choice self-administration paradigm as a preclinical model of addiction, we examined changes in motivation for cocaine and recidivism to drug seeking in cocaine-preferring and pellet-preferring rats. We also examined behavior in males and females to identify sex differences in this "addicted" phenotype.Preferences were identified during self-administration on a fixed-ratio schedule with cocaine-only, pellet-only and choice sessions. Motivation for each reward was probed early and late during self-administration using a progressive-ratio schedule. Reinstatement of cocaine- and pellet-seeking was examined following exposure to their cues and non-contingent delivery of each reward.Cocaine preferring rats increased their drug intake at the expense of pellets, displayed increased motivation for cocaine, attenuated motivation for pellets and greater cocaine and cue-induced reinstatement of drug seeking. Females were more likely to develop cocaine preferences and recidivism of cocaine- and pellet-seeking was sexually dimorphic.The choice self-administration paradigm is a valid preclinical model of addiction. The unbiased selection criteria also revealed sex-specific vulnerability factors that could be differentiated from generalized sex differences in behavior, which has implications for the neurobiology of addiction and effective treatments in each sex.

  7. β-Endorphin via the Delta Opioid Receptor is a Major Factor in the Incubation of Cocaine Craving

    Science.gov (United States)

    Dikshtein, Yahav; Barnea, Royi; Kronfeld, Noam; Lax, Elad; Roth-Deri, Ilana; Friedman, Alexander; Gispan, Iris; Elharrar, Einat; Levy, Sarit; Ben-Tzion, Moshe; Yadid, Gal

    2013-01-01

    Cue-induced cocaine craving intensifies, or ‘incubates', during the first few weeks of abstinence and persists over extended periods of time. One important factor implicated in cocaine addiction is the endogenous opioid β-endorphin. In the present study, we examined the possible involvement of β-endorphin in the incubation of cocaine craving. Rats were trained to self-administer cocaine (0.75 mg/kg, 10 days, 6 h/day), followed by either a 1-day or a 30-day period of forced abstinence. Subsequent testing for cue-induced cocaine-seeking behavior (without cocaine reinforcement) was performed. Rats exposed to the drug-associated cue on day 1 of forced abstinence demonstrated minimal cue-induced cocaine-seeking behavior concurrently with a significant increase in β-endorphin release in the nucleus accumbens (NAc). Conversely, exposure to the cue on day 30 increased cocaine seeking, while β-endorphin levels remained unchanged. Intra-NAc infusion of an anti-β-endorphin antibody (4 μg) on day 1 increased cue-induced cocaine seeking, whereas infusion of a synthetic β-endorphin peptide (100 ng) on day 30 significantly decreased cue response. Both intra-NAc infusions of the δ opioid receptor antagonist naltrindole (1 μg) on day 1 and naltrindole together with β-endorphin on day 30 increased cue-induced cocaine-seeking behavior. Intra-NAc infusion of the μ opioid receptor antagonist CTAP (30 ng and 3 μg) had no behavioral effect. Altogether, these results demonstrate a novel role for β-endorphin and the δ opioid receptor in the development of the incubation of cocaine craving. PMID:23800967

  8. Role of glucocorticoid receptor-mediated mechanisms in cocaine memory enhancement.

    Science.gov (United States)

    Stringfield, S J; Higginbotham, J A; Wang, R; Berger, A L; McLaughlin, R J; Fuchs, R A

    2017-09-01

    The basolateral amygdala (BLA) is a critical site for the reconsolidation of labile contextual cocaine memories following retrieval-induced reactivation/destabilization. Here, we examined whether glucocorticoid receptors (GR), which are abundant in the BLA, mediate this phenomenon. Rats were trained to lever press for cocaine reinforcement in a distinct environmental context, followed by extinction training in a different context. Rats were then briefly exposed to the cocaine-paired context (to elicit memory reactivation and reconsolidation) or their home cages (no reactivation control). Exposure to the cocaine-paired context elicited greater serum corticosterone concentrations than home cage stay. Interestingly, the GR antagonist, mifepristone (3-10 ng/hemisphere), administered into the BLA after memory reactivation produced a further, dose-dependent increase in serum corticosterone concentrations during the putative time of cocaine-memory reconsolidation but produced an inverted U-shaped dose-effect curve on subsequent cocaine-seeking behavior 72 h later. This effect was anatomically selective, dependent on memory reactivation (i.e., not observed after home cage exposure), and did not reflect protracted hyperactivity. However, the effect was also observed when mifepristone was administered after novelty stress that mimics drug context-induced hypothalamic-pituitary-adrenal (HPA) axis activation without explicit memory reactivation. Together, these findings suggest that, similar to explicit memory retrieval, a stressful event is sufficient to destabilize cocaine memories and permit their manipulation. Furthermore, BLA GR stimulation exerts inhibitory feedback upon HPA axis activation and thus suppresses cocaine-memory reconsolidation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. The First American Cocaine Epidemic.

    Science.gov (United States)

    Courtwright, David T.

    1991-01-01

    Discusses the wave of cocaine abuse that followed the drug's recommendation by the late nineteenth-century medical community as a cure all. Details drug addiction among ethnic and social groups at the turn of the century. Warns that drug epidemics have important social and legal consequences. Suggests legal pressure may alter the form of drug…

  10. Effects of continuous nicotine treatment and subsequent termination on cocaine versus food choice in male rhesus monkeys.

    Science.gov (United States)

    Schwienteck, Kathryn L; Negus, S Stevens; Poklis, Justin L; Banks, Matthew L

    2015-10-01

    One complicating factor in cocaine addiction may be concurrent exposure and potential dependence on nicotine. The aim of the present study was to determine the effects of continuous nicotine treatment and subsequent termination on cocaine versus food choice in rhesus monkeys (Macaca mulatta). For comparison, we also determined effects of the nicotinic receptor antagonist mecamylamine on cocaine versus food choice during continuous saline and nicotine treatment. Rhesus monkeys (N = 3) responded under a concurrent schedule of food pellet (1 g) and intravenous cocaine (0-0.1 mg/kg/injection) availability. Saline and ascending nicotine doses (0.1-1.0 mg/kg/hr, intravenous) were continuously infused for 7-day treatment periods and separated by 24-hr saline treatment periods. Acute effects of mecamylamine (0.32-1.8 mg/kg, intramuscular, 15 min pretreatment) were determined during continuous saline and 0.32-mg/kg/hr nicotine treatments. During saline treatment, cocaine maintained a dose-dependent increase in cocaine choice. Nicotine treatment did not alter cocaine versus food choice. In contrast, preference of 0.032 mg/kg/injection cocaine was attenuated 24 hr following termination of 0.32-mg/kg/hr nicotine treatment, despite no somatic abstinence signs being observed. Acute mecamylamine enhanced cocaine choice during saline treatment and mainly suppressed rates of behavior during nicotine treatment. Overall, continuous nicotine exposure, up to 1 mg/kg/hr, does not enhance cocaine choice and does not produce nicotine dependence, as demonstrated by the lack of abstinence signs. (c) 2015 APA, all rights reserved).

  11. Comparative analysis of transcriptomic responses to repeated-dose exposure to 2-MCPD and 3-MCPD in rat kidney, liver and testis.

    Science.gov (United States)

    Buhrke, Thorsten; Schultrich, Katharina; Braeuning, Albert; Lampen, Alfonso

    2017-08-01

    3-Chloro-1,2-propanediol (3-MCPD) and its isomer 2-chloro-1,3-propanediol (2-MCPD) are heat-induced food contaminants present in oil- and fat-containing foodstuff. Kidney and testes are among the main target organs of 3-MCPD. Almost no data on 2-MCPD toxicity are available. Here, transcriptomic responses following repeated-dose exposure of rats to non-toxic doses of 10 mg/kg body weight per day 2-MCPD or 3-MCPD for 28 days were characterized by microarray analysis of kidney, liver, and testes. 3-MCPD exerted more pronounced effects than 2-MCPD in all organs. The limited overlap between the datasets indicates that 2-MCPD and 3-MCPD do not share the same molecular mechanisms of toxicity. By combining transcriptomic data with datasets on proteomic regulation by 3-MCPD, a comprehensive view on 3-MCPD-induced regulation of glucose utilization and oxidative stress response was developed. Bioinformatic analyses revealed that Nrf2 (nuclear factor (erythroid-derived 2)-like 2) signaling is likely to be involved in mediating the oxidative stress response to 3-MCPD. In summary, this study for the first time presents data on alterations in global gene expression by two important food contaminants, 2-MCPD and 3-MCPD. Data demonstrate profound differences between the effects of the two compounds and substantially broaden our knowledge on molecular details of 3-MCPD-induced disturbance of glucose utilization and redox balance. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. The Queensland study of Melanoma: Environmental and Genetic Associations (Q-MEGA). Study design, baseline characteristics, and repeatability of phenotype and sun exposure measures

    Science.gov (United States)

    Baxter, Amanda J.; Hughes, Maria Celia; Kvaskoff, Marina; Siskind, Victor; Shekar, Sri; Aitken, Joanne F.; Green, Adele C.; Duffy, David L.; Hayward, Nicholas K.; Martin, Nicholas G.; Whiteman, David C.

    2013-01-01

    Cutaneous malignant melanoma (CMM) is a major health issue in Queensland, Australia which has the world’s highest incidence. Recent molecular and epidemiologic studies suggest that CMM arises through multiple etiological pathways involving gene-environment interactions. Understanding the potential mechanisms leading to CMM requires larger studies than those previously conducted. This article describes the design and baseline characteristics of Q-MEGA, the Queensland study of Melanoma: Environmental and Genetic Associations, which followed-up four population-based samples of CMM patients in Queensland, including children, adolescents, men aged over 50, and a large sample of adult cases and their families, including twins. Q-MEGA aims to investigate the roles of genetic and environmental factors, and their interaction, in the etiology of melanoma. 3,471 participants took part in the follow-up study and were administered a computer-assisted telephone interview in 2002–2005. Updated data on environmental and phenotypic risk factors, and 2,777 blood samples were collected from interviewed participants as well as a subset of relatives. This study provides a large and well-described population-based sample of CMM cases with follow-up data. Characteristics of the cases and repeatability of sun exposure and phenotype measures between the baseline and the follow-up surveys, from six to 17 years later, are also described. PMID:18361720

  13. The effects of cocaine, alcohol and cocaine/alcohol combinations in conditioned taste aversion learning.

    Science.gov (United States)

    Busse, Gregory D; Verendeev, Andrey; Jones, Jermaine; Riley, Anthony L

    2005-09-01

    We have recently reported that alcohol attenuates cocaine place preferences. Although the basis for this effect is unknown, alcohol may attenuate cocaine reward by potentiating its aversive effects. To examine this possibility, these experiments assessed the effects of alcohol on cocaine-induced taste aversions under conditions similar to those that resulted in attenuated place preferences. Specifically, Experiments 1 and 2 assessed the effects of alcohol (0.5 g/kg) on taste aversions induced by 20, 30 and 40 mg/kg cocaine. Experiment 3 examined the role of intertrial interval in the effects of alcohol (0.5 g/kg) on cocaine (30 mg/kg) taste aversions. In Experiments 1 and 2, cocaine was effective at conditioning aversions. Alcohol produced no measurable effect. Combining cocaine and alcohol produced no greater aversion than cocaine alone (and, in fact, weakened aversions at the lowest dose of cocaine). In Experiment 3, varying the intertrial interval from 3 days (as in the case of Experiments 1 and 2) to 1 day (a procedure identical to that in which alcohol attenuated cocaine place preferences) resulted in significant alcohol- and cocaine-induced taste aversions. Nonetheless, alcohol remained ineffective in potentiating cocaine aversions. Thus, under these conditions alcohol does not potentiate cocaine's aversiveness. These results were discussed in terms of their implication for the effects of alcohol on cocaine-induced place preferences. Further, the effects of alcohol on place preferences conditioned by cocaine were discussed in relation to other assessments of the effects of alcohol on the affective properties of cocaine and the implications of these interactions for alcohol and cocaine co-use.

  14. Cigarette Cue Attentional Bias in Cocaine-Smoking and Non-Cocaine-Using Cigarette Smokers.

    Science.gov (United States)

    Marks, Katherine R; Alcorn, Joseph L; Stoops, William W; Rush, Craig R

    2016-09-01

    Cigarette smoking in cocaine users is nearly four times higher than the national prevalence and cocaine use increases cigarette smoking. The mechanisms underlying cigarette smoking in cocaine-using individuals need to be identified to promote cigarette and cocaine abstinence. Previous studies have examined the salience of cigarette and cocaine cues separately. The present aim was to determine whether cigarette attentional bias (AB) is higher in cigarettes smokers who smoke cocaine relative to individuals who only smoke cigarettes. Twenty cigarette smokers who smoke cocaine and 20 non-cocaine-using cigarette smokers completed a visual probe task with eye-tracking technology. During this task, the magnitude of cigarette and cocaine AB was assessed through orienting bias, fixation time, and response time. Cocaine users displayed an orienting bias towards cigarette cues. Cocaine users also endorsed a more urgent desire to smoke to relieve negative affect associated with cigarette craving than non-cocaine users (g = 0.6). Neither group displayed a cigarette AB, as measured by fixation time. Cocaine users, but not non-cocaine users, displayed a cocaine AB as measured by orienting bias (g = 2.0) and fixation time (g = 1.2). There were no significant effects for response time data. Cocaine-smoking cigarettes smokers display an initial orienting bias toward cigarette cues, but not sustained cigarette AB. The incentive motivation underlying cigarette smoking also differs. Cocaine smokers report more urgent desire to smoke to relieve negative affect. Identifying differences in motivation to smoke cigarettes may provide new treatment targets for cigarette and cocaine use disorders. These results suggest that cocaine-smoking cigarette smokers display an initial orienting bias towards cigarette cues, but not sustained attention towards cigarette cues, relative to non-cocaine-using smokers. Smoked cocaine users also report a more urgent desire to smoke to relieve negative affect

  15. Cocaine-induced behavioral sensitization decreases the expression of endocannabinoid signaling-related proteins in the mouse hippocampus.

    Science.gov (United States)

    Blanco, Eduardo; Galeano, Pablo; Palomino, Ana; Pavón, Francisco J; Rivera, Patricia; Serrano, Antonia; Alen, Francisco; Rubio, Leticia; Vargas, Antonio; Castilla-Ortega, Estela; Decara, Juan; Bilbao, Ainhoa; de Fonseca, Fernando Rodríguez; Suárez, Juan

    2016-03-01

    In the reward mesocorticolimbic circuits, the glutamatergic and endocannabinoid systems are implicated in neurobiological mechanisms underlying cocaine addiction. However, the involvement of both systems in the hippocampus, a critical region to process relational information relevant for encoding drug-associated memories, in cocaine-related behaviors remains unknown. In the present work, we studied whether the hippocampal gene/protein expression of relevant glutamate signaling components, including glutamate-synthesizing enzymes and metabotropic and ionotropic receptors, and the hippocampal gene/protein expression of cannabinoid type 1 (CB1) receptor and endocannabinoid metabolic enzymes were altered following acute and/or repeated cocaine administration resulting in conditioned locomotion and locomotor sensitization. Results showed that acute cocaine administration induced an overall down-regulation of glutamate-related gene expression and, specifically, a low phosphorylation level of GluA1. In contrast, locomotor sensitization to cocaine produced an up-regulation of several glutamate receptor-related genes and, specifically, an increased protein expression of the GluN1 receptor subunit. Regarding the endocannabinoid system, acute and repeated cocaine administration were associated with an increased gene/protein expression of CB1 receptors and a decreased gene/protein expression of the endocannabinoid-synthesis enzymes N-acyl phosphatidylethanolamine D (NAPE-PLD) and diacylglycerol lipase alpha (DAGLα). These changes resulted in an overall decrease in endocannabinoid synthesis/degradation ratios, especially NAPE-PLD/fatty acid amide hydrolase and DAGLα/monoacylglycerol lipase, suggesting a reduced endocannabinoid production associated with a compensatory up-regulation of CB1 receptor. Overall, these findings suggest that repeated cocaine administration resulting in locomotor sensitization induces a down-regulation of the endocannabinoid signaling that could

  16. Comparing attitudes about legal sanctions and teratogenic effects for cocaine, alcohol, tobacco and caffeine: A randomized, independent samples design

    Directory of Open Access Journals (Sweden)

    Alanis Kelly L

    2006-02-01

    Full Text Available Abstract Background Establishing more sensible measures to treat cocaine-addicted mothers and their children is essential for improving U.S. drug policy. Favorable post-natal environments have moderated potential deleterious prenatal effects. However, since cocaine is an illicit substance having long been demonized, we hypothesized that attitudes toward prenatal cocaine exposure would be more negative than for licit substances, alcohol, nicotine and caffeine. Further, media portrayals about long-term outcomes were hypothesized to influence viewers' attitudes, measured immediately post-viewing. Reducing popular crack baby stigmas could influence future policy decisions by legislators. In Study 1, 336 participants were randomly assigned to 1 of 4 conditions describing hypothetical legal sanction scenarios for pregnant women using cocaine, alcohol, nicotine or caffeine. Participants rated legal sanctions against pregnant women who used one of these substances and risk potential for developing children. In Study 2, 139 participants were randomly assigned to positive, neutral and negative media conditions. Immediately post-viewing, participants rated prenatal cocaine-exposed or non-exposed teens for their academic performance and risk for problems at age18. Results Participants in Study 1 imposed significantly greater legal sanctions for cocaine, perceiving prenatal cocaine exposure as more harmful than alcohol, nicotine or caffeine. A one-way ANOVA for independent samples showed significant differences, beyond .0001. Post-hoc Sheffe test illustrated that cocaine was rated differently from other substances. In Study 2, a one-way ANOVA for independent samples was performed on difference scores for the positive, neutral or negative media conditions about prenatal cocaine exposure. Participants in the neutral and negative media conditions estimated significantly lower grade point averages and more problems for the teen with prenatal cocaine exposure

  17. Deployment Repeatability

    Science.gov (United States)

    2016-04-01

    evaluating the deployment repeatability builds upon the testing or analysis of deployment kinematics (Chapter 6) and adds repetition. Introduction...material yield or failure during a test. For the purposes of this chapter, zero shift will refer to permanent changes in the structure, while reversible ...the content of other chapters in this book: Gravity Compensation (Chapter 4) and Deployment Kinematics and Dynamics (Chapter 6). Repeating the

  18. Reduced attentional scope in cocaine polydrug users.

    Directory of Open Access Journals (Sweden)

    Lorenza S Colzato

    Full Text Available Cocaine is Europe's second preferred recreational drug after cannabis but very little is known about possible cognitive impairments in the upcoming type of recreational cocaine user (monthly consumption. We asked whether recreational use of cocaine impacts early attentional selection processes. Cocaine-free polydrug controls (n = 18 and cocaine polydrug users (n = 18 were matched on sex, age, alcohol consumption, and IQ (using the Raven's progressive matrices, and were tested by using the Global-Local task to measure the scope of attention. Cocaine polydrug users attended significantly more to local aspects of attended events, which fits with the idea that a reduced scope of attention may be associated with the perpetuation of the use of the drug.

  19. Hormones, Nicotine and Cocaine: Clinical Studies

    Science.gov (United States)

    Mello, Nancy K.

    2009-01-01

    Nicotine and cocaine each stimulate hypothalamic-pituitary-adrenal and -gonadal axis hormones, and there is increasing evidence that the hormonal milieu may modulate the abuse-related effects of these drugs. This review summarizes some clinical studies of the acute effects of cigarette smoking or IV cocaine on plasma drug and hormone levels, and subjective effects ratings. The temporal covariance between these dependent measures was assessed with a rapid (two min) sampling procedure in nicotine-dependent volunteers or current cocaine users. Cigarette smoking and IV cocaine each stimulated a rapid increase in LH and ACTH, followed by gradual increases in cortisol and DHEA. Positive subjective effects ratings increased immediately after initiation of cigarette smoking or IV cocaine administration. However, in contrast to cocaine’s sustained positive effects (hormones on nicotine dependence and cocaine abuse, and implications for treatment of these addictive disorders is discussed. PMID:19835877

  20. Alterations in tryptophan and purine metabolism in cocaine addiction: a metabolomic study.

    Science.gov (United States)

    Patkar, Ashwin A; Rozen, Steve; Mannelli, Paolo; Matson, Wayne; Pae, Chi-Un; Krishnan, K Ranga; Kaddurah-Daouk, Rima

    2009-10-01

    Mapping metabolic "signatures" can provide new insights into addictive mechanisms and potentially identify biomarkers and therapeutic targets. We examined the differences in metabolites related to the tyrosine, tryptophan, purine, and oxidative stress pathways between cocaine-dependent subjects and healthy controls. Several of these metabolites serve as biological indices underlying the mechanisms of reinforcement, toxicity, and oxidative stress. Metabolomic analysis was performed in 18 DSM-IV-diagnosed cocaine-dependent individuals with at least 2 weeks of abstinence and ten drug-free controls. Plasma concentrations of 37 known metabolites were analyzed and compared using a liquid chromatography electrochemical array platform. Multivariate analyses were used to study the relationship between severity of drug use [Addiction Severity Index (ASI) scores] and biological measures. Cocaine subjects showed significantly higher levels of n-methylserotonin (p cocaine and control groups with no overlap. Alterations in the methylation processes in the serotonin pathways and purine metabolism seem to be associated with chronic exposure to cocaine. Given the preliminary nature and cross-sectional design of the study, the findings need to be confirmed in larger samples of cocaine-dependent subjects, preferably in a longitudinal design.

  1. Impaired insight in cocaine addiction: laboratory evidence and effects on cocaine-seeking behaviour

    Science.gov (United States)

    Maloney, Thomas; Parvaz, Muhammad A.; Alia-Klein, Nelly; Woicik, Patricia A.; Telang, Frank; Wang, Gene-Jack; Volkow, Nora D.; Goldstein, Rita Z.

    2010-01-01

    Neuropsychiatric disorders are often characterized by impaired insight into behaviour. Such an insight deficit has been suggested, but never directly tested, in drug addiction. Here we tested for the first time this impaired insight hypothesis in drug addiction, and examined its potential association with drug-seeking behaviour. We also tested potential modulation of these effects by cocaine urine status, an individual difference known to impact underlying cognitive functions and prognosis. Sixteen cocaine addicted individuals testing positive for cocaine in urine, 26 cocaine addicted individuals testing negative for cocaine in urine, and 23 healthy controls completed a probabilistic choice task that assessed objective preference for viewing four types of pictures (pleasant, unpleasant, neutral and cocaine). This choice task concluded by asking subjects to report their most selected picture type; correspondence between subjects’ self-reports with their objective choice behaviour provided our index of behavioural insight. Results showed that the urine positive cocaine subjects exhibited impaired insight into their own choice behaviour compared with healthy controls; this same study group also selected the most cocaine pictures (and fewest pleasant pictures) for viewing. Importantly, however, it was the urine negative cocaine subjects whose behaviour was most influenced by insight, such that impaired insight in this subgroup only was associated with higher cocaine-related choice on the task and more severe actual cocaine use. These findings suggest that interventions to enhance insight may decrease drug-seeking behaviour, especially in urine negative cocaine subjects, potentially to improve their longer-term clinical outcomes. PMID:20395264

  2. Oxytocin decreases cocaine taking, cocaine seeking, and locomotor activity in female rats.

    Science.gov (United States)

    Leong, Kah-Chung; Zhou, Luyi; Ghee, Shannon M; See, Ronald E; Reichel, Carmela M

    2016-02-01

    Oxytocin has been shown to decrease cocaine taking and seeking in male rats, suggesting potential treatment efficacy for drug addiction. In the present study, we extended these findings to the assessment of cocaine seeking and taking in female rats. Further, we made direct comparisons of oxytocin's impact on cocaine induced locomotor activity in both males and females. In females, systemic oxytocin (0.3, 1.0, 3.0 mg/kg) attenuated lever pressing for cocaine during self-administration and oxytocin (1.0 mg/kg) attenuated cue-induced cocaine seeking following extinction. Cocaine increased baseline locomotor activity to a greater degree in females relative to males. Oxytocin (0.1, 0.3, 1.0, and 3.0 mg/kg) reduced cocaine-induced locomotor activity in females, but not significantly in males. These data illustrate sex similarities in oxytocin's attenuation of cocaine seeking, but sex differences in cocaine-induced locomotor effects. While reductions in cocaine seeking cannot be attributed to a reduction in locomotor activity in males, attenuation of locomotor function cannot be entirely ruled out as an explanation for a decrease in cocaine seeking in females suggesting that oxytocin's effect on cocaine seeking may be mediated by different mechanisms in male and females. PsycINFO Database Record (c) 2016 APA, all rights reserved.

  3. Impaired insight in cocaine addiction: laboratory evidence and effects on cocaine-seeking behaviour

    Energy Technology Data Exchange (ETDEWEB)

    Moeller, S.J.; Moeller, S.J.; Maloney, T.; Parvaz, M.A.; Alia-Klein, N.; Woicik, P.A.; Telang, F.; Wang, G.-J.; Volkow, N.D.; Goldstein, R.Z.

    2010-04-15

    Neuropsychiatric disorders are often characterized by impaired insight into behaviour. Such an insight deficit has been suggested, but never directly tested, in drug addiction. Here we tested for the first time this impaired insight hypothesis in drug addiction, and examined its potential association with drug-seeking behaviour. We also tested potential modulation of these effects by cocaine urine status, an individual difference known to impact underlying cognitive functions and prognosis. Sixteen cocaine addicted individuals testing positive for cocaine in urine, 26 cocaine addicted individuals testing negative for cocaine in urine, and 23 healthy controls completed a probabilistic choice task that assessed objective preference for viewing four types of pictures (pleasant, unpleasant, neutral and cocaine). This choice task concluded by asking subjects to report their most selected picture type; correspondence between subjects self-reports with their objective choice behaviour provided our index of behavioural insight. Results showed that the urine positive cocaine subjects exhibited impaired insight into their own choice behaviour compared with healthy controls; this same study group also selected the most cocaine pictures (and fewest pleasant pictures) for viewing. Importantly, however, it was the urine negative cocaine subjects whose behaviour was most influenced by insight, such that impaired insight in this subgroup only was associated with higher cocaine-related choice on the task and more severe actual cocaine use. These findings suggest that interventions to enhance insight may decrease drug-seeking behaviour, especially in urine negative cocaine subjects, potentially to improve their longer-term clinical outcomes.

  4. N-Acetylcysteine Reverses Cocaine Induced Metaplasticity

    OpenAIRE

    Moussawi, Khaled; Pacchioni, Alejandra; Moran, Megan; Olive, M. Foster; Gass, Justin T.; Lavin, Antonieta; Kalivas, Peter W

    2009-01-01

    Cocaine addiction is characterized by an impaired ability to develop adaptive behaviors that can compete with cocaine seeking, implying a deficit in the ability to induce plasticity in cortico-accumbens circuitry critical for regulating motivated behavior. RWe found that rats withdrawn from cocaine self-administration had a marked in vivo deficit in the ability to develop long-term potentation (LTP) and depression (LTD) in the nucleus accumbens core subregion following stimulation of prefront...

  5. Prospective study of leptospirosis transmission in an urban slum community: role of poor environment in repeated exposures to the Leptospira agent.

    Science.gov (United States)

    Felzemburgh, Ridalva D M; Ribeiro, Guilherme S; Costa, Federico; Reis, Renato B; Hagan, José E; Melendez, Astrid X T O; Fraga, Deborah; Santana, Francisco S; Mohr, Sharif; dos Santos, Balbino L; Silva, Adriano Q; Santos, Andréia C; Ravines, Romy R; Tassinari, Wagner S; Carvalho, Marília S; Reis, Mitermayer G; Ko, Albert I

    2014-01-01

    Leptospirosis has emerged as an urban health problem as slum settlements have rapidly spread worldwide and created conditions for rat-borne transmission. Prospective studies have not been performed to determine the disease burden, identify risk factors for infection and provide information needed to guide interventions in these marginalized communities. We enrolled and followed a cohort of 2,003 residents from a slum community in the city of Salvador, Brazil. Baseline and one-year serosurveys were performed to identify primary and secondary Leptospira infections, defined as respectively, seroconversion and four-fold rise in microscopic agglutination titers. We used multinomial logistic regression models to evaluate risk exposures for acquiring primary and secondary infection. A total of 51 Leptospira infections were identified among 1,585 (79%) participants who completed the one-year follow-up protocol. The crude infection rate was 37.8 per 1,000 person-years. The secondary infection rate was 2.3 times higher than that of primary infection rate (71.7 and 31.1 infections per 1,000 person-years, respectively). Male gender (OR 2.88; 95% CI 1.40-5.91) and lower per capita household income (OR 0.54; 95% CI, 0.30-0.98 for an increase of $1 per person per day) were independent risk factors for primary infection. In contrast, the 15-34 year age group (OR 10.82, 95% CI 1.38-85.08), and proximity of residence to an open sewer (OR 0.95; 0.91-0.99 for an increase of 1 m distance) were significant risk factors for secondary infection. This study found that slum residents had high risk (>3% per year) for acquiring a Leptospira infection. Re-infection is a frequent event and occurs in regions of slum settlements that are in proximity to open sewers. Effective prevention of leptospirosis will therefore require interventions that address the infrastructure deficiencies that contribute to repeated exposures among slum inhabitants.

  6. Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines

    International Nuclear Information System (INIS)

    Dumont, Julie; Josse, Rozenn; Lambert, Carine; Antherieu, Sebastien; Laurent, Veronique; Loyer, Pascal; Robin, Marie-Anne; Guillouzo, Andre

    2010-01-01

    2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) are two of the most common heterocyclic aromatic amines (HAA) produced during cooking of meat, fish and poultry. Both HAA produce different tumor profiles in rodents and are suspected to be carcinogenic in humans. In order to better understand the molecular basis of HAA toxicity, we have analyzed gene expression profiles in the metabolically competent human HepaRG cells using pangenomic oligonucleotide microarrays, after either a single (24-h) or a repeated (28-day) exposure to 10 μM PhIP or MeIQx. The most responsive genes to both HAA were downstream targets of the arylhydrocarbon receptor (AhR): CYP1A1 and CYP1A2 after both time points and CYP1B1 and ALDH3A1 after 28 days. Accordingly, CYP1A1/1A2 induction in HAA-treated HepaRG cells was prevented by chemical inhibition or small interference RNA-mediated down-regulation of the AhR. Consistently, HAA induced activity of the CYP1A1 promoter, which contains a consensus AhR-related xenobiotic-responsive element (XRE). In addition, several other genes exhibited both time-dependent and compound-specific expression changes with, however, a smaller magnitude than previously reported for the prototypical AhR target genes. These changes concerned genes mainly related to cell growth and proliferation, apoptosis, and cancer. In conclusion, these results identify the AhR gene battery as the preferential target of PhIP and MeIQx in HepaRG cells and further support the hypothesis that intake of HAA in diet might increase human cancer risk.

  7. Cocaine: from addiction to functional imaging

    International Nuclear Information System (INIS)

    Tamgac, F.; Baillet, G.; Moretti, J.L.; Tikofski, R.

    1997-01-01

    Cocaine is wrongly held as a benign recreative drug whereas it is a highly addictive substance with possible dreadful cardiac a neurologic complications. Cocaine abuse results in patchy cerebral hypoperfusion and hypo-metabolism, clearly demonstrated by PET and SPECT imaging. Improvement after drug withdrawal is still unclear. Cocaine binds with a very high affinity to the dopamine reuptake transporter. Labelled cocaine congeners can be used to assess dopaminergic pathways, especially nigrostriatal neurons that play a key role in movement control. 123 I labelled beta-CIT can reproducibly be used to measure dopamine transporter density in the striatum, in one day. This approach seems very promising. (authors)

  8. Adenosine A2A receptors in the nucleus accumbens bi-directionally alter cocaine seeking in rats.

    Science.gov (United States)

    O'Neill, Casey E; LeTendre, McKenzie L; Bachtell, Ryan K

    2012-04-01

    Repeated cocaine administration enhances dopamine D(2) receptor sensitivity in the mesolimbic dopamine system, which contributes to drug relapse. Adenosine A(2A) receptors are colocalized with D(2) receptors on nucleus accumbens (NAc) medium spiny neurons where they antagonize D(2) receptor activity. Thus, A(2A) receptors represent a target for reducing enhanced D(2) receptor sensitivity that contributes to cocaine relapse. The aim of these studies were to determine the effects of adenosine A(2A) receptor modulation in the NAc on cocaine seeking in rats that were trained to lever press for cocaine. Following at least 15 daily self-administration sessions and 1 week of abstinence, lever pressing was extinguished in daily extinction sessions. We subsequently assessed the effects of intra-NAc core microinjections of the A(2A) receptor agonist, CGS 21680 (4-[2-[[6-amino-9-(N-ethyl-b-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid hydrochloride), and the A(2A) receptor antagonist, MSX-3 (3,7-dihydro-8-[(1E)-2-(3-methoxyphenyl)ethenyl]-7-methyl-3-[3-(phosphonooxy)propyl-1-(2-propynyl)-1H-purine-2,6-dione disodium salt hydrate), in modulating cocaine- and quinpirole-induced reinstatement to cocaine seeking. Intra-NAc pretreatment of CGS 21680 reduced both cocaine- and quinpirole-induced reinstatement. These effects were specific to cocaine reinstatement as intra-NAc CGS 21680 had no effect on sucrose seeking in rats trained to self-administer sucrose pellets. Intra-NAc treatment with MSX-3 modestly reinstated cocaine seeking when given alone, and exacerbated both cocaine- and quinpirole-induced reinstatement. Interestingly, the exacerbation of cocaine seeking produced by MSX-3 was only observed at sub-threshold doses of cocaine and quinpirole, suggesting that removing tonic A(2A) receptor activity enables behaviors mediated by dopamine receptors. Taken together, these findings suggest that A(2A) receptor stimulation reduces, while A(2A) blockade

  9. Adenosine A2A Receptors in the Nucleus Accumbens Bi-Directionally Alter Cocaine Seeking in Rats

    Science.gov (United States)

    O'Neill, Casey E; LeTendre, Mckenzie L; Bachtell, Ryan K

    2012-01-01

    Repeated cocaine administration enhances dopamine D2 receptor sensitivity in the mesolimbic dopamine system, which contributes to drug relapse. Adenosine A2A receptors are colocalized with D2 receptors on nucleus accumbens (NAc) medium spiny neurons where they antagonize D2 receptor activity. Thus, A2A receptors represent a target for reducing enhanced D2 receptor sensitivity that contributes to cocaine relapse. The aim of these studies were to determine the effects of adenosine A2A receptor modulation in the NAc on cocaine seeking in rats that were trained to lever press for cocaine. Following at least 15 daily self-administration sessions and 1 week of abstinence, lever pressing was extinguished in daily extinction sessions. We subsequently assessed the effects of intra-NAc core microinjections of the A2A receptor agonist, CGS 21680 (4-[2-[[6-amino-9-(N-ethyl-b--ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid hydrochloride), and the A2A receptor antagonist, MSX-3 (3,7-dihydro-8-[(1E)-2-(3-methoxyphenyl)ethenyl]-7-methyl-3-[3-(phosphonooxy)propyl-1-(2-propynyl)-1H-purine-2,6-dione disodium salt hydrate), in modulating cocaine- and quinpirole-induced reinstatement to cocaine seeking. Intra-NAc pretreatment of CGS 21680 reduced both cocaine- and quinpirole-induced reinstatement. These effects were specific to cocaine reinstatement as intra-NAc CGS 21680 had no effect on sucrose seeking in rats trained to self-administer sucrose pellets. Intra-NAc treatment with MSX-3 modestly reinstated cocaine seeking when given alone, and exacerbated both cocaine- and quinpirole-induced reinstatement. Interestingly, the exacerbation of cocaine seeking produced by MSX-3 was only observed at sub-threshold doses of cocaine and quinpirole, suggesting that removing tonic A2A receptor activity enables behaviors mediated by dopamine receptors. Taken together, these findings suggest that A2A receptor stimulation reduces, while A2A blockade amplifies, D2 receptor

  10. Effects of progesterone stimulated allopregnanolone on craving and stress response in cocaine dependent men and women.

    Science.gov (United States)