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Sample records for significantly increased cocaine

  1. Mice lacking neuropeptide Y show increased sensitivity to cocaine

    DEFF Research Database (Denmark)

    Sørensen, Gunnar; Woldbye, David Paul Drucker

    2012-01-01

    There is increasing data implicating neuropeptide Y (NPY) in the neurobiology of addiction. This study explored the possible role of NPY in cocaine-induced behavior using NPY knockout mice. The transgenic mice showed a hypersensitive response to cocaine in three animal models of cocaine addiction...

  2. Estradiol increases choice of cocaine over food in male rats.

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    Bagley, Jared R; Adams, Julia; Bozadjian, Rachel V; Bubalo, Lana; Ploense, Kyle L; Kippin, Tod E

    2017-10-19

    Estradiol modulates the rewarding and reinforcing properties of cocaine in females, including an increase in selection of cocaine over alternative reinforcers. However, the effects of estradiol on male cocaine self-administration behavior are less studied despite equivalent levels of estradiol in the brains of adult males and females, estradiol effects on motivated behaviors in males that share underlying neural substrates with cocaine reinforcement as well as expression of estrogen receptors in the male brain. Therefore, we sought to characterize the effects of estradiol in males on choice between concurrently-available cocaine and food reinforcement as well as responding for cocaine or food in isolation. Male castrated rats (n=46) were treated daily with estradiol benzoate (EB) (5μg/0.1, S.C.) or vehicle (peanut oil) throughout operant acquisition of cocaine (1mg/kg, IV; FI20 sec) and food (3×45mg; FI20 sec) responding, choice during concurrent access and cocaine and food reinforcement under progressive ratio (PR) schedules. EB increased cocaine choice, both in terms of percent of trials on which cocaine was selected and the proportion of rats exhibiting a cocaine preference as well as increased cocaine, but not food, intake under PR. Additionally, within the EB treated group, cocaine-preferring rats exhibited enhanced acquisition of cocaine, but not food, reinforcement whereas no acquisition differences were observed across preferences in the vehicle treated group. These findings demonstrate that estradiol increases cocaine choice in males similarly to what is observed in females. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Risky decisions in a lottery task are associated with an increase of cocaine use

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    Amrei eWittwer

    2016-05-01

    Full Text Available Cocaine use disorder is associated with maladaptive decision-making behaviour, which strongly contributes to the harmful consequences of chronic drug use. Prior research has shown that cocaine users exhibit impaired neuropsychological test performances, particularly with regard to attention, learning, and memory but also in executive functions such as decision-making and impulse control. However, to what extent cocaine users show impaired decision-making under risk without feedback has not yet been investigated systematically. Therefore, to examine risk-taking behaviour, 31 chronic cocaine users and 26 stimulant-naïve healthy controls, who were part of the Zurich Cocaine Cognition Study, performed the Randomized Lottery Task (RALT with winning lotteries consisting of an uncertain and a certain prospect. Results revealed that risky decisions were associated with male sex, increased cocaine use in the past year, higher cocaine concentrations in the hair, and younger age. In addition, higher levels of cocaine in the hair and cumulative lifetime consumption were associated with risky decisions, whereas potentially confounding factors including cognition and psychiatric symptoms had no significant effect. Taken together, our results indicate that cocaine users who increased their consumption over a period of one year show deficits in the processing of risky information accompanied with increased risk-taking. Future research should analyse whether risky decisions could potentially serve as a prognostic marker for cocaine use disorder.

  4. Depleting adult dentate gyrus neurogenesis increases cocaine-seeking behavior.

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    Deroche-Gamonet, Véronique; Revest, Jean-Michel; Fiancette, Jean-François; Balado, Eric; Koehl, Muriel; Grosjean, Noëlle; Abrous, Djoher Nora; Piazza, Pier-Vincenzo

    2018-03-05

    The hippocampus is the main locus for adult dentate gyrus (DG) neurogenesis. A number of studies have shown that aberrant DG neurogenesis correlates with many neuropsychiatric disorders, including drug addiction. Although clear causal relationships have been established between DG neurogenesis and memory dysfunction or mood-related disorders, evidence of the causal role of DG neurogenesis in drug-seeking behaviors has not been established. Here we assessed the role of new DG neurons in cocaine self-administration using an inducible transgenic approach that selectively depletes adult DG neurogenesis. Our results show that transgenic mice with decreased adult DG neurogenesis exhibit increased motivation to self-administer cocaine and a higher seeking response to cocaine-related cues. These results identify adult hippocampal neurogenesis as a key factor in vulnerability to cocaine addiction.

  5. 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 ...

  6. Cocaine

    Science.gov (United States)

    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 ...

  7. Active cocaine use does not increase the likelihood of hyperglycemic crisis.

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    Modzelewski, Katherine L; Rybin, Denis V; Weinberg, Janice M; Alexanian, Sara M; McDonnell, Marie E; Steenkamp, Devin W

    2017-09-01

    Hyperglycemic crisis encompasses a group of diabetes emergencies characterized by insulin deficiency with high morbidity and mortality. Cocaine use is increasingly prevalent in the United States and may be associated with increased risk of diabetic ketoacidosis. The objective was to determine if active cocaine use at hospital admission could be considered a risk factor for development of hyperglycemic crisis. A retrospective case-control analysis was performed on 950 inpatients with hyperglycemia at an urban academic hospital. Patients admitted with non-emergent hyperglycemia were compared to patients who met criteria for diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state (HHS), and hyperosmolar ketoacidosis (HK), based on the absence or presence of cocaine metabolites on urine toxicology screen. Outcomes included frequency of cocaine use in patients with DKA, HHS, HK, and non-emergent hyperglycemia; phenotypic characteristics of cocaine users vs. non-users with hyperglycemia; phenotypic characteristics of patients with hyperglycemic crisis vs. non-emergent hyperglycemia. 950 patients were admitted with hyperglycemia, 133 of which met criteria for hyperglycemic crisis. There was no significant difference in the frequency of cocaine use in individuals with non-emergent hyperglycemia compared to individuals with hyperglycemic crisis (16.9% vs. 17.2%, p = 0.90). 16.9% of patients with DKA, 16.4% of patients with HHS, and 6.4% of patients with HK were cocaine users. We found no association between active cocaine use at the time of hospital admission and development of hyperglycemic crisis, when compared to non-emergent hyperglycemia. The role of routine screening for cocaine use in patients with hyperglycemic crisis is unclear.

  8. Gas revenue increasingly significant

    International Nuclear Information System (INIS)

    Megill, R.E.

    1991-01-01

    This paper briefly describes the wellhead prices of natural gas compared to crude oil over the past 70 years. Although natural gas prices have never reached price parity with crude oil, the relative value of a gas BTU has been increasing. It is one of the reasons that the total amount of money coming from natural gas wells is becoming more significant. From 1920 to 1955 the revenue at the wellhead for natural gas was only about 10% of the money received by producers. Most of the money needed for exploration, development, and production came from crude oil. At present, however, over 40% of the money from the upstream portion of the petroleum industry is from natural gas. As a result, in a few short years natural gas may become 50% of the money revenues generated from wellhead production facilities

  9. Was an increase in cocaine use among injecting drug users in New South Wales, Australia, accompanied by an increase in violent crime?

    Directory of Open Access Journals (Sweden)

    Conroy Elizabeth

    2005-04-01

    Full Text Available Abstract Background A sharp reduction in heroin supply in Australia in 2001 was followed by a large but transient increase in cocaine use among injecting drug users (IDU in Sydney. This paper assesses whether the increase in cocaine use among IDU was accompanied by increased rates of violent crime as occurred in the United States in the 1980s. Specifically, the paper aims to examine the impact of increased cocaine use among Sydney IDU upon police incidents of robbery with a weapon, assault and homicide. Methods Data on cocaine use among IDU was obtained from the Illicit Drug Reporting System (IDRS. Monthly NSW Police incident data on arrests for cocaine possession/use, robbery offences, homicides, and assaults, were obtained from the Bureau of Crime Statistics and Research. Time series analysis was conducted on the police data series where possible. Semi-structured interviews were conducted with representatives from law enforcement and health agencies about the impacts of cocaine use on crime and policing. Results There was a significant increase in cocaine use and cocaine possession offences in the months immediately following the reduction in heroin supply. There was also a significant increase in incidents of robbery where weapons were involved. There were no increases in offences involving firearms, homicides or reported assaults. Conclusion The increased use of cocaine among injecting drug users following the heroin shortage led to increases in violent crime. Other States and territories that also experienced a heroin shortage but did not show any increases in cocaine use did not report any increase in violent crimes. The violent crimes committed did not involve guns, most likely because of its stringent gun laws, in contrast to the experience of American cities that have experienced high rates of cocaine use and violent crime.

  10. 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: ...

  11. 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/ ...

  12. The Contingency of Cocaine Administration Accounts for Structural and Functional Medial Prefrontal Deficits and Increased Adrenocortical Activation

    Science.gov (United States)

    Anderson, Rachel M.; Cosme, Caitlin V.; Glanz, Ryan M.; Miller, Mary C.; Romig-Martin, Sara A.; LaLumiere, Ryan T.

    2015-01-01

    The prelimbic region (PL) of the medial prefrontal cortex (mPFC) is implicated in the relapse of drug-seeking behavior. Optimal mPFC functioning relies on synaptic connections involving dendritic spines in pyramidal neurons, whereas prefrontal dysfunction resulting from elevated glucocorticoids, stress, aging, and mental illness are each linked to decreased apical dendritic branching and spine density in pyramidal neurons in these cortical fields. The fact that cocaine use induces activation of the stress-responsive hypothalamo-pituitary-adrenal axis raises the possibility that cocaine-related impairments in mPFC functioning may be manifested by similar changes in neuronal architecture in mPFC. Nevertheless, previous studies have generally identified increases, rather than decreases, in structural plasticity in mPFC after cocaine self-administration. Here, we use 3D imaging and analysis of dendritic spine morphometry to show that chronic cocaine self-administration leads to mild decreases of apical dendritic branching, prominent dendritic spine attrition in PL pyramidal neurons, and working memory deficits. Importantly, these impairments were largely accounted for in groups of rats that self-administered cocaine compared with yoked-cocaine- and saline-matched counterparts. Follow-up experiments failed to demonstrate any effects of either experimenter-administered cocaine or food self-administration on structural alterations in PL neurons. Finally, we verified that the cocaine self-administration group was distinguished by more protracted increases in adrenocortical activity compared with yoked-cocaine- and saline-matched controls. These studies suggest a mechanism whereby increased adrenocortical activity resulting from chronic cocaine self-administration may contribute to regressive prefrontal structural and functional plasticity. SIGNIFICANCE STATEMENT Stress, aging, and mental illness are each linked to decreased prefrontal plasticity. Here, we show that chronic

  13. Increased sensorimotor gating in recreational and dependent cocaine users is modulated by craving and attention-deficit/hyperactivity disorder symptoms.

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    Preller, Katrin H; Ingold, Nina; Hulka, Lea M; Vonmoos, Matthias; Jenni, Daniela; Baumgartner, Markus R; Vollenweider, Franz X; Quednow, Boris B

    2013-02-01

    Cocaine dependence has been associated with blunted dopamine and norepinephrine signaling, but it is unknown if recreational cocaine use is also associated with alterations of catecholamine systems. Prepulse inhibition (PPI) of the acoustic startle response-a measure of sensorimotor gating-is highly sensitive for manipulations of the catecholamine system. Therefore, we investigated whether relatively pure recreational users (RCU) and dependent cocaine users (DCU) display alterations of PPI, startle reactivity, and habituation. Moreover, the influences of methylenedioxymethamphetamine and cannabis co-use, craving, and attention-deficit/hyperactivity disorder (ADHD) symptoms on startle measures were examined. In 64 RCU, 29 DCU, and 66 stimulant-naïve control subjects, PPI of acoustic startle response, startle reactivity, habituation, ADHD symptoms, and cocaine craving were assessed. Drug use of all participants was controlled by hair and urine toxicologies. Both RCU and DCU showed increased PPI in comparison with control participants (Cohen's d=.38 and d=.67, respectively), while RCU and DCU did not differ in PPI measures (d=.12). No significant group differences were found in startle reactivity or habituation measures. In cocaine users, PPI was positively correlated with cumulative cocaine dose used, craving for cocaine, and ADHD symptoms. Users with a diagnosis of ADHD and strong craving symptoms displayed the highest PPI levels compared with control subjects (d=.78). The augmented PPI in RCU and DCU suggests that recreational use of cocaine is associated with altered catecholamine signaling, in particular if ADHD or craving symptoms are present. Finally, ADHD might be a critical risk factor for cocaine-induced changes of the catecholamine system. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  14. CRF1 receptor-deficiency increases cocaine reward.

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    Contarino, Angelo; Kitchener, Pierre; Vallée, Monique; Papaleo, Francesco; Piazza, Pier-Vincenzo

    2017-05-01

    Stimulant drugs produce reward but also activate stress-responsive systems. The corticotropin-releasing factor (CRF) and the related hypothalamus-pituitary-adrenal (HPA) axis stress-responsive systems are activated by stimulant drugs. However, their role in stimulant drug-induced reward remains poorly understood. Herein, we report that CRF 1 receptor-deficient (CRF 1 -/-), but not wild-type, mice show conditioned place preference (CPP) responses to a relatively low cocaine dose (5 mg/kg, i.p.). Conversely, wild-type, but not CRF 1 -/-, mice display CPP responses to a relatively high cocaine dose (20 mg/kg, i.p.), indicating that CRF 1 receptor-deficiency alters the rewarding effects of cocaine. Acute pharmacological antagonism of the CRF 1 receptor by antalarmin also eliminates cocaine reward. Nevertheless, CRF 1 -/- mice display higher stereotypy responses to cocaine than wild-type mice. Despite the very low plasma corticosterone concentration, CRF 1 -/- mice show higher nuclear glucocorticoid receptor (GR) levels in the brain region of the hippocampus than wild-type mice. Full rescue of wild-type-like corticosterone and GR circadian rhythm and level in CRF 1 -/- mice by exogenous corticosterone does not affect CRF 1 receptor-dependent cocaine reward but induces stereotypy responses to cocaine. These results indicate a critical role for the CRF 1 receptor in cocaine reward, independently of the closely related HPA axis activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Increased orbitofrontal brain activation after administration of a selective adenosine A2A antagonist in cocaine dependent subjects

    Directory of Open Access Journals (Sweden)

    F. Gerard eMoeller

    2012-05-01

    Full Text Available Background: Positron Emission Tomography imaging studies provide evidence of reduced dopamine function in cocaine dependent subjects in the striatum, which is correlated with prefrontal cortical glucose metabolism, particularly in the orbitofrontal cortex. However, whether enhancement of dopamine in the striatum in cocaine dependent subjects would be associated with changes in prefrontal cortical brain activation is unknown. One novel class of medications that enhance dopamine function via heteromer formation with dopamine receptors in the striatum is the selective adenosine A2A receptor antagonists. This study sought to determine the effects administration of the selective adenosine A2A receptor antagonist SYN115 on brain function in cocaine dependent subjects. Methodology/Principle Findings: Twelve cocaine dependent subjects underwent two fMRI scans (one after a dose of placebo and one after a dose of 100 mg of SYN115 while performing a working memory task with 3 levels of difficulty (3, 5, and 7 digits. fMRI results showed that for 7-digit working memory activation there was significantly greater activation from SYN115 compared to placebo in portions of left (L lateral orbitofrontal cortex, L insula, and L superior and middle temporal pole. Conclusion/Significance: These findings are consistent with enhanced dopamine function in the striatum in cocaine dependent subjects via blockade of adenosine A2A receptors producing increased brain activation in the orbitofrontal cortex and other cortical regions. This suggests that at least some of the changes in brain activation in prefrontal cortical regions in cocaine dependent subjects may be related to altered striatal dopamine function, and that enhancement of dopamine function via adenosine A2A receptor blockade could be explored further for amelioration of neurobehavioral deficits associated with chronic cocaine use.

  16. Lack of increased immediate early gene expression in rats reinstating cocaine-seeking behavior to discrete sensory cues.

    Directory of Open Access Journals (Sweden)

    Matthew D Riedy

    Full Text Available Drug-seeking behavior elicited by drug-associated cues contributes to relapse in addiction; however, whether relapse elicited by drug-associated conditioned reinforcers (CR versus discriminative stimuli (DS involves distinct or overlapping neuronal populations is unknown. To address this question, we developed a novel cocaine self-administration and cue-induced reinstatement paradigm that exposed the same rats to distinct cocaine-associated CR and DS. Rats were trained to self-administer cocaine in separate sessions. In one, a DS signaled cocaine availability; in the other, cocaine delivery was paired with a different CR. After extinction training and reinstatement testing, where both cues were presented in separate sessions, rats were sacrificed and processed for cellular analysis of temporal activity by fluorescent in situ hybridization (CatFISH for activity regulated cytoskeleton-associated protein (Arc mRNA and for radioactive in situ hybridization for Arc and zif268 mRNAs. CatFISH did not reveal significant changes in Arc mRNA expression. Similar results were obtained with radioactive in situ hybridization. We have shown that while rats reinstate drug seeking in response to temporally discrete presentations of distinct drug-associated cues, such reinstatement is not associated with increased transcriptional activation of Arc or zif268 mRNAs, suggesting that expression of these genes may not be necessary for cue-induced reinstatement of drug-seeking behavior.

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

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    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

  18. Cocaine adulteration.

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    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.

  19. Sign-tracking predicts increased choice of cocaine over food in rats.

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    Tunstall, Brendan J; Kearns, David N

    2015-03-15

    The purpose of this study was to determine whether the tendency to sign-track to a food cue was predictive of rats' choice of cocaine over food. First, rats were trained on a procedure where insertion of a retractable lever was paired with food. A sub-group of rats - sign-trackers - primarily approached and contacted the lever, while another sub-group - goal-trackers - approached the site of food delivery. Rats were then trained on a choice task where they could choose between an infusion of cocaine (1.0 mg/kg) and a food pellet (45 mg). Sign-trackers chose cocaine over food significantly more often than did goal-trackers. These results support the incentive-salience theory of addiction and add to a growing number of studies which suggest that sign-trackers may model an addiction-prone phenotype. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Adaptive increase in D3 dopamine receptors in the brain reward circuits of human cocaine fatalities.

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    Staley, J K; Mash, D C

    1996-10-01

    The mesolimbic dopaminergic system plays a primary role in mediating the euphoric and rewarding effects of most abused drugs. Chronic cocaine use is associated with an increase in dopamine neurotransmission resulting from the blockade of dopamine uptake and is mediated by the activation of dopamine receptors. Recent studies have suggested that the D3 receptor subtype plays a pivotal role in the reinforcing effects of cocaine. The D3 receptor-preferring agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) is a reinforcer in rhesus monkeys trained to self-administer cocaine, but not in cocainenaive monkeys. In vitro autoradiographic localization of [3H]-(+)-7-OH-DPAT binding in the human brain demonstrated that D3 receptors were prevalent and highly localized over the ventromedial sectors of the striatum. Pharmacological characterization of [3H]-(+)-7-OH-DPAT binding to the human nucleus accumbens demonstrated a rank order of potency similar to that observed for binding to the cloned D3 receptor expressed in transfected cell lines. Region-of-interest analysis of [3H]-(+)-7-OH-DPAT binding to the D3 receptor demonstrated a one- to threefold elevation in the number of binding sites over particular sectors of the striatum and substantia nigra in cocaine overdose victims as compared with age-matched and drug-free control subjects. The elevated number of [3H]-(+)-7-OH-DPAT binding sites demonstrates that adaptive changes in the D3 receptor in the reward circuitry of the brain are associated with chronic cocaine abuse. These results suggest that the D3 receptor may be a useful target for drug development of anticocaine medications.

  1. 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

  2. Prior Cocaine Self-Administration Increases Response-Outcome Encoding That Is Divorced from Actions Selected in Dorsal Lateral Striatum.

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    Burton, Amanda C; Bissonette, Gregory B; Zhao, Adam C; Patel, Pooja K; Roesch, Matthew R

    2017-08-09

    Dorsal lateral striatum (DLS) is a highly associative structure that encodes relationships among environmental stimuli, behavioral responses, and predicted outcomes. DLS is known to be disrupted after chronic drug abuse; however, it remains unclear what neural signals in DLS are altered. Current theory suggests that drug use enhances stimulus-response processing at the expense of response-outcome encoding, but this has mostly been tested in simple behavioral tasks. Here, we investigated what neural correlates in DLS are affected by previous cocaine exposure as rats performed a complex reward-guided decision-making task in which predicted reward value was independently manipulated by changing the delay to or size of reward associated with a response direction across a series of trial blocks. After cocaine self-administration, rats exhibited stronger biases toward higher-value reward and firing in DLS more strongly represented action-outcome contingencies independent from actions subsequently taken rather than outcomes predicted by selected actions (chosen-outcome contingencies) and associations between stimuli and actions (stimulus-response contingencies). These results suggest that cocaine self-administration strengthens action-outcome encoding in rats (as opposed to chosen-outcome or stimulus-response encoding), which abnormally biases behavior toward valued reward when there is a choice between two options during reward-guided decision-making. SIGNIFICANCE STATEMENT Current theories suggest that the impaired decision-making observed in individuals who chronically abuse drugs reflects a decrease in goal-directed behaviors and an increase in habitual behaviors governed by neural representations of response-outcome (R-O) and stimulus-response associations, respectively. We examined the impact that prior cocaine self-administration had on firing in dorsal lateral striatum (DLS), a brain area known to be involved in habit formation and affected by drugs of abuse

  3. Stress system changes associated with marijuana dependence may increase craving for alcohol and cocaine

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    Fox, Helen C.; Tuit, Keri L.; Sinha, Rajita

    2013-01-01

    Objective To date, little research exists defining bio-behavioral adaptations associated with both marijuana abuse and risk of craving and relapse to other drugs of abuse during early abstinence. Method Fifty-nine treatment-seeking individuals dependent on alcohol and cocaine were recruited. Thirty of these individuals were also marijuana (MJ) dependent; 29 were not. Twenty-six socially drinking healthy controls were also recruited. All participants were exposed to three 5-min guided imagery conditions (stress, alcohol/cocaine cue and relaxing), presented randomly, one per day across three consecutive days. Measures of craving, anxiety, heart rate, blood pressure, plasma adrenocorticotrophic hormone and cortisol were collected at baseline and subsequent recovery time points. Results The MJ-dependent group showed increased basal anxiety ratings and cardiovascular output alongside enhanced alcohol craving and cocaine craving, and dampened cardiovascular response to stress and cue. They also demonstrated elevated cue-induced anxiety and stress-induced cortisol and adrenocorticotrophic hormone levels, which were not observed in the non-MJ-dependent group or controls. Cue-related alcohol craving and anxiety were both predictive of a shorter number of days to marijuana relapse following discharge from inpatient treatment. Conclusions Findings provide some support for drug cross-sensitization in terms of motivational processes associated with stress-related and cue-related craving and relapse. PMID:23280514

  4. Oxytocin decreases cocaine taking, cocaine seeking, and locomotor activity in female rats.

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    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.

  5. Food restriction increases acquisition, persistence and drug prime-induced expression of a cocaine-conditioned place preference in rats.

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    Zheng, Danielle; Cabeza de Vaca, Soledad; Carr, Kenneth D

    2012-01-01

    Cocaine conditioned place preference (CPP) is more persistent in food-restricted than ad libitum fed rats. This study assessed whether food restriction acts during conditioning and/or expression to increase persistence. In Experiment 1, rats were food-restricted during conditioning with a 7.0 mg/kg (i.p.) dose of cocaine. After the first CPP test, half of the rats were switched to ad libitum feeding for three weeks, half remained on food restriction, and this was followed by CPP testing. Rats tested under the ad libitum feeding condition displayed extinction by the fifth test. Their CPP did not reinstate in response to overnight food deprivation or a cocaine prime. Rats maintained on food restriction displayed a persistent CPP. In Experiment 2, rats were ad libitum fed during conditioning with the 7.0 mg/kg dose. In the first test only a trend toward CPP was displayed. Rats maintained under the ad libitum feeding condition did not display a CPP during subsequent testing and did not respond to a cocaine prime. Rats tested under food-restriction also did not display a CPP, but expressed a CPP following a cocaine prime. In Experiment 3, rats were ad libitum fed during conditioning with a 12.0 mg/kg dose. After the first test, half of the rats were switched to food restriction for three weeks. Rats that were maintained under the ad libitum condition displayed extinction by the fourth test. Their CPP was not reinstated by a cocaine prime. Rats tested under food-restriction displayed a persistent CPP. These results indicate that food restriction lowers the threshold dose for cocaine CPP and interacts with a previously acquired CPP to increase its persistence. In so far as CPP models Pavlovian conditioning that contributes to addiction, these results suggest the importance of diet and the physiology of energy balance as modulatory factors. Copyright © 2011 Elsevier Inc. All rights reserved.

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

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    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.

  7. Effects of 21-day d-amphetamine and risperidone treatment on cocaine vs food choice and extended-access cocaine intake in male rhesus monkeys.

    Science.gov (United States)

    Hutsell, Blake A; Negus, S Stevens; Banks, Matthew L

    2016-11-01

    Clinical trial data suggest amphetamine treatment is most efficacious in moderate to high frequency cocaine users. However, preclinical studies have examined amphetamine treatment effects under relatively limited cocaine access conditions with low to moderate cocaine intakes. This study determined d-amphetamine treatment effects on cocaine self-administration in rhesus monkeys under cocaine access conditions allowing for high daily cocaine intake. For comparison and as a negative control, treatment effects with the antipsychotic risperidone were also examined. Continuous 21-day treatments with ramping doses of d-amphetamine (days 1-7: 0.032mg/kg/h; days 8-21: 0.1mg/kg/h, i.v.) or risperidone (days 1-7: 0.001mg/kg/h; days 8-14: 0.0032mg/kg/h; days 15-21: 0.0056mg/kg/h, i.v.) were administered to rhesus monkeys (n=4) with daily access to two types of cocaine self-administration sessions: (1) a 2-h 'choice' session with concurrent availability of 1-g food pellets and intravenous cocaine injections (0-0.1mg/kg per injection) and (2) a 20-h 'extended-access' session with 0.1mg/kg per injection cocaine availability. Total daily cocaine intake increased >6-fold during extended cocaine access. d-Amphetamine significantly decreased total cocaine intake, but not cocaine vs food choice. In contrast, risperidone did not significantly alter either total cocaine intake or cocaine vs. food choice. These results confirm and extend previous results supporting treatment effectiveness for monoamine releasers, but not dopamine antagonists, to reduce cocaine self-administration. Moreover, these results suggest amphetamine treatment efficacy to decrease preclinical cocaine vs. food choice may depend upon cocaine access conditions. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  8. 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.

  9. Monitoring cocaine use and abstinence among cocaine users for contingency management interventions.

    Science.gov (United States)

    Holtyn, August F; Knealing, Todd W; Jarvis, Brantley P; Subramaniam, Shrinidhi; Silverman, Kenneth

    2017-06-01

    During contingency management interventions, reinforcement of cocaine abstinence is arranged by delivering an incentive when a urine sample tests cocaine-negative. The use of qualitative versus quantitative urinalysis testing may have important implications for effects on cocaine abstinence. Qualitative testing (i.e., testing that solely identifies whether a particular substance is present or absent) may not detect short-term cocaine abstinence because a single instance of cocaine use can result in cocaine-positive urine over many days. Quantitative testing (i.e., testing that identifies how much of a substance is present) may be more sensitive to short-term cocaine abstinence; however, the selection of a criterion for distinguishing new use versus carryover from previous use is an important consideration. The present study examined benzoylecgonine concentrations, the primary metabolite of cocaine, in urine samples collected three times per week for 30 weeks from 28 cocaine users who were exposed to a cocaine abstinence contingency. Of the positive urine samples (benzoylecgonine concentration >300 ng/ml), 29%, 21%, 14%, and 5% of the samples decreased in benzoylecgonine concentration by more than 20%, 40%, 60%, and 80% per day, respectively. As the size of the decrease increased, the likelihood of that sample occurring during a period leading to a cocaine-negative urine sample (benzoylecgonine concentration ≤300 ng/ml) also increased. The number of days required to produce a cocaine-negative sample following a positive sample ranged from 1 to 10 days and was significantly correlated with the starting benzoylecgonine level ( r = 0.43, p contingency management interventions.

  10. Increased corticolimbic connectivity in cocaine dependence versus pathological gambling is associated with drug severity and emotion-related impulsivity.

    Science.gov (United States)

    Contreras-Rodríguez, Oren; Albein-Urios, Natalia; Vilar-López, Raquel; Perales, Jose C; Martínez-Gonzalez, Jose M; Fernández-Serrano, Maria J; Lozano-Rojas, Oscar; Clark, Luke; Verdejo-García, Antonio

    2016-05-01

    Neural biomarkers for the active detrimental effects of cocaine dependence (CD) are lacking. Direct comparisons of brain connectivity in cocaine-targeted networks between CD and behavioural addictions (i.e. pathological gambling, PG) may be informative. This study therefore contrasted the resting-state functional connectivity networks of 20 individuals with CD, 19 individuals with PG and 21 healthy individuals (controls). Study groups were assessed to rule out psychiatric co-morbidities (except alcohol abuse and nicotine dependence) and current substance use or gambling (except PG). We first examined global connectivity differences in the corticolimbic reward network and then utilized seed-based analyses to characterize the connectivity of regions displaying between-group differences. We examined the relationships between seed-based connectivity and trait impulsivity and cocaine severity. CD compared with PG displayed increased global functional connectivity in a large-scale ventral corticostriatal network involving the orbitofrontal cortex, caudate, thalamus and amygdala. Seed-based analyses showed that CD compared with PG exhibited enhanced connectivity between the orbitofrontal and subgenual cingulate cortices and between caudate and lateral prefrontal cortex, which are involved in representing the value of decision-making feedback. CD and PG compared with controls showed overlapping connectivity changes between the orbitofrontal and dorsomedial prefrontal cortices and between amygdala and insula, which are involved in stimulus-outcome learning. Orbitofrontal-subgenual cingulate cortical connectivity correlated with impulsivity and caudate/amygdala connectivity correlated with cocaine severity. We conclude that CD is linked to enhanced connectivity in a large-scale ventral corticostriatal-amygdala network that is relevant to decision making and likely to reflect an active cocaine detrimental effect. © 2015 Society for the Study of Addiction.

  11. Cocaine-induced cardiovascular effects: lack of evidence for a central nervous system site of action based on hemodynamic studies with cocaine methiodide.

    Science.gov (United States)

    Dickerson, L W; Rodak, D J; Kuhn, F E; Wahlstrom, S K; Tessel, R E; Visner, M S; Schaer, G L; Gillis, R A

    1999-01-01

    It has been suggested that cocaine acts directly in the brain to enhance central sympathetic outflow. However, some studies suggested that the cardiovascular effects of cocaine are related to a peripheral action. To characterize further the site of cocaine's cardiovascular effect, we compared the hemodynamic effects of cocaine (2 mg/kg, i.v. bolus) with those observed after administration of an equimolar dose (2.62 mg/kg, i.v. bolus) of cocaine methiodide, a quaternary derivative of cocaine that does not penetrate the blood-brain barrier, by using sufentanil-sedated dogs. Cocaine produced significant (p < 0.05) increases in heart rate (+37+/-11 beats/min), mean arterial pressure (+55+/-11 mm Hg), left ventricular end-diastolic pressure (+5.3+/-1.0 mm Hg), and cardiac output (+2.4+/-0.9 L/min). Cocaine methiodide produced increases in heart rate (+57+/-11 beats/min), mean arterial pressure (+45+/-11 mm Hg), left ventricular end-diastolic pressure (+3.4+/-1.0 mm Hg), and cardiac output (1.1+/-0.9 L/min), which were not significantly different from those observed with cocaine. Because opiate sedation potentially might have attenuated central sympathetic outflow, we further confirmed the qualitative similarity of the actions of cocaine and cocaine methiodide on heart rate and blood pressure in unsedated, conscious dogs. Our data suggest that the cardiovascular effects of cocaine result primarily from a peripheral site of action.

  12. Self-reported cue-induced physical symptoms of craving as an indicator of cocaine dependence.

    Science.gov (United States)

    Vorspan, Florence; Fortias, Maeva; Zerdazi, El-Hadi; Karsinti, Emily; Bloch, Vanessa; Lépine, Jean-Pierre; Bellivier, Frank; Brousse, Georges; van den Brink, Wim; Derks, Eske M

    2015-12-01

    The presence of cocaine dependence is under-recognized by cocaine users and requires a careful standardized interview to be ascertained by clinicians. To test if past experiences of cue-induced physical symptoms of craving (nausea, vomiting, sweating, shaking, nervousness) before cocaine use could be a useful way to boost the diagnosis of cocaine dependence. A cross-sectional study of 221 cocaine users from several outpatient addiction treatment services in France, addressing the most severe period of cocaine use. DSM-IV cocaine dependence was determined with the MINI International Neuropsychiatric Interview (MINI). Physical symptoms before using cocaine were retrospectively assessed with a single item rated on a 0-5 scale. The prevalence of DSM-IV cocaine dependence was 84.6%. The mean score on the physical symptoms item was 1.3 (SD 1.3). A cut-off score of ≥ 1 on this item alone resulted in a sensitivity of 62%, a specificity of 88.2%, a positive predictive value of 96.6% and a negative predictive value of 29.7% to detect DSM IV cocaine dependence in this sample. Adding this item to a model with the frequency of cocaine use significantly increased the predictive power: Nagelkerke's R(2) increased from .149 to .326 (p physical signs of cocaine craving is associated with a clinical diagnosis of lifetime cocaine dependence and could be a simple way to improve its detection in clinical settings. © American Academy of Addiction Psychiatry.

  13. 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.

  14. 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

  15. 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

  16. Plant-expressed cocaine hydrolase variants of butyrylcholinesterase exhibit altered allosteric effects of cholinesterase activity and increased inhibitor sensitivity

    OpenAIRE

    Larrimore, Katherine E.; Kazan, I. Can; Kannan, Latha; Kendle, R. Player; Jamal, Tameem; Barcus, Matthew; Bolia, Ashini; Brimijoin, Stephen; Zhan, Chang-Guo; Ozkan, S. Banu; Mor, Tsafrir S.

    2017-01-01

    Butyrylcholinesterase (BChE) is an enzyme with broad substrate and ligand specificities and may function as a generalized bioscavenger by binding and/or hydrolyzing various xenobiotic agents and toxicants, many of which target the central and peripheral nervous systems. Variants of BChE were rationally designed to increase the enzyme?s ability to hydrolyze the psychoactive enantiomer of cocaine. These variants were cloned, and then expressed using the magnICON transient expression system in p...

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

    Science.gov (United States)

    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.

  18. Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout mice

    DEFF Research Database (Denmark)

    Schmidt, Lene Sørensen; Thomsen, Morgane; Weikop, Pia

    2011-01-01

    Rationale The reinforcing effects of cocaine are mediated by the mesolimbic dopamine system. Behavioral and neurochemical studies have shown that the cholinergic muscarinic M4 receptor subtype plays an important role in regulation of dopaminergic neurotransmission. Objectives Here we investigated...... of drug addiction...

  19. 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.

  20. Increase in cocaine- and amphetamine-regulated transcript (CART) in specific areas of the mouse brain by acute caffeine administration.

    Science.gov (United States)

    Cho, Jin Hee; Cho, Yun Ha; Kim, Hyo Young; Cha, Seung Ha; Ryu, Hyun; Jang, Wooyoung; Shin, Kyung Ho

    2015-04-01

    Caffeine produces a variety of behavioral effects including increased alertness, reduced food intake, anxiogenic effects, and dependence upon repeated exposure. Although many of the effects of caffeine are mediated by its ability to block adenosine receptors, it is possible that other neural substrates, such as cocaine- and amphetamine-regulated transcript (CART), may be involved in the effects of caffeine. Indeed, a recent study demonstrated that repeated caffeine administration increases CART in the mouse striatum. However, it is not clear whether acute caffeine administration alters CART in other areas of the brain. To explore this possibility, we investigated the dose- and time-dependent changes in CART immunoreactivity (CART-IR) after a single dose of caffeine in mice. We found that a high dose of caffeine (100 mg/kg) significantly increased CART-IR 2 h after administration in the nucleus accumbens shell (AcbSh), dorsal bed nucleus of the stria terminalis (dBNST), central nucleus of the amygdala (CeA), paraventricular hypothalamic nucleus (PVN), arcuate hypothalamic nucleus (Arc), and locus coeruleus (LC), and returned to control levels after 8 h. But this increase was not observed in other brain areas. In addition, caffeine administration at doses of 25 and 50 mg/kg appears to produce dose-dependent increases in CART-IR in these brain areas; however, the magnitude of increase in CART-IR observed at a dose of 50 mg/kg was similar or greater than that observed at a dose of 100 mg/kg. This result suggests that CART-IR in AcbSh, dBNST, CeA, PVN, Arc, and LC is selectively affected by caffeine administration. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Bioavailability and Pharmacokinetics of Oral Cocaine in Humans.

    Science.gov (United States)

    Coe, Marion A; Jufer Phipps, Rebecca A; Cone, Edward J; Walsh, Sharon L

    2018-06-01

    The pharmacokinetic profile of oral cocaine has not been fully characterized and prospective data on oral bioavailability are limited. A within-subject study was performed to characterize the bioavailability and pharmacokinetics of oral cocaine. Fourteen healthy inpatient participants (six males) with current histories of cocaine use were administered two oral doses (100 and 200 mg) and one intravenous (IV) dose (40 mg) of cocaine during three separate dosing sessions. Plasma samples were collected for up to 24 h after dosing and analyzed for cocaine and metabolites by gas chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by non-compartmental analysis, and a two-factor model was used to assess for dose and sex differences. The mean ± SEM oral cocaine bioavailability was 0.32 ± 0.04 after 100 and 0.45 ± 0.06 after 200 mg oral cocaine. Volume of distribution (Vd) and clearance (CL) were both greatest after 100 mg oral (Vd = 4.2 L/kg; CL = 116.2 mL/[min kg]) compared to 200 mg oral (Vd = 2.9 L/kg; CL = 87.5 mL/[min kg]) and 40 mg IV (Vd = 1.3 L/kg; CL = 32.7 mL/[min kg]). Oral cocaine area-under-thecurve (AUC) and peak concentration increased in a dose-related manner. AUC metabolite-to-parent ratios of benzoylecgonine and ecgonine methyl ester were significantly higher after oral compared to IV administration and highest after the lower oral dose. In addition, minor metabolites were detected in higher concentrations after oral compared to IV cocaine. Oral cocaine produced a pharmacokinetic profile different from IV cocaine, which appears as a rightward and downward shift in the concentration-time profile. Cocaine bioavailability values were similar to previous estimates. Oral cocaine also produced a unique metabolic profile, with greater concentrations of major and minor metabolites.

  2. Mixed-amphetamine salts increase abstinence from marijuana in patients with co-occurring attention-deficit/hyperactivity disorder and cocaine dependence.

    Science.gov (United States)

    Notzon, Daniel P; Mariani, John J; Pavlicova, Martina; Glass, Andrew; Mahony, Amy L; Brooks, Daniel J; Grabowski, John; Levin, Frances R

    2016-12-01

    The prevalence of ADHD is greater in substance use disorders than the general population, and ADHD and substance use disorders share neurobiological features such as dysregulation of reward circuitry. We tested the hypothesis that stimulants would decrease marijuana use in a randomized controlled trial of extended release mixed amphetamine salts (MAS-XR) for treatment of co-occurring ADHD and cocaine use disorders. Marijuana users were defined as participants reporting use in the 30 days before study initiation, collected with timeline follow-back. The original 14-week trial utilized a 3-arm randomized design, comparing placebo, MAS-XR 60 mg, and MAS-XR 80 mg. For this analysis, both MAS-XR groups were combined, leaving n = 20 in the placebo group and n = 37 in the MAS-XR group. The primary outcome was proportion of subjects reporting any marijuana use per study week. Comparisons between groups were made using a logistic mixed effects model incorporating multiple predictors and modeling time-by-treatment interactions. There were no significant baseline differences in marijuana use frequency and quantity. There was a significant decrease in the proportion of participants using marijuana over time in the MAS-XR group, but no difference in the proportion of marijuana-use days over time. Treatment of ADHD and comorbid cocaine use disorders with MAS-XR is associated with increased weekly abstinence from marijuana but not with a decrease in the proportion of marijuana using days per week. Stimulant treatment of ADHD and cocaine use disorders may diminish co-occurring cannabis use. (Am J Addict 2016;25:666-672). © 2016 American Academy of Addiction Psychiatry.

  3. 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.

  4. 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.

  5. 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.

  6. 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

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

    Science.gov (United States)

    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.

  8. Cannabidiol Rescues Acute Hepatic Toxicity and Seizure Induced by Cocaine

    Directory of Open Access Journals (Sweden)

    Luciano Rezende Vilela

    2015-01-01

    Full Text Available Cocaine is a commonly abused illicit drug that causes significant morbidity and mortality. The most severe and common complications are seizures, ischemic strokes, myocardial infarction, and acute liver injury. Here, we demonstrated that acute cocaine intoxication promoted seizure along with acute liver damage in mice, with intense inflammatory infiltrate. Considering the protective role of the endocannabinoid system against cell toxicity, we hypothesized that treatment with an anandamide hydrolysis inhibitor, URB597, or with a phytocannabinoid, cannabidiol (CBD, protects against cocaine toxicity. URB597 (1.0 mg/kg abolished cocaine-induced seizure, yet it did not protect against acute liver injury. Using confocal liver intravital microscopy, we observed that CBD (30 mg/kg reduced acute liver inflammation and damage induced by cocaine and prevented associated seizure. Additionally, we showed that previous liver damage induced by another hepatotoxic drug (acetaminophen increased seizure and lethality induced by cocaine intoxication, linking hepatotoxicity to seizure dynamics. These findings suggest that activation of cannabinoid system may have protective actions on both liver and brain induced by cocaine, minimizing inflammatory injury promoted by cocaine, supporting its further clinical application in the treatment of cocaine abuse.

  9. 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/ ...

  10. Effects of cocaine on [11C]norepinephrine and [11C]β-CIT uptake in the primate peripheral organs measured by PET

    International Nuclear Information System (INIS)

    Suhara, Tetsuya; Farde, L.; Halldin, C.; Karlsson, P.; Nagren, K.

    1996-01-01

    The toxic properties of cocaine are related to both the central and peripheral effects. To identify possible lethal mechanisms and the accumulation of cocaine in various organs, the effects of cocaine on [ 11 C] norepinephrine and cocaine congener [ 11 C]β-CIT uptake in Cynomolgus monkeys were measured by positron emission tomography (PET). Cocaine (5 mg/kg) noticeably inhibited [ 11 C] norepinephrine uptake in the heart. The uptake of [ 11 C]β-CIT in the heart and lung was reduced by pretreatment with cocaine. There was a significant uptake in the liver which was increased following cocaine pretreatment. The results of this study confirm that cocaine blocks the neuronal uptake of norepinephrine in sympathetic nerve terminals in the myocardium. The effect of cocaine on [ 11 C]β-CIT uptake indicates that the binding sites in the heart and lung are saturable, while the uptake mechanism in the liver is different from those of the heart and lung. (author)

  11. Development of a translational model to screen medications for cocaine use disorder I: Choice between cocaine and food in rhesus monkeys.

    Science.gov (United States)

    Johnson, Amy R; Banks, Matthew L; Blough, Bruce E; Lile, Joshua A; Nicholson, Katherine L; Negus, S Stevens

    2016-08-01

    Homologous cocaine self-administration procedures in laboratory animals and humans may facilitate translational research for medications development to treat cocaine dependence. This study, therefore, sought to establish choice between cocaine and an alternative reinforcer in rhesus monkeys responding under a procedure back-translated from previous human studies and homologous to a human laboratory procedure described in a companion paper. Four rhesus monkeys with chronic indwelling intravenous catheters had access to cocaine injections (0, 0.043, 0.14, or 0.43mg/kg/injection) and food (0, 1, 3, or 10 1g banana-flavored food pellets). During daily 5h sessions, a single cocaine dose and a single food-reinforcer magnitude were available in 10 30-min trials. During the initial "sample" trial, the available cocaine and food reinforcer were delivered non-contingently. During each of the subsequent nine "choice" trials, responding could produce either the cocaine or food reinforcer under an independent concurrent progressive-ratio schedule. Preference was governed by the cocaine dose and food-reinforcer magnitude, and increasing cocaine doses produced dose-dependent increases in cocaine choice at all food-reinforcer magnitudes. Effects of the candidate medication lisdexamfetamine (0.32-3.2mg/kg/day) were then examined on choice between 0.14mg/kg/injection cocaine and 10 pellets. Under baseline conditions, this reinforcer pair maintained an average of approximately 6 cocaine and 3 food choices. Lisdexamfetamine dose-dependently decreased cocaine choice in all monkeys, but food choice was not significantly altered. These results support utility of this procedure in rhesus monkeys as one component of a platform for translational research on medications development to treat cocaine use disorder. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  12. 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.

  13. 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.

  14. A mathematical model of a recombinant humanized anti-cocaine monoclonal antibody's effects on cocaine pharmacokinetics in mice.

    Science.gov (United States)

    Wetzel, Hanna N; Zhang, Tongli; Norman, Andrew B

    2017-09-01

    A recombinant humanized anti-cocaine monoclonal antibody (mAb), h2E2, is at an advanced stage of pre-clinical development as an immunotherapy for cocaine abuse. It is hypothesized that h2E2 binds to and sequesters cocaine in the blood. A three-compartment model of the effects of h2E2 on cocaine's distribution was constructed. The model assumes that h2E2 binds to cocaine and that the h2E2-cocaine complex does not enter the brain but distributes between the central and peripheral compartments. Free cocaine is eliminated from both the central and peripheral compartments, and h2E2 and the h2E2-cocaine complex are eliminated from the central compartment only. This model was tested against a new dataset measuring cocaine concentrations in the brain and plasma over 1h in the presence and absence of h2E2. The mAb significantly increased plasma cocaine concentrations with a concomitant significant decrease in brain concentration. Plasma concentrations declined over the 1-hour sampling period in both groups. With a set of parameters within reasonable physiological ranges, the three-compartment model was able to qualitatively and quantitatively simulate the increased plasma concentration in the presence of the antibody and the decreased peak brain concentration in the presence of antibody. Importantly, the model explained the decline in plasma concentrations over time as distribution of the cocaine-h2E2 complex into a peripheral compartment. This model will facilitate the targeting of ideal mAb PK/PD properties thus accelerating the identification of lead candidate anti-drug mAbs. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. 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.

  16. [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.

  17. CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction

    Science.gov (United States)

    Xi, Zheng-Xiong; Song, Rui; Li, Xia; Lu, Guan-Yi; Peng, Xiao-Qing; He, Yi; Bi, Guo-Hua; Sheng, Siyuan Peter; Yang, Hong-Ju; Zhang, Haiying; Li, Jin; Froimowitz, Mark; Gardner, Eliot L

    2017-01-01

    Agonist-replacement therapies have been successfully used for treatment of opiate and nicotine addiction, but not for cocaine addiction. One of the major obstacles is the cocaine-like addictive potential of the agonists themselves. We report here an atypical dopamine (DA) transporter (DAT) inhibitor, CTDP-32476, that may have translational potential for treating cocaine addiction. In vitro ligand-binding assays suggest that CTDP-32476 is a potent and selective DAT inhibitor and a competitive inhibitor of cocaine binding to the DAT. Systemic administration of CTDP-32476 alone produced a slow-onset, long-lasting increase in extracellular nucleus accumbens DA, locomotion, and brain-stimulation reward. Drug-naive rats did not self-administer CTDP-32476. In a substitution test, cocaine self-administration rats displayed a progressive reduction in CTDP-32476 self-administration with an extinction pattern of drug-taking behavior, suggesting significantly lower addictive potential than cocaine. Pretreatment with CTDP-32476 inhibited cocaine self-administration, cocaine-associated cue-induced relapse to drug seeking, and cocaine-enhanced extracellular DA in the nucleus accumbens. These findings suggest that CTDP-32476 is a unique DAT inhibitor that not only could satisfy ‘drug hunger' through its slow-onset long-lasting DAT inhibitor action, but also render subsequent administration of cocaine ineffectual—thus constituting a novel and unique compound with translational potential as an agonist therapy for treatment of cocaine addiction. PMID:27534265

  18. 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.

  19. Methylphenidate treatment beyond adolescence maintains increased cocaine self-administration in the spontaneously hypertensive rat model of attention deficit/hyperactivity disorder.

    Science.gov (United States)

    Baskin, Britahny M; Dwoskin, Linda P; Kantak, Kathleen M

    2015-04-01

    extending methylphenidate treatment beyond adolescence does not ameliorate explicitly the long-term consequences of adolescent methylphenidate treatment. Pre-session methylphenidate may mask temporarily the detection of an increase in cocaine self-administration following chronic methylphenidate treatment. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. 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.

  1. Long Withdrawal of Methylphenidate Induces a Differential Response of the Dopaminergic System and Increases Sensitivity to Cocaine in the Prefrontal Cortex of Spontaneously Hypertensive Rats.

    Directory of Open Access Journals (Sweden)

    Maurício dos Santos Pereira

    Full Text Available Methylphenidate (MPD is one of the most prescribed drugs for alleviating the symptoms of Attention Deficit/Hyperactivity Disorder (ADHD. However, changes in the molecular mechanisms related to MPD withdrawal and susceptibility to consumption of other psychostimulants in normal individuals or individuals with ADHD phenotype are not completely understood. The aims of the present study were: (i to characterize the molecular differences in the prefrontal dopaminergic system of SHR and Wistar strains, (ii to establish the neurochemical consequences of short- (24 hours and long-term (10 days MPD withdrawal after a subchronic treatment (30 days with Ritalin® (Methylphenidate Hydrochloride; 2.5 mg/kg orally, (iii to investigate the dopaminergic synaptic functionality after a cocaine challenge in adult MPD-withdrawn SHR and Wistar rats. Our results indicate that SHR rats present reduced [3H]-Dopamine uptake and cAMP accumulation in the prefrontal cortex (PFC and are not responsive to dopaminergic stimuli in when compared to Wistar rats. After a 24-hour withdrawal of MPD, SHR did not present any alterations in [3H]-Dopamine Uptake, [3H]-SCH 23390 binding and cAMP production; nonetheless, after a 10-day MPD withdrawal, the results showed a significant increase of [3H]-Dopamine uptake, of the quantity of [3H]-SCH 23390 binding sites and of cAMP levels in these animals. Finally, SHR that underwent a 10-day MPD withdrawal and were challenged with cocaine (10 mg/kg i.p. presented reduced [3H]-Dopamine uptake and increased cAMP production. Wistar rats were affected by the 10-day withdrawal of MPD in [3H]-dopamine uptake but not in cAMP accumulation; in addition, cocaine was unable to induce significant modifications in [3H]-dopamine uptake and in cAMP levels after the 10-day withdrawal of MPD. These results indicate a mechanism that could explain the high comorbidity between ADHD adolescent patients under methylphenidate treatment and substance abuse in adult

  2. 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......-trimester pregnant nonhuman primates, cocaine at doses typically used by drug abusers significantly increased brain glucose metabolism to the same extent in the mother as in the fetus (approximately 100%). Inasmuch as brain glucose metabolism is a sensitive marker of brain function, the current findings provide...

  3. Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain

    International Nuclear Information System (INIS)

    Volkow, N.D.

    1999-01-01

    The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Though cocaine and methylphenidate have similar in vitro affinities for DAT the abuse of methylphenidate in humans is substantially lower than of cocaine. To test if differences in in vivo potency at the DAT between these two drugs could account for the differences in their abuse liability the authors compared the levels of DAT occupancies that they had previously reported separately for intravenous methylphenidate in controls and for intravenous cocaine in cocaine abusers. DAT occupancies were measured with Positron Emission Tomography using [ 11 C]cocaine, as a DAT ligand, in 8 normal controls for the methylphenidate study and in 17 active cocaine abusers for the cocaine study. The ratio of the distribution volume of [ 11 C]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd+1, was used as measure of DAT availability. Parallel measures were obtained to assess the cardiovascular effects of these two drugs. Methylphenidate and cocaine produced comparable dose-dependent blockage of DAT with an estimated ED 50 for methylphenidate of 0.07 mg/kg and for cocaine of 0.13 mg/kg. Both drugs induced similar increases in heart rate and blood pressure but the duration of the effects were significantly longer for methylphenidate than for cocaine

  4. Sex differences in selecting between food and cocaine reinforcement are mediated by estrogen.

    Science.gov (United States)

    Kerstetter, Kerry A; Ballis, Maya A; Duffin-Lutgen, Stevie; Carr, Amanda E; Behrens, Alexandra M; Kippin, Tod E

    2012-11-01

    Cocaine-dependent women, relative to their male counterparts, report shorter cocaine-free periods and report transiting faster from first use to entering treatment for addiction. Similarly, preclinical studies indicate that female rats, particularly those in the estrus phase of their reproductive cycle, show increased operant responding for cocaine under a wide variety of schedules. Making maladaptive choices is a component of drug dependence, and concurrent reinforcement schedules that examine cocaine choice offers an animal model of the conditions of human drug use; therefore, the examination of sex differences in decision-making may be critical to understanding why women display a more severe profile of cocaine addiction than men. Accordingly, we assessed sex and estrous cycle differences in choice between food (45 mg grain pellets) and intravenous cocaine (0.4 or 1.0 mg/kg per infusion) reinforcement in male, female (freely cycling), and ovariectomized (OVX) females treated with either estrogen benzoate (EB; 5 μg per day) or vehicle. At both cocaine doses, intact female rats choose cocaine over food significantly more than male rats. However, the estrous cycle did not impact the level of cocaine choice in intact females. Nevertheless, OVX females treated with vehicle exhibited a substantially lower cocaine choice compared with those receiving daily EB or to intact females. These results demonstrate that intact females have a greater preference for cocaine over food compared with males. Furthermore, this higher preference is estrogen-dependent, but does not vary across the female reproductive cycle, suggesting that ovarian hormones regulate cocaine choice. The present findings indicate that there is a biological predisposition for females to forgo food reinforcement to obtain cocaine reinforcement, which may substantially contribute to women experiencing a more severe profile of cocaine addiction than men.

  5. Cocaine's appetite for fat and the consequences on body weight.

    Science.gov (United States)

    Billing, Lawrence; Ersche, Karen D

    2015-03-01

    For many individuals in treatment for cocaine dependence, weight gain is a substantial problem during recovery. This weight gain causes significant distress and seems to increase the risk of relapse. The mechanisms underlying cocaine's effects on weight remain elusive. It is widely assumed that this weight gain reflects a metabolic or behavioural compensatory response to the cessation of cocaine use. Here we challenge this assumption and outline potential mechanisms by which chronic cocaine use produces disturbances in the regulation of fat intake and storage, through its effects on the central and peripheral nervous systems, specifically the sympathetic nervous system. We hypothesize that the cocaine-induced alteration in fat regulation results in cocaine users developing a pronounced appetite for fatty food but keeps their fat mass low. This altered fat appetite subsequently leads to excessive weight gain when individuals enter treatment and stop using cocaine. Our aim is to shed light on the neurobiological mechanisms that may underlie the alterations in eating and fat regulation in cocaine-dependent individuals, to open up potential new avenues to support these individuals in recovery.

  6. 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.

  7. Maritime security report : cocaine smuggling from South America to Europe and the United States increased in 2000 via commercial maritime and other modes of transport

    Science.gov (United States)

    2001-09-01

    An increase in the detected and estimated transatlantic flow of cocaine smuggled from South America to the United States and Europe in 2000 has been reported by the U.S. Office of National Drug Control Policy (ONDCP). According to the ONDCP "Annual A...

  8. Maintenance on naltrexone+amphetamine decreases cocaine-vs.-food choice in male rhesus monkeys.

    Science.gov (United States)

    Moerke, Megan J; Banks, Matthew L; Cheng, Kejun; Rice, Kenner C; Negus, S Stevens

    2017-12-01

    Cocaine use disorder remains a significant public health issue for which there are no FDA-approved pharmacotherapies. Amphetamine maintenance reduces cocaine use in preclinical and clinical studies, but the mechanism of this effect is unknown. Previous studies indicate a role for endogenous opioid release and subsequent opioid receptor activation in some amphetamine effects; therefore, the current study examined the role of mu-opioid receptor activation in d-amphetamine treatment effects in an assay of cocaine-vs-food choice. Adult male rhesus monkeys with double-lumen intravenous catheters responded for concurrently available food pellets and cocaine injections (0-0.1mg/kg/injection) during daily sessions. Cocaine choice and overall reinforcement rates were evaluated during 7-day treatments with saline or test drugs. During saline treatment, cocaine maintained a dose-dependent increase in cocaine-vs.-food choice. The mu-opioid receptor agonist morphine (0.032-0.32mg/kg/h) dose-dependently increased cocaine choice and decreased rates of reinforcement. A dose of the mu-selective opioid receptor antagonist naltrexone (0.0032mg/kg/h) that completely blocked morphine effects had no effect on cocaine choice when it was administered alone, but it enhanced the effectiveness of a threshold dose of 0.032mg/kg/h amphetamine to decrease cocaine choice without also enhancing nonselective behavioral disruption by this dose of amphetamine. Conversely, the kappa-selective opioid antagonist norbinalorphimine did not enhance amphetamine effects on cocaine choice. These results suggest that amphetamine maintenance produces mu opioid-receptor mediated effects that oppose its anti-cocaine effects. Co-administration of naltrexone may selectively enhance amphetamine potency to decrease cocaine choice without increasing amphetamine potency to produce general behavioral disruption. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Cocaine versus food choice procedure in rats: environmental manipulations and effects of amphetamine.

    Science.gov (United States)

    Thomsen, Morgane; Barrett, Andrew C; Negus, S Stevens; Caine, S Barak

    2013-03-01

    We have adapted a nonhuman primate model of cocaine versus food choice to the rat species. To evaluate the procedure, we tested cocaine versus food choice under a variety of environmental manipulations as well as pharmacological pretreatments. Complete cocaine-choice dose-effect curves (0-1.0 mg/kg/infusion) were obtained for each condition under concurrent fixed ratio schedules of reinforcement. Percentage of responding emitted on the cocaine-reinforced lever was not affected significantly by removal of cocaine-associated visual or auditory cues, but it was decreased after removal of response-contingent or response-independent cocaine infusions. Cocaine choice was sensitive to the magnitude and fixed ratio requirement of both the cocaine and food reinforcers. We also tested the effects of acute (0.32, 0.56, 1.0, 1.8 mg/kg) and chronic (0.1, 0.32 mg/kg/hr) d-amphetamine treatment on cocaine choice. Acute and chronic d-amphetamine had opposite effects, with acute increasing and chronic decreasing cocaine choice, similar to observations in humans and in nonhuman primates. The results suggest feasibility and utility of the choice procedure in rats and support its comparability to similar procedures used in humans and monkeys. © Society for the Experimental Analysis of Behavior.

  10. 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

  11. Cocaine Versus Food Choice Procedure in Rats: Environmental Manipulations and Effects of Amphetamine

    Science.gov (United States)

    Thomsen, Morgane; Barrett, Andrew C.; Negus, S. Stevens; Caine, S. Barak

    2014-01-01

    We have adapted a nonhuman primate model of cocaine versus food choice to the rat species. To evaluate the procedure, we tested cocaine versus food choice under a variety of environmental manipulations as well as pharmacological pretreatments. Complete cocaine-choice dose-effect curves (0–1.0 mg/kg/infusion) were obtained for each condition under concurrent fixed ratio schedules of reinforcement. Percentage of responding emitted on the cocaine-reinforced lever was not affected significantly by removal of cocaine-associated visual or auditory cues, but it was decreased after removal of response-contingent or response-independent cocaine infusions. Cocaine choice was sensitive to the magnitude and fixed ratio requirement of both the cocaine and food reinforcers. We also tested the effects of acute (0.32, 0.56, 1.0, 1.8 mg/kg) and chronic (0.1, 0.32 mg/kg/hr) d-amphetamine treatment on cocaine choice. Acute and chronic d-amphetamine had opposite effects, with acute increasing and chronic decreasing cocaine choice, similar to observations in humans and in nonhuman primates. The results suggest feasibility and utility of the choice procedure in rats and support its comparability to similar procedures used in humans and monkeys. PMID:23319458

  12. Chronic treatment with extended release methylphenidate does not alter dopamine systems or increase vulnerability for cocaine self-administration: a study in nonhuman primates.

    Science.gov (United States)

    Gill, Kathryn E; Pierre, Peter J; Daunais, James; Bennett, Allyson J; Martelle, Susan; Gage, H Donald; Swanson, James M; Nader, Michael A; Porrino, Linda J

    2012-11-01

    Despite the widespread use of stimulant medications for the treatment of attention deficit hyperactivity disorder, few studies have addressed their long-term effects on the developing brain or susceptibility to drug use in adolescence. Here, we determined the effects of chronic methylphenidate (MPH) treatment on brain dopamine (DA) systems, developmental milestones, and later vulnerability to substance abuse in juvenile nonhuman primates. Male rhesus monkeys (approximately 30 months old) were treated daily with either a sustained release formulation of MPH or placebo (N=8 per group). Doses were titrated to achieve initial drug blood serum levels within the therapeutic range in children and adjusted throughout the study to maintain target levels. Growth, including measures of crown-rump length and weight, was assessed before and after 1 year of treatment and after 3-5 months washout. In addition, positron emission tomography scans were performed to quantify binding availability of D2/D3 receptors and dopamine transporters (DATs). Distribution volume ratios were calculated to quantify binding of [¹⁸F]fluoroclebopride (DA D2/D3) and [¹⁸F]-(+)-N-(4-fluorobenzyl)-2β-propanoyl-3β-(4-chlorophenyl)tropane (DAT). Chronic MPH did not differentially alter the course of weight gain or other measures of growth, nor did it influence DAT or D2/D3 receptor availability after 1 year of treatment. However, after washout, the D2/D3 receptor availability of MPH-treated animals did not continue to decline at the same rate as control animals. Acquisition of intravenous cocaine self-administration was examined by first substituting saline for food reinforcement and then cocaine doses (0.001-0.1 mg/kg per injection) in ascending order. Each dose was available for at least five consecutive sessions. The lowest dose of cocaine that maintained response rates significantly higher than saline-contingent rates was operationally defined as acquisition of cocaine reinforcement. There

  13. 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 ...

  14. Prenatal and postnatal cocaine exposure predict teen cocaine use

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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.

  16. Selective dopamine D3 receptor antagonism by SB-277011A attenuates cocaine reinforcement as assessed by progressive-ratio and variable-cost–variable-payoff fixed-ratio cocaine self-administration in rats

    Science.gov (United States)

    Xi, Zheng-Xiong; Gilbert, Jeremy G.; Pak, Arlene C.; Ashby, Charles R.; Heidbreder, Christian A.; Gardner, Eliot L.

    2013-01-01

    In rats, acute administration of SB-277011A, a highly selective dopamine (DA) D3 receptor antagonist, blocks cocaine-enhanced brain stimulation reward, cocaine-seeking behaviour and reinstatement of cocaine-seeking behaviour. Here, we investigated whether SB-277011A attenuates cocaine reinforcement as assessed by cocaine self-administration under variable-cost–variable-payoff fixed-ratio (FR) and progressive-ratio (PR) reinforcement schedules. Acute i.p. administration of SB-277011A (3–24 mg/kg) did not significantly alter cocaine (0.75 mg/kg/infusion) self-administration reinforced under FR1 (one lever press for one cocaine infusion) conditions. However, acute administration of SB-277011A (24 mg/kg, i.p.) progressively attenuated cocaine self-administration when: (a) the unit dose of self-administered cocaine was lowered from 0.75 to 0.125–0.5 mg/kg, and (b) the work demand for cocaine reinforcement was increased from FR1 to FR10. Under PR (increasing number of lever presses for each successive cocaine infusion) cocaine reinforcement, acute administration of SB-277011A (6–24 mg/kg i.p.) lowered the PR break point for cocaine self-administration in a dose-dependent manner. The reduction in the cocaine (0.25–1.0 mg/kg) dose–response break-point curve produced by 24 mg/kg SB-277011A is consistent with a reduction in cocaine’s reinforcing efficacy. When substituted for cocaine, SB-277011A alone did not sustain self-administration behaviour. In contrast with the mixed DA D2/D3 receptor antagonist haloperidol (1 mg/kg), SB-277011A (3, 12 or 24 mg/kg) failed to impede locomotor activity, failed to impair rearing behaviour, failed to produce catalepsy and failed to impair rotarod performance. These results show that SB-277011A significantly inhibits acute cocaine-induced reinforcement except at high cocaine doses and low work requirement for cocaine. If these results extrapolate to humans, SB-277011A or similar selective DA D3 receptor antagonists may be

  17. 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.

  18. Prenatal cocaine increases striatal serotonin innervation without altering the patch/matrix organization of intrinsic cell types.

    Science.gov (United States)

    Snyder-Keller, A M; Keller, R W

    1993-08-20

    The effect of prenatal cocaine on the anatomical development of the striatum was examined. The distribution and density of dopaminergic innervation of the striatum of animals exposed to cocaine during the second and third week of gestation was not noticeably different from prenatally saline-injected or untreated controls at any age. The patch/matrix organization of the striatum also appeared unaltered: neurons exhibiting dense substance P staining were localized to patches that overlapped dopamine terminal patches early in development, and enkephalin- and calbindin-immunoreactive neurons were found segregated to the matrix. Histochemical staining for acetylcholinesterase and NADPH diaphorase also revealed no differences between prenatally cocaine-treated and control brains. Whereas prenatal cocaine treatment failed to modify the basic compartmental organization of the striatum, it did lead to a hyperinnervation of serotonin-immunoreactive fibers which developed slowly after birth. Thus prenatal exposure to cocaine is capable of altering the ingrowth of serotonergic projections to the striatum while producing no change in the organization of neurons intrinsic to the striatum.

  19. 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 ...

  20. Cocaine- and amphetamine-regulated transcript peptide increases mitochondrial respiratory chain complex II activity and protects against oxygen-glucose deprivation in neurons.

    Science.gov (United States)

    Sha, Dujuan; Wang, Luna; Zhang, Jun; Qian, Lai; Li, Qiming; Li, Jin; Qian, Jian; Gu, Shuangshuang; Han, Ling; Xu, Peng; Xu, Yun

    2014-09-25

    The mechanisms of ischemic stroke, a main cause of disability and death, are complicated. Ischemic stroke results from the interaction of various factors including oxidative stress, a key pathological mechanism that plays an important role during the acute stage of ischemic brain injury. This study demonstrated that cocaine- and amphetamine-regulated transcript (CART) peptide, specifically CART55-102, increased the survival rate, but decreased the mortality of neurons exposed to oxygen-glucose deprivation (OGD), in a dose-dependent manner. The above-mentioned effects of CART55-102 were most significant at 0.4nM. These results indicated that CART55-102 suppressed neurotoxicity and enhanced neuronal survival after oxygen-glucose deprivation. CART55-102 (0.4nM) significantly diminished reactive oxygen species levels and markedly increased the activity of mitochondrial respiratory chain complex II in oxygen-glucose deprived neurons. In summary, CART55-102 suppressed oxidative stress in oxygen-glucose deprived neurons, possibly through elevating the activity of mitochondrial respiratory chain complex II. This result provides evidence for the development of CART55-102 as an antioxidant drug. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Role of GABA-active neurosteroids in the efficacy of metyrapone against cocaine addiction.

    Science.gov (United States)

    Schmoutz, Christopher D; Guerin, Glenn F; Goeders, Nicholas E

    2014-09-01

    Previous research has demonstrated a complicated role for stress and HPA axis activation in potentiating various cocaine-related behaviors in preclinical models of drug dependence. However, the investigation of several antiglucocorticoid therapies has yielded equivocal results in reducing cocaine-related behaviors, possibly because of varying mechanisms of actions. Specifically, research suggests that metyrapone (a corticosterone synthesis inhibitor) may reduce cocaine self-administration in rats via a nongenomic, extra-adrenal mechanism without altering plasma corticosterone. In the current experiments, male rats were trained to self-administer cocaine infusions and food pellets in a multiple, alternating schedule of reinforcement. Metyrapone pretreatment dose-dependently decreased cocaine self-administration as demonstrated previously. Pharmacological inhibition of neurosteroid production by finasteride had significant effects on cocaine self-administration, regardless of metyrapone pretreatment. However, metyrapone's effects on cocaine self-administration were significantly attenuated with bicuculline pretreatment, suggesting a role for GABA-active neurosteroids in cocaine-reinforced behaviors. In vitro binding data also confirmed that metyrapone does not selectively bind to GABA-related proteins. The results of these experiments support the hypothesis that metyrapone may increase neurosteroidogenesis to produce effects on cocaine-related behaviors. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Social interaction and cocaine conditioning in mice increase spontaneous spike frequency in the nucleus accumbens or septal nuclei as revealed by multielectrode array recordings.

    Science.gov (United States)

    Kummer, Kai K; El Rawas, Rana; Kress, Michaela; Saria, Alois; Zernig, Gerald

    2015-01-01

    Both cocaine and social interaction place preference conditioning lead to increased neuronal expression of the immediate early gene EGR1 in the nucleus accumbens, a central region of the reward pathway, suggesting that both drug and natural rewards may be processed in similar brain regions. In order to gain novel insights into the intrinsic in vitro electrical activity of the nucleus accumbens and adjacent brain regions and to explore the effects of reward conditioning on network activity, we performed multielectrode array recordings of spontaneous firing in acute brain slices of mice conditioned to either cocaine or social interaction place preference. Cocaine conditioning increased the spike frequency of neurons in the septal nuclei, whereas social interaction conditioning increased the spike frequency in the nucleus accumbens compared to saline control animals. In addition, social interaction conditioning decreased the amount of active neuron clusters in the nucleus accumbens. Our findings suggest that place preference conditioning for both drug and natural rewards may induce persistent changes in neuronal network activity in the nucleus accumbens and the septum that are still preserved in acute slice preparations. © 2015 S. Karger AG, Basel.

  3. Reward Contingencies Improve Goal-Directed Behavior by Enhancing Posterior Brain Attentional Regions and Increasing Corticostriatal Connectivity in Cocaine Addicts.

    Science.gov (United States)

    Rosell-Negre, Patricia; Bustamante, Juan-Carlos; Fuentes-Claramonte, Paola; Costumero, Víctor; Llopis-Llacer, Juan-José; Barrós-Loscertales, Alfonso

    2016-01-01

    The dopaminergic system provides the basis for the interaction between motivation and cognition. It is triggered by the possibility of obtaining rewards to initiate the neurobehavioral adaptations necessary to achieve them by directing the information from motivational circuits to cognitive and action circuits. In drug addiction, the altered dopamine (DA) modulation of the meso-cortico-limbic reward circuitry, such as the prefrontal cortex (PFC), underlies the disproportionate motivational value of drug use at the expense of other non-drug reinforcers and the user's loss of control over his/her drug intake. We examine how the magnitude of the reward affects goal-directed processes in healthy control (HC) subjects and abstinent cocaine dependent (ACD) patients by using functional magnetic resonance imaging (fMRI) during a counting Stroop task with blocked levels of monetary incentives of different magnitudes (€0, €0.01, €0.5, €1 or €1.5). Our results showed that increasing reward magnitude enhances (1) performance facilitation in both groups; (2) left dorsolateral prefrontal cortex (DLPFC) activity in HC and left superior occipital cortex activity in ACD; and (3) left DLPFC and left putamen connectivity in ACD compared to HC. Moreover, we observed that (4) dorsal striatal and pallidum activity was associated with craving and addiction severity during the parametric increases in the monetary reward. In conclusion, the brain response to gradients in monetary value was different in HC and ACD, but both groups showed improved task performance due to the possibility of obtaining greater monetary rewards.

  4. Reward Contingencies Improve Goal-Directed Behavior by Enhancing Posterior Brain Attentional Regions and Increasing Corticostriatal Connectivity in Cocaine Addicts

    Science.gov (United States)

    Rosell-Negre, Patricia; Bustamante, Juan-Carlos; Fuentes-Claramonte, Paola; Costumero, Víctor; Llopis-Llacer, Juan-José; Barrós-Loscertales, Alfonso

    2016-01-01

    The dopaminergic system provides the basis for the interaction between motivation and cognition. It is triggered by the possibility of obtaining rewards to initiate the neurobehavioral adaptations necessary to achieve them by directing the information from motivational circuits to cognitive and action circuits. In drug addiction, the altered dopamine (DA) modulation of the meso-cortico-limbic reward circuitry, such as the prefrontal cortex (PFC), underlies the disproportionate motivational value of drug use at the expense of other non-drug reinforcers and the user’s loss of control over his/her drug intake. We examine how the magnitude of the reward affects goal-directed processes in healthy control (HC) subjects and abstinent cocaine dependent (ACD) patients by using functional magnetic resonance imaging (fMRI) during a counting Stroop task with blocked levels of monetary incentives of different magnitudes (€0, €0.01, €0.5, €1 or €1.5). Our results showed that increasing reward magnitude enhances (1) performance facilitation in both groups; (2) left dorsolateral prefrontal cortex (DLPFC) activity in HC and left superior occipital cortex activity in ACD; and (3) left DLPFC and left putamen connectivity in ACD compared to HC. Moreover, we observed that (4) dorsal striatal and pallidum activity was associated with craving and addiction severity during the parametric increases in the monetary reward. In conclusion, the brain response to gradients in monetary value was different in HC and ACD, but both groups showed improved task performance due to the possibility of obtaining greater monetary rewards. PMID:27907134

  5. Reward Contingencies Improve Goal-Directed Behavior by Enhancing Posterior Brain Attentional Regions and Increasing Corticostriatal Connectivity in Cocaine Addicts.

    Directory of Open Access Journals (Sweden)

    Patricia Rosell-Negre

    Full Text Available The dopaminergic system provides the basis for the interaction between motivation and cognition. It is triggered by the possibility of obtaining rewards to initiate the neurobehavioral adaptations necessary to achieve them by directing the information from motivational circuits to cognitive and action circuits. In drug addiction, the altered dopamine (DA modulation of the meso-cortico-limbic reward circuitry, such as the prefrontal cortex (PFC, underlies the disproportionate motivational value of drug use at the expense of other non-drug reinforcers and the user's loss of control over his/her drug intake. We examine how the magnitude of the reward affects goal-directed processes in healthy control (HC subjects and abstinent cocaine dependent (ACD patients by using functional magnetic resonance imaging (fMRI during a counting Stroop task with blocked levels of monetary incentives of different magnitudes (€0, €0.01, €0.5, €1 or €1.5. Our results showed that increasing reward magnitude enhances (1 performance facilitation in both groups; (2 left dorsolateral prefrontal cortex (DLPFC activity in HC and left superior occipital cortex activity in ACD; and (3 left DLPFC and left putamen connectivity in ACD compared to HC. Moreover, we observed that (4 dorsal striatal and pallidum activity was associated with craving and addiction severity during the parametric increases in the monetary reward. In conclusion, the brain response to gradients in monetary value was different in HC and ACD, but both groups showed improved task performance due to the possibility of obtaining greater monetary rewards.

  6. 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.

  7. 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.

  8. Cocaine behavioral economics: From the naturalistic environment to the controlled laboratory setting

    Science.gov (United States)

    Greenwald, Mark K.; Steinmiller, Caren L.

    2017-01-01

    Background We previously observed that behavioral economic factors predict naturalistic heroin seeking behavior that correlates with opioid seeking in the experimental laboratory. The present study sought to replicate and extend these prior findings with regular cocaine users. Methods Participants (N = 83) completed a semi-structured interview to establish income-generating and cocaine-purchasing/use repertoire during the past month. Questions addressed sources/amounts of income and expenditures; price (money and time) per purchase; and frequency/amounts of cocaine purchased and consumed. Naturalistic cocaine purchasing and use patterns were: (1) analyzed as a function of income quartile, (2) perturbed by hypothetical changes in cost factors to assess changes in purchasing/use habits, and (3) correlated with experimental cocaine seeking. Results Income was positively related to naturalistic cocaine seeking/use pattern (i.e., income elastic), and behaviors were cost-efficient and sensitive to supply chain. Income was unrelated to proportional expenditure on cocaine (≈55%) but inversely related to food expenditure. In all hypothetical scenarios (changes in income or dealer, loss of income assistance from government or family/friends, and increasing arrest risk when purchasing), the high-income group reported they would continue to use more cocaine daily than other groups. Number of laboratory cocaine choices significantly correlated with cocaine purchase time (positively) and purity of cocaine (negatively) in the naturalistic setting. Conclusions These results replicate and extend findings with regular heroin users, demonstrate the importance of income, cost-efficiency and supply-mindedness in cocaine seeking/use, and suggest that this interview-based approach has good external validity. PMID:24878248

  9. Direct fluorescence anisotropy assay for cocaine using tetramethylrhodamine-labeled aptamer.

    Science.gov (United States)

    Liu, Yingxiong; Zhao, Qiang

    2017-06-01

    Development of simple, sensitive, and rapid method for cocaine detection is important in medicine and drug abuse monitoring. Taking advantage of fluorescence anisotropy and aptamer, this study reports a direct fluorescence anisotropy (FA) assay for cocaine by employing an aptamer probe with tetramethylrhodamine (TMR) labeled on a specific position. The binding of cocaine and the aptamer causes a structure change of the TMR-labeled aptamer, leading to changes of the interaction between labeled TMR and adjacent G bases in aptamer sequence, so FA of TMR varies with increasing of cocaine. After screening different labeling positions of the aptamer, including thymine (T) bases and terminals of the aptamer, we obtained a favorable aptamer probe with TMR labeled on the 25th base T in the sequence, which exhibited sensitive and significant FA-decreasing responses upon cocaine. Under optimized assay conditions, this TMR-labeled aptamer allowed for direct FA detection of cocaine as low as 5 μM. The maximum FA change reached about 0.086. This FA method also enabled the detection of cocaine spiked in diluted serum and urine samples, showing potential for applications. Graphical Abstract The binding of cocaine to the TMR-labeled aptamer causes conformation change and alteration of the intramolecular interaction between TMR and bases of aptamer, leading to variance of fluorescence anisotropy (FA) of TMR, so direct FA analyis of cocaine is achieved.

  10. Imaging of cocaine-induced global and regional myocardial ischemia

    International Nuclear Information System (INIS)

    Oster, Z.H.; Som, P.; Wang, G.J.; Weber, D.A.

    1991-01-01

    Severe and often fatal cardiac complications have been reported in cocaine users with narrowed coronary arteries caused by atherosclerosis as well as in young adults with normal coronaries. The authors have found that in normal dogs cocaine induces severe temporary hypoperfusion of the left ventricle as indicated by a significantly lower 201Tl concentration compared to the baseline state. The most significant decrease in uptake occurred 5 min after injection and was more pronounced in the septal and apical segments. Following intravenous administration of cocaine, instead of gradual disappearance of 201Tl from the left ventricle, there was continuous increase in 201Tl concentration in the left ventricle. These imaging experiments indicate that the deleterious effects of cocaine on the heart are probably due to spasm of the coronaries and decreased myocardial perfusion. Since spasm of the large subpericardial vessels does not seem to explain the magnitude of the increased coronary resistance and decreased coronary flow after cocaine as described in the literature, it is suggested that microvascular spasm of smaller vessels plays a major role in the temporary decrease in perfusion. The data may also suggest that severe temporary myocardial ischemia is probably the initiating factor for the cardiac complications induced by cocaine

  11. 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.

  12. 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.

  13. Wheel-running attenuates intravenous cocaine self-administration in rats: sex differences.

    Science.gov (United States)

    Cosgrove, Kelly P; Hunter, Robb G; Carroll, Marilyn E

    2002-10-01

    This experiment examines the effect of access to a running-wheel on intravenous cocaine self-administration in male and female rats. Rats maintained at 85% of their free-feeding body weight were first exposed to the running-wheel alone during the 6-h sessions until behavior stabilized for 14 days. Intravenous cannulae were then implanted, and the rats were trained to self-administer a low dose of cocaine (0.2 mg/kg) under a fixed-ratio (FR 1) schedule during the 6-h sessions, while the wheel remained inactive and cocaine self-administration stabilized (cocaine-only condition). Next, the wheel access and cocaine self-administration were concurrently available followed by a period of cocaine-only. Behavior was allowed to stabilize for 10 days at each phase. During wheel access, cocaine infusions decreased by 21.9% in males and 70.6% in females compared to the cocaine-only condition; the effect was statistically significant in females. Infusions increased to baseline levels when wheel access was terminated. When cocaine infusions were concurrently available, wheel revolutions were reduced by 63.7% and 61.5% in males and females, respectively, compared to the wheel-only condition. This result did not differ due to sex, but it was statistically significant when data from males and females were combined. These results indicate that wheel-running activity had a greater suppressant effect on cocaine self-administration in females than in males, and in females, wheel-running and cocaine self-administration are substitutable as reinforcers.

  14. Sixteen-Day Bedrest Significantly Increases Plasma Colloid Osmotic Pressure

    Science.gov (United States)

    Hargens, Alan R.; Hsieh, S. T.; Murthy, G.; Ballard, R. E.; Convertino, V. A.; Wade, Charles E. (Technical Monitor)

    1994-01-01

    Upon exposure to microgravity, astronauts lose up to 10% of their total plasma volume, which may contribute to orthostatic intolerance after space flight. Because plasma colloid osmotic pressure (COP) is a primary factor maintaining plasma volume, our objective was to measure time course changes in COP during microgravity simulated by 6 deg. head-down tilt (HDT). Seven healthy male subjects (30-55 years of age) were placed in HDT for 16 days. For the purpose of another study, three of the seven subjects were chosen to exercise on a cycle ergometer on day 16. Blood samples were drawn immediately before bedrest on day 14 of bedrest, 18-24 hours following exercise while all subjects were still in HDT and 1 hour following bedrest termination. Plasma COP was measured in all 20 microliter EDTA-treated samples using an osmometer fitted with a PM 30 membrane. Data were analyzed with paired and unpaired t-tests. Plasma COP on day 14 of bedrest (29.9 +/- 0.69 mmHg) was significantly higher (p less than 0.005) than the control, pre-bedrest value (23.1 +/- 0.76 mmHg). At one hour of upright recovery after HDT, plasma COP remained significantly elevated (exercise: 26.9 +/- 0.87 mmHg; no exercise: 26.3 +/- 0.85 mmHg). Additionally, exercise had no significant effect on plasma COP 18-24 hours following exercise (exercise: 27.8 +/- 1.09 mmHg; no exercise: 27.1 +/- 0.78 mmHg). Our results demonstrate that plasma COP increases significantly with microgravity simulated by HDT. However, preliminary results indicate exercise during HDT does not significantly affect plasma COP.

  15. 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

  16. Significance in the increase of women psychiatrists in Korea.

    Science.gov (United States)

    Kim, Ha Kyoung; Kim, Soo In

    2008-01-01

    The number of female doctors has increased in Korea; 18.9% (13,083) of the total medical doctors registered (69,097) were women in 2006, compared to 13.6% (2,216) in 1975. The proportion of female doctors will jump up by 2010 considering that nearly 40% of the medical students are women as of today. This trend has had strong influence on the field of psychiatry; the percentage of women psychiatrists rose from 1.6 (6)% to 18% (453), from 1975 to 2006 and now women residents comprise 39% (206) of all. This is not only a reflection of a social phenomenon of the increase in professional women but also attributed to some specific characteristics of the psychiatry. Psychiatric practice may come more natural to women. While clinical activities of women psychiatrists are expanding, there are few women leaders and much less women are involving in academic activities in this field as yet. Though there is less sexual discrimination in the field of psychiatry, women psychiatrists are still having a lot of difficulties in balancing work and family matters. Many women psychiatrists also report they've ever felt an implied discrimination in their careers. In this study, we are to identify the characteristics of women psychiatrists and to explore the significance of the increase in women psychiatrists in Korea and the situation in which they are.

  17. 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

  18. Cocaine addiction is associated with abnormal prefrontal function, increased striatal connectivity and sensitivity to monetary incentives, and decreased connectivity outside the human reward circuit.

    Science.gov (United States)

    Vaquero, Lucía; Cámara, Estela; Sampedro, Frederic; Pérez de Los Cobos, José; Batlle, Francesca; Fabregas, Josep Maria; Sales, Joan Artur; Cervantes, Mercè; Ferrer, Xavier; Lazcano, Gerardo; Rodríguez-Fornells, Antoni; Riba, Jordi

    2017-05-01

    Cocaine addiction has been associated with increased sensitivity of the human reward circuit to drug-related stimuli. However, the capacity of non-drug incentives to engage this network is poorly understood. Here, we characterized the functional sensitivity to monetary incentives and the structural integrity of the human reward circuit in abstinent cocaine-dependent (CD) patients and their matched controls. We assessed the BOLD response to monetary gains and losses in 30 CD patients and 30 healthy controls performing a lottery task in a magnetic resonance imaging scanner. We measured brain gray matter volume (GMV) using voxel-based morphometry and white matter microstructure using voxel-based fractional anisotropy (FA). Functional data showed that, after monetary incentives, CD patients exhibited higher activation in the ventral striatum than controls. Furthermore, we observed an inverted BOLD response pattern in the prefrontal cortex, with activity being highest after unexpected high gains and lowest after losses. Patients showed increased GMV in the caudate and the orbitofrontal cortex, increased white matter FA in the orbito-striatal pathway but decreased FA in antero-posterior association bundles. Abnormal activation in the prefrontal cortex correlated with GMV and FA increases in the orbitofrontal cortex. While functional abnormalities in the ventral striatum were inversely correlated with abstinence duration, structural alterations were not. In conclusion, results suggest abnormal incentive processing in CD patients with high salience for rewards and punishments in subcortical structures but diminished prefrontal control after adverse outcomes. They further suggest that hypertrophy and hyper-connectivity within the reward circuit, to the expense of connectivity outside this network, characterize cocaine addiction. © 2016 Society for the Study of Addiction.

  19. Higher Impulsivity As a Distinctive Trait of Severe Cocaine Addiction among Individuals Treated for Cocaine or Alcohol Use Disorders

    Directory of Open Access Journals (Sweden)

    Nuria García-Marchena

    2018-02-01

    Full Text Available AimsDespite alcohol being the most often used addictive substance among addicted patients, use of other substances such as cocaine has increased over recent years, and the combination of both drugs aggravates health impairment and complicates clinical assessment. The aim of this study is to identify and characterize heterogeneous subgroups of cocaine- and alcohol-addicted patients with common characteristics based on substance use disorders, psychiatric comorbidity and impulsivity.MethodsA total of 214 subjects with cocaine and/or alcohol use disorders were recruited from outpatient treatment programs and clinically assessed. A latent class analysis was used to establish phenotypic categories according to diagnosis of cocaine and alcohol use disorders, mental disorders, and impulsivity scores. Relevant variables were examined in the latent classes (LCs using correlation and analyses of variance and covariance.ResultsFour LCs of addicted patients were identified: Class 1 (45.3% formed by alcohol-dependent patients exhibiting lifetime mood disorder diagnosis and mild impulsivity; Class 2 (14% formed mainly by lifetime cocaine use disorder patients with low probability of comorbid mental disorders and mild impulsivity; Class 3 (10.7% formed by cocaine use disorder patients with elevated probability to course with lifetime anxiety, early and personality disorders, and greater impulsivity scores; and Class 4 (29.9% formed mainly by patients with alcohol and cocaine use disorders, with elevated probability in early and personality disorders and elevated impulsivity. Furthermore, there were significant differences among classes in terms of Diagnostic and Statistical Manual of Mental Disorders-4th Edition-Text Revision criteria for abuse and dependence: Class 3 showed more criteria for cocaine use disorders than other classes, while Class 1 and Class 4 showed more criteria for alcohol use disorders.ConclusionCocaine- and alcohol-addicted patients who

  20. Early-life adversity facilitates acquisition of cocaine self-administration and induces persistent anhedonia

    Directory of Open Access Journals (Sweden)

    Jessica L. Bolton

    2018-02-01

    Full Text Available Early-life adversity increases the risk for emotional disorders such as depression and schizophrenia. Anhedonia, thought to be a core feature of these disorders, is provoked by our naturalistic rodent model of childhood adversity (i.e., rearing pups for one week in cages with limited bedding and nesting, LBN. Drug use and addiction are highly comorbid with psychiatric disorders featuring anhedonia, yet effects of LBN on drug-seeking behavior and the reward and stress-related circuits that underlie it remain unknown. Here we examined the effects of LBN on cocaine intake and seeking, using a battery of behavioral tests measuring distinct aspects of cocaine reward, and for comparison, chocolate intake. We also examined activation of neurons within the pleasure/reward and stress circuits following cocaine in LBN and control rats. Early-life adversity reduced spontaneous intake of palatable chocolate, extending prior reports of sucrose and social-play anhedonia. In a within-session cocaine behavioral economic test, LBN rats self-administered lower dosages of cocaine under low-effort conditions, consistent with a reduced hedonic set-point for cocaine, and potentially anhedonia. In contrast, cocaine demand elasticity was not consistently affected, indicating no major changes in motivation to maintain preferred cocaine blood levels. These changes were selective, as LBN did not cause an overt anxiety-like phenotype, nor did it affect sensitivity to self-administered cocaine dose, responding for cocaine under extinction conditions, cocaine- or cue-induced reinstatement of cocaine seeking, or locomotor response to acute cocaine. However, high Fos expression was seen after cocaine in both reward- and stress-related brain regions of LBN rats, including nucleus accumbens core, central amygdala, and lateral habenula. In contrast, hypothalamic orexin neuron activation after cocaine was significantly attenuated in LBN rats. Together, these findings demonstrate

  1. 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

  2. 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

  3. 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

  4. Post-sensitization treatment with rimonabant blocks the expression of cocaine-induced behavioral sensitization and c-Fos protein in mice.

    Science.gov (United States)

    Marinho, Eduardo A V; Oliveira-Lima, Alexandre J; Yokoyama, Thais S; Santos-Baldaia, Renan; Ribeiro, Luciana T C; Baldaia, Marilia A; da Silva, Raphael Wuo; Hollais, Andre Willian; Talhati, Fernanda; Longo, Beatriz Monteiro; Berro, Lais Fernanda; Frussa-Filho, Roberto

    2017-05-01

    CB1 receptor antagonists have been shown to prevent acute and long-term behavioral effects of cocaine. Here we evaluate the effectiveness of the CB1 receptor antagonist rimonabant to modify sensitized responses to cocaine. Mice were treated with saline or cocaine injections in a 15-day intermittent sensitization treatment and subsequently treated with either vehicle, 1 or 10mg/kg rimonabant in the drug-associated environment for 8 consecutive days. Animals were then challenged with saline and cocaine in the open-field apparatus on subsequent days to evaluate the expression of conditioned and sensitized effects to cocaine. c-Fos protein expression was evaluated in the nucleus accumbens (NAcc), ventral tegmental area (VTA), basolateral amygdala (BLA), medial prefrontal cortex (mPFC) and caudate-putamen (CPu) after the last (cocaine) challenge. Previous treatment with 10mg/kg rimonabant blocked the expression of conditioned hyperlocomotion and behavioral sensitization to cocaine, but not acute cocaine-induced hyperlocomotion. These behavioral effects were accompanied by significant changes in c-Fos expression in the brain reward system. Chronic cocaine sensitization blunted a subsequent acute cocaine-induced increase in c-Fos protein in the NAcc, effect that was reversed by previous treatment with rimonabant. Treatment with 10mg/kg rimonabant also attenuated the significant increase in c-Fos expression in the CPu, mPFC and BLA induced by previous chronic sensitization with cocaine. Our findings add to the evidence that drugs targeting CB1 receptors are good candidates for the treatment of cocaine abuse and provide further insights into the mechanisms underlying endocannabinoid signaling within the brain reward system in the context of cocaine abuse. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. 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.

  6. 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.

  7. Increasing the statistical significance of entanglement detection in experiments.

    Science.gov (United States)

    Jungnitsch, Bastian; Niekamp, Sönke; Kleinmann, Matthias; Gühne, Otfried; Lu, He; Gao, Wei-Bo; Chen, Yu-Ao; Chen, Zeng-Bing; Pan, Jian-Wei

    2010-05-28

    Entanglement is often verified by a violation of an inequality like a Bell inequality or an entanglement witness. Considerable effort has been devoted to the optimization of such inequalities in order to obtain a high violation. We demonstrate theoretically and experimentally that such an optimization does not necessarily lead to a better entanglement test, if the statistical error is taken into account. Theoretically, we show for different error models that reducing the violation of an inequality can improve the significance. Experimentally, we observe this phenomenon in a four-photon experiment, testing the Mermin and Ardehali inequality for different levels of noise. Furthermore, we provide a way to develop entanglement tests with high statistical significance.

  8. Increasing the statistical significance of entanglement detection in experiments

    Energy Technology Data Exchange (ETDEWEB)

    Jungnitsch, Bastian; Niekamp, Soenke; Kleinmann, Matthias; Guehne, Otfried [Institut fuer Quantenoptik und Quanteninformation, Innsbruck (Austria); Lu, He; Gao, Wei-Bo; Chen, Zeng-Bing [Hefei National Laboratory for Physical Sciences at Microscale and Department of Modern Physics, University of Science and Technology of China, Hefei (China); Chen, Yu-Ao; Pan, Jian-Wei [Hefei National Laboratory for Physical Sciences at Microscale and Department of Modern Physics, University of Science and Technology of China, Hefei (China); Physikalisches Institut, Universitaet Heidelberg (Germany)

    2010-07-01

    Entanglement is often verified by a violation of an inequality like a Bell inequality or an entanglement witness. Considerable effort has been devoted to the optimization of such inequalities in order to obtain a high violation. We demonstrate theoretically and experimentally that such an optimization does not necessarily lead to a better entanglement test, if the statistical error is taken into account. Theoretically, we show for different error models that reducing the violation of an inequality can improve the significance. We show this to be the case for an error model in which the variance of an observable is interpreted as its error and for the standard error model in photonic experiments. Specifically, we demonstrate that the Mermin inequality yields a Bell test which is statistically more significant than the Ardehali inequality in the case of a photonic four-qubit state that is close to a GHZ state. Experimentally, we observe this phenomenon in a four-photon experiment, testing the above inequalities for different levels of noise.

  9. 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

  10. Effects of cocaine on norepinephrine stimulated phosphoinositide hydrolysis and locomotor activity in rat

    International Nuclear Information System (INIS)

    Mosaddeghi, M.

    1989-01-01

    The function of α 1 -adrenoceptors was determined by stimulating cortical tissue slices, which were pre-labeled with [ 3 H]inositol, with norepinephrine (NE) in the presence of 8 mM LiCl. Results of in vitro studies showed that cocaine 10 μM potentiated maximal NE-stimulated PI hydrolysis by 30%. In addition, the EC 50 was decreased from 3.93 ± 0.42 to 1.91 ± 0.31 μM NE. Concentrations of 0.1-100 μM and 0.1-10 μM cocaine enhanced PI hydrolysis stimulated by 0.3 and 3 μM NE, respectively. The concentration-effect curves for NE-stimulated PI hydrolysis were shifted to the right 100-fold in the presence of 0.1 μM prazosin. Cocaine (10 μM) did not potentiate NE-stimulated PI hydrolysis in the presence of 0.1 μM prazosin. [ 3 H]Prazosin saturation and NE [ 3 H]prazosin competition binding studies using crude membrane preparations showed that 10 μM cocaine did not alter binding parameters B max , K d , Hill slope, and IC 50 . Together, these results implied that cocaine in vitro potentiated NE-stimulated PI hydrolysis by blocking NE reuptake. For in vivo studies, the locomotor activity was determined after an acute or chronic injections of either cocaine or saline. Cocaine or saline-treated rats were killed after measurement of the locomotor activity, and NE-stimulated PI hydrolysis was measured. Acute administration of cocaine 3.2-42 mg/kg (i.p.) produced an inverted U shaped dose-response curve on locomotor activity. The peak increase in locomotor activity was at 32 mg/kg cocaine. A dose of 42 mg/kg cocaine produced a significant depression of maximal NE-stimulated PI hydrolysis

  11. 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.

  12. 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.

  13. Behavioral factors predicting response to employment-based reinforcement of cocaine abstinence in methadone patients.

    Science.gov (United States)

    Holtyn, August F; Washington, Wendy Donlin; Knealing, Todd W; Wong, Conrad J; Kolodner, Ken; Silverman, Kenneth

    2016-06-01

    We sought to identify behavioral factors associated with response to an employment-based intervention, in which participants had to provide drug-free urine samples to gain access to paid employment. The present secondary analysis included data from a randomized clinical trial. The trial evaluated whether employment-based reinforcement could decrease cocaine use in community methadone patients. Participants (N=56) in the trial worked in a model workplace for 4 hr every weekday and earned about $10 per hr. After a 4-week baseline, participants were randomly assigned to an Abstinence & Work (n = 28) or Work Only (n = 28) condition and could work for an additional 26 weeks. Abstinence & Work participants had to provide cocaine-negative urine samples to work and maintain maximum pay. Work Only participants only had to work to earn pay. For Work Only participants, cocaine abstinence during baseline and the intervention period were significantly ( r s = .72, p workplace attendance was marginally correlated ( r s = .32, p = .098) with cocaine abstinence during the intervention period. Furthermore, participants who provided over 60% cocaine-negative urine samples during the intervention period (i.e., responders) had significantly higher baseline rates of opiate abstinence ( p workplace attendance ( p = .042) than non-responders. Employment-based reinforcement of cocaine abstinence may be improved by increasing opiate abstinence and workplace attendance prior to initiating the cocaine-abstinence intervention.

  14. White Matter Changes in HIV+ Women with a History of Cocaine Dependence

    Directory of Open Access Journals (Sweden)

    Kathryn-Mary Wakim

    2017-10-01

    Full Text Available Cocaine use is associated with the transmission of human immunodeficiency (HIV virus through risky sexual behavior. In HIV+ individuals, cocaine use is linked with poor health outcomes, including HIV-medication non-adherence and faster disease progression. Both HIV and cocaine dependence are associated with reduced integrity of cerebral white matter (WM, but the effects of HIV during cocaine abstinence have not yet been explored. We used diffusion tensor imaging (DTI to understand the effect of combined HIV+ serostatus and former cocaine dependence on cerebral WM integrity. DTI data obtained from 15 HIV+ women with a history of cocaine dependence (COC+/HIV+ and 21 healthy females were included in the analysis. Diffusion-based measures [fractional anisotropy (FA, radial diffusivity (RD, mean diffusivity, and axial diffusivity] were examined using tract-based spatial statistics and region-of-interest analyses. In a whole-brain analysis, COC+/HIV+ women showed significantly reduced FA and increased RD in all major WM tracts, except the left corticospinal tract for RD. The tract with greatest percentage of voxels showing significant between-group differences was the forceps minor (FA: 75.6%, RD: 59.7%. These widespread changes in diffusion measures indicate an extensive neuropathological effect of HIV and former cocaine dependence on WM.

  15. MCG101-induced cancer anorexia-cachexia features altered expression of hypothalamic Nucb2 and Cartpt and increased plasma levels of cocaine- and amphetamine-regulated transcript peptides.

    Science.gov (United States)

    Burgos, Jonathan R; Iresjö, Britt-Marie; Smedh, Ulrika

    2016-04-01

    The aim of the present study was to explore central and peripheral host responses to an anorexia-cachexia producing tumor. We focused on neuroendocrine anorexigenic signals in the hypothalamus, brainstem, pituitary and from the tumor per se. Expression of mRNA for corticotropin-releasing hormone (CRH), cocaine- and amphetamine-regulated transcript (CART), nesfatin-1, thyrotropin (TSH) and the TSH receptor were explored. In addition, we examined changes in plasma TSH, CART peptides (CARTp) and serum amyloid P component (SAP). C57BL/6 mice were implanted with MCG101 tumors or sham-treated. A sham-implanted, pair‑fed (PF) group was included to delineate between primary tumor and secondary effects from reduced feeding. Food intake and body weight were measured daily. mRNA levels from microdissected mouse brain samples were assayed using qPCR, and plasma levels were determined using ELISA. MCG101 tumors expectedly induced anorexia and loss of body weight. Tumor-bearing (TB) mice exhibited an increase in nesfatin-1 mRNA as well as a decrease in CART mRNA in the paraventricular area (PVN). The CART mRNA response was secondary to reduced caloric intake whereas nesfatin-1 mRNA appeared to be tumor-specifically induced. In the pituitary, CART and TSH mRNA were upregulated in the TB and PF animals compared to the freely fed controls. Plasma levels for CARTp were significantly elevated in TB but not PF mice whereas levels of TSH were unaffected. The plasma CARTp response was correlated to the degree of inflammation represented by SAP. The increase in nesfatin-1 mRNA in the PVN highlights nesfatin-1 as a plausible candidate for causing tumor-induced anorexia. CART mRNA expression in the PVN is likely an adaptation to reduced caloric intake secondary to a cancer anorexia-cachexia syndrome (CACS)‑inducing tumor. The MCG101 tumor did not express CART mRNA, thus the elevation of plasma CARTp is host derived and likely driven by inflammation.

  16. 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.

  17. Cocaine dependent individuals discount future rewards more than future losses for both cocaine and monetary outcomes.

    Science.gov (United States)

    Johnson, Matthew W; Bruner, Natalie R; Johnson, Patrick S

    2015-01-01

    Cocaine dependence and other forms of drug dependence are associated with steeper devaluation of future outcomes (delay discounting). Although studies in this domain have typically assessed choices between monetary gains (e.g., receive less money now versus receive more money after a delay), delay discounting is also applicable to decisions involving losses (e.g., small loss now versus larger delayed loss), with gains typically discounted more than losses (the "sign effect"). It is also known that drugs are discounted more than equivalently valued money. In the context of drug dependence, however, relatively little is known about the discounting of delayed monetary and drug losses and the presence of the sign effect. In this within-subject, laboratory study, delay discounting for gains and losses was assessed for cocaine and money outcomes in cocaine-dependent individuals (n=89). Both cocaine and monetary gains were discounted at significantly greater rates than cocaine and monetary losses, respectively (i.e., the sign effect). Cocaine gains were discounted significantly more than monetary gains, but cocaine and monetary losses were discounted similarly. Results suggest that cocaine is discounted by cocaine-dependent individuals in a systematic manner similar to other rewards. Because the sign effect was shown for both cocaine and money, delayed aversive outcomes may generally have greater impact than delayed rewards in shaping present behavior in this population. Copyright © 2014. Published by Elsevier Ltd.

  18. 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

  19. Sensing cocaine in saliva with infrared laser spectroscopy

    Science.gov (United States)

    Hans, Kerstin M.-C.; Müller, Matthias; Gianella, Michele; Wägli, Ph.; Sigrist, Markus W.

    2013-02-01

    Increasing numbers of accidents caused by drivers under the influence of drugs, raise drug tests to worldwide interest. We developed a one-step extraction technique for cocaine in saliva and analyzed reference samples with laser spectroscopy employing two different schemes. The first is based on attenuated total reflection (ATR), which is applied to dried samples. The second scheme uses transmission measurements for the analysis of liquid samples. ATR spectroscopy achieved a limit of detection (LOD) of 3μg/ml. The LOD for the transmission approach in liquid samples is cocaine. An improved stabilization of the set-up should lower the limit of detection significantly.

  20. Central and peripheral contributions to dynamic changes in nucleus accumbens glucose induced by intravenous cocaine

    Directory of Open Access Journals (Sweden)

    Ken Taro Wakabayashi

    2015-02-01

    Full Text Available The pattern of neural, physiological and behavioral effects induced by cocaine is consistent with metabolic neural activation, yet direct attempts to evaluate central metabolic effects of this drug have produced controversial results. Here, we used enzyme-based glucose sensors coupled with high-speed amperometry in freely moving rats to examine how intravenous cocaine at a behaviorally active dose affects extracellular glucose levels in the nucleus accumbens (NAc, a critical structure within the motivation-reinforcement circuit. In drug-naive rats, cocaine induced a bimodal increase in glucose, with the first, ultra-fast phasic rise appearing during the injection (latency 6-8 s; ~50 µM or ~5% of baseline followed by a larger, more prolonged tonic elevation (~100 µM or 10% of baseline, peak ~15 min. While the rapid, phasic component of the glucose response remained stable following subsequent cocaine injections, the tonic component progressively decreased. Cocaine-methiodide, cocaine’s peripherally acting analog, induced an equally rapid and strong initial glucose rise, indicating cocaine’s action on peripheral neural substrates as its cause. However, this analog did not induce increases in either locomotion or tonic glucose, suggesting direct central mediation of these cocaine effects. Under systemic pharmacological blockade of dopamine transmission, both phasic and tonic components of the cocaine-induced glucose response were only slightly reduced, suggesting a significant role of non-dopamine mechanisms in cocaine-induced accumbal glucose influx. Hence, intravenous cocaine induces rapid, strong inflow of glucose into NAc extracellular space by involving both peripheral and central, non-dopamine drug actions, thus preventing a possible deficit resulting from enhanced glucose use by brain cells.

  1. Individual differences in cocaine addiction: maladaptive behavioural traits

    NARCIS (Netherlands)

    Homberg, J.R.; Karel, P.G.A.; Verheij, M.M.M.

    2014-01-01

    Cocaine use leads to addiction in only a subset of individuals. Understanding the mechanisms underlying these individual differences in the transition from cocaine use to cocaine abuse is important to develop treatment strategies. There is agreement that specific behavioural traits increase the risk

  2. Eating high fat chow enhances the locomotor-stimulating effects of cocaine in adolescent and adult female rats.

    Science.gov (United States)

    Baladi, Michelle G; Koek, Wouter; Aumann, Megan; Velasco, Fortino; France, Charles P

    2012-08-01

    Dopamine systems vary through development in a manner that can impact drugs acting on those systems. Dietary factors can also impact the effects of drugs acting on dopamine systems. This study examined whether eating high fat chow alters locomotor effects of cocaine (1-56 mg/kg) in adolescent and adult female rats. Cocaine was studied in rats (n = 6/group) with free access to standard (5.7% fat) or high fat (34.3%) chow or restricted access to high fat chow (body weight matched to rats eating standard chow). After 1 week of eating high fat chow (free or restricted access), sensitivity to cocaine was significantly increased in adolescent and adult rats, compared with rats eating standard chow. Sensitivity to cocaine was also increased in adolescent rats with restricted, but not free, access to high fat chow for 4 weeks. When adolescent and adult rats that previously ate high fat chow ate standard chow, sensitivity to cocaine returned to normal. In adolescent and adult female rats eating high fat chow, but not those eating standard chow, sensitivity to cocaine increased progressively over once weekly tests with cocaine (i.e., sensitization) in a manner that was not statistically different between adolescents and adults. These results show that eating high fat chow alters sensitivity of female rats to acutely administered cocaine and also facilitates the development of sensitization to cocaine. That the type of food consumed can increase drug effects might have relevance to vulnerability to abuse cocaine in the female population.

  3. Interaction between behavioral and pharmacological treatment strategies to decrease cocaine choice in rhesus monkeys.

    Science.gov (United States)

    Banks, Matthew L; Blough, Bruce E; Negus, S Stevens

    2013-02-01

    Behavioral and pharmacotherapeutic approaches constitute two prominent strategies for treating cocaine dependence. This study investigated interactions between behavioral and pharmacological strategies in a preclinical model of cocaine vs food choice. Six rhesus monkeys, implanted with a chronic indwelling double-lumen venous catheter, initially responded under a concurrent schedule of food delivery (1-g pellets, fixed-ratio (FR) 100 schedule) and cocaine injections (0-0.1 mg/kg/injection, FR 10 schedule) during continuous 7-day treatment periods with saline or the agonist medication phenmetrazine (0.032-0.1 mg/kg/h). Subsequently, the FR response requirement for cocaine or food was varied (food, FR 100; cocaine, FR 1-100; cocaine, FR 10; food, FR 10-300), and effects of phenmetrazine on cocaine vs food choice were redetermined. Decreases in the cocaine FR or increases in the food FR resulted in leftward shifts in the cocaine choice dose-effect curve, whereas increases in the cocaine FR or decreases in the food FR resulted in rightward shifts in the cocaine choice dose-effect curve. The efficacy of phenmetrazine to decrease cocaine choice varied systematically as a function of the prevailing response requirements, such that phenmetrazine efficacy was greatest when cocaine choice was maintained by relatively low unit cocaine doses. These results suggest that efficacy of pharmacotherapies to modulate cocaine use can be influenced by behavioral contingencies of cocaine availability. Agonist medications may be most effective under contingencies that engender choice of relatively low cocaine doses.

  4. 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.

  5. 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...

  6. Manipulating a "cocaine engram" in mice.

    Science.gov (United States)

    Hsiang, Hwa-Lin Liz; Epp, Jonathan R; van den Oever, Michel C; Yan, Chen; Rashid, Asim J; Insel, Nathan; Ye, Li; Niibori, Yosuke; Deisseroth, Karl; Frankland, Paul W; Josselyn, Sheena A

    2014-10-15

    Experience with drugs of abuse (such as cocaine) produces powerful, long-lasting memories that may be important in the development and persistence of drug addiction. The neural mechanisms that mediate how and where these cocaine memories are encoded, consolidated and stored are unknown. Here we used conditioned place preference in mice to examine the precise neural circuits that support the memory of a cocaine-cue association (the "cocaine memory trace" or "cocaine engram"). We found that a small population of neurons (∼10%) in the lateral nucleus of amygdala (LA) were recruited at the time of cocaine-conditioning to become part of this cocaine engram. Neurons with increased levels of the transcription factor CREB were preferentially recruited or allocated to the cocaine engram. Ablating or silencing neurons overexpressing CREB (but not a similar number of random LA neurons) before testing disrupted the expression of a previously acquired cocaine memory, suggesting that neurons overexpressing CREB become a critical hub in what is likely a larger cocaine memory engram. Consistent with theories that coordinated postencoding reactivation of neurons within an engram or cell assembly is crucial for memory consolidation (Marr, 1971; Buzsáki, 1989; Wilson and McNaughton, 1994; McClelland et al., 1995; Girardeau et al., 2009; Dupret et al., 2010; Carr et al., 2011), we also found that post-training suppression, or nondiscriminate activation, of CREB overexpressing neurons impaired consolidation of the cocaine memory. These findings reveal mechanisms underlying how and where drug memories are encoded and stored in the brain and may also inform the development of treatments for drug addiction. Copyright © 2014 the authors 0270-6474/14/3414115-13$15.00/0.

  7. Atomoxetine Does Not Alter Cocaine Use in Cocaine Dependent Individuals: A Double Blind Randomized Trial

    Science.gov (United States)

    Middleton, Lisa S.; Wong, Conrad J.; Nuzzo, Paul A.; Campbell, Charles L.; Rush, Craig R.; Lofwall, Michelle R.

    2016-01-01

    Background Cocaine abuse continues to be a significant public health problem associated with morbidity and mortality. To date, no pharmacotherapeutic approach has proven effective for treating cocaine use disorders. Preclinical and clinical evidence suggests that noradrenergic activity may play a role in mediating some effects of cocaine and may be a rational target for treatment. Methods This double blind, placebo-controlled randomized, parallel group, 12-week outpatient clinical trial enrolled cocaine dependent individuals seeking treatment to examine the potential efficacy of the selective norepinephrine reuptake inhibitor, atomoxetine (80 mg/day; p.o.; n=25), compared to placebo (n=25). Subjects were initially stratified on cocaine use (atomoxetine and placebo groups (X2=0.2, p=.66; OR=0.89 [95% CI 0.41 – 1.74). Atomoxetine was generally well tolerated in this population. Conclusions These data provide no support for the utility of atomoxetine in the treatment of cocaine dependence. PMID:23200303

  8. 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.

  9. Noradrenergic α1 Receptor Antagonist Treatment Attenuates Positive Subjective Effects of Cocaine in Humans: A Randomized Trial

    Science.gov (United States)

    Newton, Thomas F.; De La Garza, Richard; Brown, Gregory; Kosten, Thomas R.; Mahoney, James J.; Haile, Colin N.

    2012-01-01

    Background Preclinical research implicates dopaminergic and noradrenergic mechanisms in mediating the reinforcing effects of drugs of abuse, including cocaine. The objective of this study was to evaluate the impact of treatment with the noradrenergic α1 receptor antagonist doxazosin on the positive subjective effects of cocaine. Methods Thirteen non-treatment seeking, cocaine-dependent volunteers completed this single-site, randomized, placebo-controlled, within-subjects study. In one study phase volunteers received placebo and in the other they received doxazosin, with the order counterbalanced across participants. Study medication was masked by over-encapsulating doxazosin tablets and matched placebo lactose served as the control. Study medication treatment was initiated at 1 mg doxazosin or equivalent number of placebo capsules PO/day and increased every three days by 1 mg. After receiving 4 mg doxazosin or equivalent number of placebo capsules participants received masked doses of 20 and 40 mg cocaine IV in that order with placebo saline randomly interspersed to maintain the blind. Results Doxazosin treatment was well tolerated and doxazosin alone produced minimal changes in heart rate and blood pressure. During treatment with placebo, cocaine produced dose-dependent increases in subjective effect ratings of “high”, “stimulated”, “like cocaine”, “desire cocaine”, “any drug effect”, and “likely to use cocaine if had access” (p<.001). Doxazosin treatment significantly attenuated the effects of 20 mg cocaine on ratings of “stimulated”, “like cocaine”, and “likely to use cocaine if had access” (p<.05). There were trends for doxazosin to reduce ratings of “stimulated”, “desire cocaine”, and “likely to use cocaine if had access” (p<.10). Conclusions Medications that block noradrenergic α1 receptors, such as doxazosin, may be useful as treatments for cocaine dependence, and should be evaluated further. Trial

  10. 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.

  11. N-Acetylcysteine reduces cocaine-cue attentional bias and differentially alters cocaine self-administration based on dosing order.

    Science.gov (United States)

    Levi Bolin, B; Alcorn, Joseph L; Lile, Joshua A; Rush, Craig R; Rayapati, Abner O; Hays, Lon R; Stoops, William W

    2017-09-01

    Disrupted glutamate homeostasis is thought to contribute to cocaine-use disorder, in particular, by enhancing the incentive salience of cocaine stimuli. n-Acetylcysteine might be useful in cocaine-use disorder by normalizing glutamate function. In prior studies, n-acetylcysteine blocked the reinstatement of cocaine seeking in laboratory animals and reduced the salience of cocaine stimuli and delayed relapse in humans. The present study determined the ability of maintenance on n-acetylcysteine (0 or 2400mg/day, counterbalanced) to reduce the incentive salience of cocaine stimuli, as measured by an attentional bias task, and attenuate intranasal cocaine self-administration (0, 30, and 60mg). Fourteen individuals (N=14) who met criteria for cocaine abuse or dependence completed this within-subjects, double-blind, crossover-design study. Cocaine-cue attentional bias was greatest following administration of 0mg cocaine during placebo maintenance, and was attenuated by n-acetylcysteine. Cocaine maintained responding during placebo and n-acetylcysteine maintenance, but the reinforcing effects of cocaine were significantly attenuated across both maintenance conditions in participants maintained on n-acetylcysteine first compared to participants maintained on placebo first. These results collectively suggest that a reduction in the incentive salience of cocaine-related stimuli during n-acetylcysteine maintenance may be accompanied by reductions in cocaine self-administration. These results are in agreement with, and link, prior preclinical and clinical trial results suggesting that n-acetylcysteine might be useful for preventing cocaine relapse by attenuating the incentive salience of cocaine cues. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Cocaine potentiates ketamine-induced loss of the righting reflex and sleeping time in mice. Role of catecholamines.

    Science.gov (United States)

    Vanderwende, C; Spoerlein, M T; Lapollo, J

    1982-07-01

    Cocaine in graded doses potentiated ketamine-induced loss of the righting reflex and sleeping time. Potentiation of drug-induced sleep with cocaine was not a generalized phenomenon inasmuch as it had no effect on sleep induced by pentobarbital or hexobarbital and decreased sleep induced by phenobarbital. Pentylenetetrazole reduced ketamine sleep but d-amphetamine had a potentiative action. dl-alpha-Methyl-p-tyrosine methyl ester itself increased both the number losing the righting reflex and the sleeping time induced by ketamine. However, the effect cocaine on sleeping time was blocked 3 h after the dl-alpha-methyl-p-tyrosine methyl ester was given. The alpha and beta adrenergic blocking drugs, phenoxybenzamine and propranolol, increased the number of animals losing the righting reflex with ketamine, and phenoxybenzamine lengthened the sleeping time. Alpha and beta adrenergic agonists, l-phenylephrine and isoproterenol, increased the number of animals going to sleep with ketamine but did not significantly alter how long they would sleep. The agonists had no effect on the cocaine interaction with ketamine, whereas the antagonists blocked the effect of cocaine. Both stimulation and blockade of dopamine receptors led to increased loss of the righting reflex and sleeping time with ketamine but only receptor blockade antagonized the effect of cocaine on ketamine-induced sleep. Thus, both the noradrenergic and dopaminergic systems appear to be involved in the ability of cocaine to potentiate ketamine-induced sleep.

  13. Mirtazapine attenuates cocaine seeking in rats.

    Science.gov (United States)

    Barbosa-Méndez, Susana; Leff, Phillipe; Arías-Caballero, Adriana; Hernández-Miramontes, Ricardo; Heinze, Gerardo; Salazar-Juárez, Alberto

    2017-09-01

    Relapse to cocaine use is a major problem in the clinical treatment of cocaine addiction. Antidepressants have been studied for their therapeutic potential to treat cocaine use disorder. Research has suggested that antidepressants attenuate both drug craving and the re-acquisition of drug-seeking and drug-taking behaviors. This study examined the efficacy of mirtazapine, an antidepressant/anxiolytic, in decreasing cocaine seeking in rats. We used the cocaine self-administration paradigm to assess the effects of mirtazapine on rats trained to self-administer cocaine or food under a fixed-ratio schedule. Mirtazapine (30 mg/kg, i.p.) was administered during extinction. Mirtazapine significantly attenuated non-reinforced lever-press responses during extinction. Moreover, the mirtazapine dosed for 30 days during extinction produced sustained attenuation of lever-press responses during re-acquisition of cocaine self-administration, without changing food-seeking behavior. Our results showed that mirtazapine attenuated the re-acquisition of cocaine-seeking responses. Our study pointed to the efficacy of mirtazapine in reducing the risk of drug relapse during abstinence, suggesting for its potential use as a novel pharmacological agent to treat drug abuse. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Effects of chronic cocaine abuse on postsynaptic dopamine receptors

    International Nuclear Information System (INIS)

    Volkow, N.D.; Fowler, J.S.; Wolf, A.P.; Schlyer, D.; Shiue, C.Y.; Alpert, R.; Dewey, S.L.; Logan, J.; Bendriem, B.; Christman, D.

    1990-01-01

    To assess the effects of chronic cocaine intoxication on dopamine receptors in human subjects, the authors evaluated [ 18 F]N-methylspiroperidol binding using positron emission tomography in 10 cocaine abusers and 10 normal control subjects. Cocaine abusers who had been detoxified for 1 week or less showed significantly lower values for uptake of [ 18 F]N-methylspiroperidol in striatum than the normal subjects, whereas the cocaine abusers who had been detoxified for 1 month showed values comparable to those obtained from normal subjects. The authors conclude that postsynaptic dopamine receptor availability decreases with chronic cocaine abuse but may recover after a drug-free interval

  15. Cocaine use in nightlife in Slovenia and Italy

    OpenAIRE

    Sande, Matej; Purkart, Barbara

    2011-01-01

    According to the 2010 annual report on the state of the drugs problem in Europe published by the EMCDDA, seizures of cocaine as well as cocaine use in Europe have increased in the last decade. Cocaine is the second most commonly used illicit drug in Europe after marijuana (EMCDDA, 2010). Due to its growing popularity and decreasing price, traditional perceptions about cocaine users and the ways in which it is consumed no longer hold true. It is no longer the case that cocaine u...

  16. Epac Signaling Is Required for Cocaine-Induced Change in AMPA Receptor Subunit Composition in the Ventral Tegmental Area.

    Science.gov (United States)

    Liu, Xiaojie; Chen, Yao; Tong, Jiaqing; Reynolds, Ashley M; Proudfoot, Sarah C; Qi, Jinshun; Penzes, Peter; Lu, Youming; Liu, Qing-Song

    2016-04-27

    Exchange protein directly activated by cAMP (Epac) and protein kinase A (PKA) are intracellular receptors for cAMP. Although PKA and its downstream effectors have been studied extensively in the context of drug addiction, whether and how Epac regulates cellular and behavioral effects of drugs of abuse remain essentially unknown. Epac is known to regulate AMPA receptor (AMPAR) trafficking. Previous studies have shown that a single cocaine exposure in vivo leads to an increase in GluA2-lacking AMPARs in dopamine neurons of the ventral tegmental area (VTA). We tested the hypothesis that Epac mediates cocaine-induced changes in AMPAR subunit composition in the VTA. We report that a single cocaine injection in vivo in wild-type mice leads to inward rectification of EPSCs and renders EPSCs sensitive to a GluA2-lacking AMPAR blocker in VTA dopamine neurons. The cocaine-induced increase in GluA2-lacking AMPARs was absent in Epac2-deficient mice but not in Epac1-deficient mice. In addition, activation of Epac with the selective Epac agonist 8-CPT-2Me-cAMP (8-CPT) recapitulated the cocaine-induced increase in GluA2-lacking AMPARs, and the effects of 8-CPT were mediated by Epac2. We also show that conditioned place preference to cocaine was impaired in Epac2-deficient mice and in mice in which Epac2 was knocked down in the VTA but was not significantly altered in Epac1-deficient mice. Together, these results suggest that Epac2 is critically involved in the cocaine-induced change in AMPAR subunit composition and drug-cue associative learning. Addictive drugs, such as cocaine, induce long-lasting adaptions in the reward circuits of the brain. A single intraperitoneal injection of cocaine leads to changes in the composition and property of the AMPAR that carries excitatory inputs to dopamine neurons. Here, we provide evidence that exchange protein directly activated by cAMP (Epac), a cAMP sensor protein, is required for the cocaine-induced changes of the AMPAR. We found that the

  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. Significant increase of Echinococcus multilocularis prevalencein foxes, but no increased predicted risk for humans

    NARCIS (Netherlands)

    Maas, M.; Dam-Deisz, W.D.C.; Roon, van A.M.; Takumi, K.; Giessen, van der J.W.B.

    2014-01-01

    The emergence of the zoonotic tapeworm Echinococcus multilocularis, causative agent ofalveolar echinococcosis (AE), poses a public health risk. A previously designed risk mapmodel predicted a spread of E. multilocularis and increasing numbers of alveolar echinococ-cosis patients in the province of

  19. 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.

  20. Increasing vaginal progesterone gel supplementation after frozen-thawed embryo transfer significantly increases the delivery rate

    DEFF Research Database (Denmark)

    Alsbjerg, Birgit; Polyzos, Nikolaos P; Elbaek, Helle Olesen

    2013-01-01

    The aim of this study was to evaluate the reproductive outcome in patients receiving frozen-thawed embryo transfer before and after doubling of the vaginal progesterone gel supplementation. The study was a retrospective study performed in The Fertility Clinic, Skive Regional Hospital, Denmark....... A total of 346 infertility patients with oligoamenorrhoea undergoing frozen-thawed embryo transfer after priming with oestradiol and vaginal progesterone gel were included. The vaginal progesterone dose was changed from 90mg (Crinone) once a day to twice a day and the reproductive outcome during the two...... rate (8.7% versus 20.5%, respectively; P=0.002). Doubling of the vaginal progesterone gel supplementation during frozen-thawed embryo transfer cycles decreased the early pregnancy loss rate, resulting in a significantly higher delivery rate. This study evaluated the reproductive outcome of 346 women...

  1. 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.

  2. Free energy profiles of cocaine esterase-cocaine binding process by molecular dynamics and potential of mean force simulations.

    Science.gov (United States)

    Zhang, Yuxin; Huang, Xiaoqin; Han, Keli; Zheng, Fang; Zhan, Chang-Guo

    2016-11-25

    The combined molecular dynamics (MD) and potential of mean force (PMF) simulations have been performed to determine the free energy profile of the CocE)-(+)-cocaine binding process in comparison with that of the corresponding CocE-(-)-cocaine binding process. According to the MD simulations, the equilibrium CocE-(+)-cocaine binding mode is similar to the CocE-(-)-cocaine binding mode. However, based on the simulated free energy profiles, a significant free energy barrier (∼5 kcal/mol) exists in the CocE-(+)-cocaine binding process whereas no obvious free energy barrier exists in the CocE-(-)-cocaine binding process, although the free energy barrier of ∼5 kcal/mol is not high enough to really slow down the CocE-(+)-cocaine binding process. In addition, the obtained free energy profiles also demonstrate that (+)-cocaine and (-)-cocaine have very close binding free energies with CocE, with a negligible difference (∼0.2 kcal/mol), which is qualitatively consistent with the nearly same experimental K M values of the CocE enzyme for (+)-cocaine and (-)-cocaine. The consistency between the computational results and available experimental data suggests that the mechanistic insights obtained from this study are reasonable. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  3. Effects of yohimbine and drug cues on impulsivity and attention in cocaine-dependent men and women and sex-matched controls.

    Science.gov (United States)

    Moran-Santa Maria, M M; Baker, N L; McRae-Clark, A L; Prisciandaro, J J; Brady, K T

    2016-05-01

    Deficits in executive function have been associated with risk for relapse. Data from previous studies suggest that relapse may be triggered by stress and drug-paired cues and that there are significant sex differences in the magnitude of these responses. The aim of this study was to examine the impact of the pharmacological stressor and alpha-2 adrenergic receptor antagonist yohimbine and cocaine cues on executive function in cocaine-dependent men and women. In a double-blind placebo controlled cross-over study, cocaine-dependent men (n=12), cocaine-dependent women (n=27), control men (n=31) and control women (n=25) received either yohimbine or placebo prior to two cocaine cue exposure sessions. Participants performed the Connors' Continuous Performance Test II prior to medication/placebo administration and immediately after each cue exposure session Healthy controls had a significant increase in commission errors under the yohimbine condition [RR (95% CI)=1.1 (1.0-1.3), χ(2)1=2.0, p=0.050]. Cocaine-dependent individuals exhibited a significant decrease in omission errors under the yohimbine condition [RR (95% CI)=0.6 (0.4-0.8), χ(2)1=8.6, p=0.003]. Cocaine-dependent women had more omission errors as compared to cocaine-dependent men regardless of treatment [RR (95% CI)=7.2 (3.6-14.7), χ(2)1=30.1, pwomen exhibited a slower hit reaction time as compared to cocaine-dependent men [Female 354 ± 13 vs. Male 415 ± 14; t89=2.6, p=0.012]. These data add to a growing literature demonstrating significant sex differences in behaviors associated with relapse in cocaine-dependent individuals. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. 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

  5. Effects of progesterone stimulated allopregnanolone on craving and stress response in cocaine dependent men and women.

    Science.gov (United States)

    Milivojevic, Verica; Fox, Helen C; Sofuoglu, Mehmet; Covault, Jonathan; Sinha, Rajita

    2016-03-01

    Fluctuations in progesterone levels during the menstrual cycle have been shown to affect physiological and subjective effects of cocaine. Furthermore, our laboratory has demonstrated that following drug-cue exposure, cocaine dependent women with high levels of circulating progesterone display lower diastolic and systolic blood pressure responses and report lower levels of anxiety and drug craving compared to cocaine dependent women with low levels of progesterone. In the current study we examined the role of the progesterone derived neuroactive steroid allopregnanolone (ALLO) on stress arousal, inhibitory control and drug craving in cocaine dependent subjects. Plasma levels of ALLO were measured using GC/MS in 46 treatment-seeking cocaine dependent men and women on day 5 of a 7-day treatment regimen of micronized progesterone (15M/8F) (400mg/day) or placebo (14M/9F) administered in a double blind, randomized manner. As a control, levels of the testosterone derived neurosteroid androstanediol (ADIOL) were also measured. All subjects participated in laboratory sessions on days 5-7 of progesterone/placebo administration in which they were exposed to a series of 5-min personalized guided imagery of either a stressful situation, cocaine use or of a neutral setting and dependent variables including subjective craving, mood, Stroop task as a measure of inhibitory control performance and plasma cortisol were assessed. Participants were grouped by high or low ALLO level and levels of dependent variables compared between ALLO groups. Progesterone relative to placebo significantly increased ALLO levels with no sex differences. There were no effects of micronized progesterone on the testosterone derived ADIOL. Individuals in the high versus the low ALLO group showed decreased levels of cortisol at baseline, and a higher cortisol response to stress; higher positive mood scores at baseline and improved Stroop performance in the drug-cue and stress conditions, and reduced cocaine

  6. Extinction of Cocaine Seeking Requires a Window of Infralimbic Pyramidal Neuron Activity after Unreinforced Lever Presses.

    Science.gov (United States)

    Gutman, Andrea L; Nett, Kelle E; Cosme, Caitlin V; Worth, Wensday R; Gupta, Subhash C; Wemmie, John A; LaLumiere, Ryan T

    2017-06-21

    The infralimbic cortex (IL) mediates extinction learning and the active suppression of cocaine-seeking behavior. However, the precise temporal relationship among IL activity, lever pressing, and extinction learning is unclear. To address this issue, we used activity-guided optogenetics in male Sprague Dawley rats to silence IL pyramidal neurons optically for 20 s immediately after unreinforced lever presses during early extinction training after cocaine self-administration. Optical inhibition of the IL increased active lever pressing during shortened extinction sessions, but did not alter the retention of the extinction learning as assessed in ensuing extinction sessions with no optical inhibition. During subsequent cued reinstatement sessions, rats that had previously received optical inhibition during the extinction sessions showed increased cocaine-seeking behavior. These findings appeared to be specific to inhibition during the post-lever press period because IL inhibition given in a noncontingent, pseudorandom manner during extinction sessions did not produce the same effects. Illumination alone (i.e., with no opsin expression) and food-seeking control experiments also failed to produce the same effects. In another experiment, IL inhibition after lever presses during cued reinstatement sessions increased cocaine seeking during those sessions. Finally, inhibition of the prelimbic cortex immediately after unreinforced lever presses during shortened extinction sessions decreased lever pressing during these sessions, but had no effect on subsequent reinstatement. These results indicate that IL activity immediately after unreinforced lever presses is necessary for normal extinction of cocaine seeking, suggesting that critical encoding of the new contingencies between a lever press and a cocaine reward occurs during that period. SIGNIFICANCE STATEMENT The infralimbic cortex (IL) contributes to the extinction of cocaine-seeking behavior, but the precise relationship

  7. The role of childhood maltreatment in the altered trait and global expression of personality in cocaine addiction

    Science.gov (United States)

    Brents, Lisa K; Tripathi, Shanti Prakash; Young, Jonathan; James, G Andrew; Kilts, Clinton D

    2015-01-01

    Background and aims Drug addictions are debilitating disorders that are highly associated with personality abnormalities. Early life stress (ELS) is a common risk factor for addiction and personality disturbances, but the relationships between ELS, addiction, and personality are poorly understood. Methods Ninety-five research participants were assessed for and grouped by ELS history and cocaine dependence. NEO-FFI personality measures were compared between the groups to define ELS− and addiction-related differences in personality traits. ELS and cocaine dependence were then examined as predictors of personality trait scores. Finally, k-means clustering was used to uncover clusters of personality trait configurations within the sample. Odds of cluster membership across subject groups was then determined. Results Trait expression differed significantly across subject groups. Cocaine-dependent subjects with a history of ELS (cocaine+/ELS+) displayed the greatest deviations in normative personality. Cocaine dependence significantly predicted four traits, while ELS predicted neuroticism and agreeableness; there was no interaction effect between ELS and cocaine dependence. The cluster analysis identified four distinct personality profiles: Open, Gregarious, Dysphoric, and Closed. Distribution of these profiles across subject groups differed significantly. Inclusion in cocaine+/ELS+, cocaine−/ELS+, and cocaine−/ELS− groups significantly increased the odds of expressing the Dysphoric, Open and Gregarious profiles, respectively. Conclusions Cocaine dependence and early life stress were significantly and differentially associated with altered expression of individual personality traits and their aggregation as personality profiles, suggesting that individuals who are at-risk for developing addictions due to ELS exposure may benefit from personality centered approaches as an early intervention and prevention. PMID:25805246

  8. 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.

  9. Myocardial uptake of cocaine and effects of cocaine on myocardial substrate utilization and perfusion in hypertensive rats

    Energy Technology Data Exchange (ETDEWEB)

    Som, P.; Wang, G.J. [Brookhaven National Lab., Upton, NY (United States); Oster, Z.H. [State Univ. of New York, Stony Brook, NY (United States); Knapp, F.F. Jr. [Oak Ridge National Lab., TN (United States); Yonekura, Y. [Kyoto Univ. (Japan). Faculty of Medicine; Fujibayashi, Y. [Kyoto Univ. (Japan). Hospital; Yamamoto, K. [Fukui Univ. (Japan). Medical School; Kubota, K. [Tohoku Univ., Sendai (Japan)

    1992-12-31

    Cocaine abuse is a problem causing world-wide concern and the number of deaths following cocaine use is increasing. Cardiovascular complications following cocaine include severe tachyarrythmias, pulmonary edema, myocardial infarction, and acute renal failure, which are major problems confronting emergency facilities. While the studies of cocaine effects on the brain have been given the most attention, it is clear that the effects of cocaine on the cardiovascular system are of great importance, given the increasing number of reports on sudden death and myocardial infarctions in young adults related to cocaine use. The precise mechanisms of cardiotoxic actions of cocaine are unclear. We investigated the whole-body distribution of C-14-labeled cocaine to determine the cocaine-binding sites, including blocking experiments to determine the nature of regional binding sites, and differential response of the normal vs. diseased heart (hypertensive cardiomyopathy) in an animal model to mimic a potentially high risk population. We investigated the acute effects of cocaine on myocardial metabolism using two myocardial energy substrate analogs, fatty acid and glucose with comparison with regional perfusion.

  10. Myocardial uptake of cocaine and effects of cocaine on myocardial substrate utilization and perfusion in hypertensive rats

    Energy Technology Data Exchange (ETDEWEB)

    Som, P.; Wang, G.J. (Brookhaven National Lab., Upton, NY (United States)); Oster, Z.H. (State Univ. of New York, Stony Brook, NY (United States)); Knapp, F.F. Jr. (Oak Ridge National Lab., TN (United States)); Yonekura, Y. (Kyoto Univ. (Japan). Faculty of Medicine); Fujibayashi, Y. (Kyoto Univ. (Japan). Hospital); Yamamoto, K. (Fukui Univ. (Japan). Medical School); Kubota, K. (Tohoku Univ., Sendai

    1992-01-01

    Cocaine abuse is a problem causing world-wide concern and the number of deaths following cocaine use is increasing. Cardiovascular complications following cocaine include severe tachyarrythmias, pulmonary edema, myocardial infarction, and acute renal failure, which are major problems confronting emergency facilities. While the studies of cocaine effects on the brain have been given the most attention, it is clear that the effects of cocaine on the cardiovascular system are of great importance, given the increasing number of reports on sudden death and myocardial infarctions in young adults related to cocaine use. The precise mechanisms of cardiotoxic actions of cocaine are unclear. We investigated the whole-body distribution of C-14-labeled cocaine to determine the cocaine-binding sites, including blocking experiments to determine the nature of regional binding sites, and differential response of the normal vs. diseased heart (hypertensive cardiomyopathy) in an animal model to mimic a potentially high risk population. We investigated the acute effects of cocaine on myocardial metabolism using two myocardial energy substrate analogs, fatty acid and glucose with comparison with regional perfusion.

  11. 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

  12. Effects of social reorganization on dopamine D2/D3 receptor availability and cocaine self-administration in male cynomolgus monkeys.

    Science.gov (United States)

    Czoty, P W; Gould, R W; Gage, H D; Nader, M A

    2017-09-01

    Studies have demonstrated that brain dopamine D2/D3 receptors (D2/D3R) and the reinforcing effects of cocaine can be influenced by a monkey's position in the social dominance hierarchy. In this study, we manipulated the social ranks of monkeys by reorganizing social groups and assessed effects on D2/D3R availability and cocaine self-administration. Male cynomolgus monkeys (N = 12) had been trained to self-administer cocaine under a concurrent cocaine-food reinforcement schedule. Previously, PET measures of D2/D3R availability in the caudate nucleus and putamen had been obtained with [ 18 F]fluoroclebopride during cocaine abstinence, while monkeys lived in stable social groups of four monkeys/pen. For this study, monkeys were reorganized into groups that consisted of (1) four previously dominant, (2) four previously subordinate, and (3) a mix of previously dominant and subordinate monkeys. After 3 months, D2/D3R availability was redetermined and cocaine self-administration was reexamined. D2/D3R availability significantly increased after reorganization in monkeys who were formerly subordinate, with the greatest increases observed in those that became dominant. No consistent changes in D2/D3R availability were observed in formerly dominant monkeys. Cocaine self-administration did not vary according to rank after reorganization of social groups. However, when compared to their previous cocaine self-administration data, the potency of cocaine as a reinforcer decreased in 9 of 11 monkeys. These results indicate that changing the social conditions can alter D2/D3R availability in subordinate monkeys in a manner suggestive of environmental enrichment. In most monkeys, social reorganization shifted the cocaine dose-response curve to the right, also consistent with environmental enrichment.

  13. Betaxolol, a selective beta(1)-adrenergic receptor antagonist, diminishes anxiety-like behavior during early withdrawal from chronic cocaine administration in rats.

    Science.gov (United States)

    Rudoy, C A; Van Bockstaele, E J

    2007-06-30

    Anxiety has been indicated as one of the main symptoms of the cocaine withdrawal syndrome in human addicts and severe anxiety during withdrawal may potentially contribute to relapse. As alterations in noradrenergic transmission in limbic areas underlie withdrawal symptomatology for many drugs of abuse, the present study sought to determine the effect of cocaine withdrawal on beta-adrenergic receptor (beta(1) and beta(2)) expression in the amygdala. Male Sprague Dawley rats were administered intraperitoneal (i.p.) injections of cocaine (20 mg/kg) once daily for 14 days. Two days following the last cocaine injection, amygdala brain regions were micro-dissected and processed for Western blot analysis. Results showed that beta(1)-adrenergic receptor, but not beta(2)-adrenergic receptor expression was significantly increased in amygdala extracts of cocaine-withdrawn animals as compared to controls. This finding motivated further studies aimed at determining whether treatment with betaxolol, a highly selective beta(1)-adrenergic receptor antagonist, could ameliorate cocaine withdrawal-induced anxiety. In these studies, betaxolol (5 mg/kg via i.p. injection) was administered at 24 and then 44 h following the final chronic cocaine administration. Anxiety-like behavior was evaluated using the elevated plus maze test approximately 2 h following the last betaxolol injection. Following behavioral testing, betaxolol effects on beta(1)-adrenergic receptor protein expression were examined by Western blotting in amygdala extracts from rats undergoing cocaine withdrawal. Animals treated with betaxolol during cocaine withdrawal exhibited a significant attenuation of anxiety-like behavior characterized by increased time spent in the open arms and increased entries into the open arms compared to animals treated with only saline during cocaine withdrawal. In contrast, betaxolol did not produce anxiolytic-like effects in control animals treated chronically with saline. Furthermore

  14. Betaxolol, a selective β1-adrenergic receptor antagonist, diminishes anxiety-like behavior during early withdrawal from chronic cocaine administration in rats

    Science.gov (United States)

    Rudoy, C.A.; Van Bockstaele, E.J.

    2007-01-01

    Background Anxiety has been indicated as one of the main symptoms of the cocaine withdrawal syndrome in human addicts and severe anxiety during withdrawal may potentially contribute to relapse. As alterations in noradrenergic transmission in limbic areas underlie withdrawal symptomatology for many drugs of abuse, the present study sought to determine the effect of cocaine withdrawal on β-adrenergic receptor (β1 and β2) expression in the amygdala. Methods Male Sprague Dawley rats were administered intraperitoneal (i.p.) injections of cocaine (20 mg/kg) once daily for 14 days. Two days following the last cocaine injection, amygdala brain regions were micro-dissected and processed for Western blot analysis. Results showed that β1–adrenergic receptor, but not β2–adrenergic receptor expression was significantly increased in amygdala extracts of cocaine-withdrawn animals as compared to controls. This finding motivated further studies aimed at determining whether treatment with betaxolol, a highly selective β1–adrenergic receptor antagonist, could ameliorate cocaine withdrawal-induced anxiety. In these studies, betaxolol (5 mg/kg via i.p. injection) was administered at 24 and then 44 hours following the final chronic cocaine administration. Anxiety-like behavior was evaluated using the elevated plus maze test approximately 2 hours following the last betaxolol injection. Following behavioral testing, betaxolol effects on β1-adrenergic receptor protein expression were examined by Western blotting in amygdala extracts from rats undergoing cocaine withdrawal. Results Animals treated with betaxolol during cocaine withdrawal exhibited a significant attenuation of anxiety-like behavior characterized by increased time spent in the open arms and increased entries into the open arms compared to animals treated with only saline during cocaine withdrawal. In contrast, betaxolol did not produce anxiolytic-like effects in control animals treated chronically with saline

  15. Associations between behavioral disinhibition and cocaine use history in individuals with cocaine dependence.

    Science.gov (United States)

    Prisciandaro, James J; Korte, Jeffrey E; McRae-Clark, Aimee L; Brady, Kathleen T

    2012-10-01

    Behavioral disinhibition has been suggested as both a cause and consequence of substance use disorders. Many studies examining associations between behavioral disinhibition and substance use history have focused on individuals with alcohol dependence or non-dependent college students. In the present study, the relationship between behavioral disinhibition and cocaine use history in individuals with cocaine dependence is examined. Forty-six non-treatment-seeking cocaine-dependent men and women completed impulsivity (Barratt impulsiveness scale; BIS) and novelty seeking (temperament and character inventory; TCI) questionnaires at the baseline visit of an ongoing study. Unadjusted, and adjusted for gender and age, Pearson correlations were calculated between BIS, TCI, and cocaine use variables from the structured clinical interview for DSM-IV and timeline follow-back (age of onset, quantity/frequency of past 30 day cocaine use). As expected, elevated motor impulsivity and novelty seeking were each associated with younger age of dependence onset. Also, individuals with lower levels of persistence on the TCI reported more days of cocaine use over the previous month. Unexpectedly, increased novelty seeking and attentional impulsivity were associated with fewer days of cocaine use and less money spent on cocaine, respectively. Controlling for age and gender did not substantially change the pattern of observed associations. The present study provides preliminary evidence for associations between behavioral disinhibition and cocaine use history in cocaine-dependent individuals. Given our relatively small sample size and the correlational nature of our findings, further research is needed to replicate and extend our results. Copyright © 2012 Elsevier Ltd. All rights reserved.

  16. 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.

  17. 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

  18. The effects of the novel DA D3 receptor antagonist SR 21502 on cocaine reward, cocaine seeking and cocaine-induced locomotor activity in rats.

    Science.gov (United States)

    Galaj, E; Ananthan, S; Saliba, M; Ranaldi, Robert

    2014-02-01

    There is a focus on developing D3 receptor antagonists as cocaine addiction treatments. We investigated the effects of a novel selective D3 receptor antagonist, SR 21502, on cocaine reward, cocaine-seeking, food reward, spontaneous locomotor activity and cocaine-induced locomotor activity in rats. In Experiment 1, rats were trained to self-administer cocaine under a progressive ratio (PR) schedule of reinforcement and tested with vehicle or one of three doses of SR 21502. In Experiment 2, animals were trained to self-administer cocaine under a fixed ratio schedule of reinforcement followed by extinction of the response. Then, animals were tested with vehicle or one of the SR 21502 doses on cue-induced reinstatement of responding. In Experiment 3, animals were trained to lever press for food under a PR schedule and tested with vehicle or one dose of the compound. In Experiments 4 and 5, in separate groups of animals, the vehicle and three doses of SR 21502 were tested on spontaneous or cocaine (10 mg/kg, IP)-induced locomotor activity, respectively. SR 21502 produced significant, dose-related (3.75, 7.5 and 15 mg/kg) reductions in breakpoint for cocaine self-administration, cue-induced reinstatement (3.75, 7.5 and 15 mg/kg) and cocaine-induced locomotor activity (3.75, 7.5 and 15 mg/kg) but failed to reduce food self-administration and spontaneous locomotor activity. SR 21502 decreases cocaine reward, cocaine-seeking and locomotor activity at doses that have no effect on food reward or spontaneous locomotor activity. These data suggest SR 21502 may selectively inhibit cocaine's rewarding, incentive motivational and stimulant effects.

  19. High affinity binding of [3H]cocaine to rat liver microsomes

    International Nuclear Information System (INIS)

    El-Maghrabi, E.A.; Calligaro, D.O.; Eldefrawi, M.E.

    1988-01-01

    ] 3 H]cocaine bound reversible, with high affinity and stereospecificity to rat liver microsomes. Little binding was detected in the lysosomal, mitochondrial and nuclear fractions. The binding kinetics were slow and the kinetically calculated K/sub D/ was 2 nM. Induction of mixed function oxidases by phenobarbital did not produce significant change in [ 3 H]cocaine binding. On the other hand, chronic administration of cocaine reduced [ 3 H]cocaine binding drastically. Neither treatment affected the affinity of the liver binding protein for cocaine. Microsomes from mouse and human livers had less cocaine-binding protein and lower affinity for cocaine than those from rat liver. Binding of [ 3 H]cocaine to rat liver microsomes was insensitive to monovalent cations and > 10 fold less sensitive to biogenic amines than the cocaine receptor in rat striatum. However, the liver protein had higher affinity for cocaine and metabolites except for norcocaine. Amine uptake inhibitors displaced [ 3 H]cocaine binding to liver with a different rank order of potency than their displacement of [ 3 H]cocaine binding to striatum. This high affinity [ 3 H]cocaine binding protein in liver is not likely to be monooxygenase, but may have a role in cocaine-induced hepatotoxicity

  20. Synapse density and dendritic complexity are reduced in the prefrontal cortex following seven days of forced abstinence from cocaine self-administration.

    Directory of Open Access Journals (Sweden)

    Khampaseuth Rasakham

    Full Text Available Chronic cocaine exposure in both human addicts and in rodent models of addiction reduces prefrontal cortical activity, which subsequently dysregulates reward processing and higher order executive function. The net effect of this impaired gating of behavior is enhanced vulnerability to relapse. Previously we have shown that cocaine-induced increases in brain-derived neurotrophic factor (BDNF expression in the medial prefrontal cortex (PFC is a neuroadaptive mechanism that blunts the reinforcing efficacy of cocaine. As BDNF is known to affect neuronal survival and synaptic plasticity, we tested the hypothesis that abstinence from cocaine self-administration would lead to alterations in neuronal morphology and synaptic density in the PFC. Using a novel technique, array tomography and Golgi staining, morphological changes in the rat PFC were analyzed following 14 days of cocaine self-administration and 7 days of forced abstinence. Our results indicate that overall dendritic branching and total synaptic density are significantly reduced in the rat PFC. In contrast, the density of thin dendritic spines are significantly increased on layer V pyramidal neurons of the PFC. These findings indicate that dynamic structural changes occur during cocaine abstinence that may contribute to the observed hypo-activity of the PFC in cocaine-addicted individuals.

  1. 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...

  2. Mechanisms of metabonomic for a gateway drug: nicotine priming enhances behavioral response to cocaine with modification in energy metabolism and neurotransmitter level.

    Directory of Open Access Journals (Sweden)

    Hongyu Li

    Full Text Available Nicotine, one of the most commonly used drugs, has become a major concern because tobacco serves as a gateway drug and is linked to illicit drug abuse, such as cocaine and marijuana. However, previous studies mainly focused on certain genes or neurotransmitters which have already been known to participate in drug addiction, lacking endogenous metabolic profiling in a global view. To further explore the mechanism by which nicotine modifies the response to cocaine, we developed two conditioned place preference (CPP models in mice. In threshold dose model, mice were pretreated with nicotine, followed by cocaine treatment at the dose of 2 mg/kg, a threshold dose of cocaine to induce CPP in mice. In high-dose model, mice were only treated with 20 mg/kg cocaine, which induced a significant CPP. (1H nuclear magnetic resonance based on metabonomics was used to investigate metabolic profiles of the nucleus accumbens (NAc and striatum. We found that nicotine pretreatment dramatically increased CPP induced by 2 mg/kg cocaine, which was similar to 20 mg/kg cocaine-induced CPP. Interestingly, metabolic profiles showed considerable overlap between these two models. These overlapped metabolites mainly included neurotransmitters as well as the molecules participating in energy homeostasis and cellular metabolism. Our results show that the reinforcing effect of nicotine on behavioral response to cocaine may attribute to the modification of some specific metabolites in NAc and striatum, thus creating a favorable metabolic environment for enhancing conditioned rewarding effect of cocaine. Our findings provide an insight into the effect of cigarette smoking on cocaine dependence and the underlying mechanism.

  3. Effects of cocaine combined with a social cue on conditioned place preference and nucleus accumbens monoamines after isolation rearing in rats

    Science.gov (United States)

    Grotewold, Susan K.; Wall, Vanessa L.; Goodell, Dayton J.; Hayter, Cassandra

    2015-01-01

    Rationale Social interaction during drug exposure can potentiate cocaine reward. Isolation rearing (ISO) during adolescence increases social interaction and may amplify this potentiation. Objectives The objectives of this study are to determine whether ISO alters conditioned place preference (CPP) for cocaine when combined with a social cue and to determine whether ISO alters the effects of cocaine when combined with social cue on nucleus accumbens shell (NAcS) dopamine (DA) and serotonin (5-HT). Methods Male and female rats were either ISO or group (GRP) reared for 4 weeks during adolescence. CPP was performed using a low dose of cocaine (2 mg/kg or saline) with or without exposure to a novel same-sex conspecific during conditioning. In vivo microdialysis was performed using the same parameters. Results ISO rats engaged in more social and aggressive behaviors during conditioning relative to GRP. Cocaine reduced social and aggressive behaviors in all rats. CPP was not influenced by rearing condition. Cocaine produced significant CPP, and a social cue produced CPP only in males. In contrast, the interaction of cocaine and a social cue on NAcS DA and 5-HT differed depending upon rearing condition. In isolates, cocaine-induced DA was attenuated, while cocaine plus a social cue produced potentiated DA and 5-HT. Conclusions Exposure to a low dose of cocaine in the presence of a social cue produced additive effects on CPP while producing synergistic effects on DA and 5-HT in the NAcS of ISO rats. The aversive effects of this compound stimulus may negate the rewarding effects in isolates. PMID:24553577

  4. CREB activity in dopamine D1 receptor expressing neurons regulates cocaine-induced behavioral effects

    Science.gov (United States)

    Bilbao, Ainhoa; Rieker, Claus; Cannella, Nazzareno; Parlato, Rosanna; Golda, Slawomir; Piechota, Marcin; Korostynski, Michal; Engblom, David; Przewlocki, Ryszard; Schütz, Günther; Spanagel, Rainer; Parkitna, Jan R.

    2014-01-01

    It is suggested that striatal cAMP responsive element binding protein (CREB) regulates sensitivity to psychostimulants. To test the cell-specificity of this hypothesis we examined the effects of a dominant-negative CREB protein variant expressed in dopamine receptor D1 (D1R) neurons on cocaine-induced behaviors. A transgenic mouse strain was generated by pronuclear injection of a BAC-derived transgene harboring the A-CREB sequence under the control of the D1R gene promoter. Compared to wild-type, drug-naïve mutants showed moderate alterations in gene expression, especially a reduction in basal levels of activity-regulated transcripts such as Arc and Egr2. The behavioral responses to cocaine were elevated in mutant mice. Locomotor activity after acute treatment, psychomotor sensitization after intermittent drug injections and the conditioned locomotion after saline treatment were increased compared to wild-type littermates. Transgenic mice had significantly higher cocaine conditioned place preference, displayed normal extinction of the conditioned preference, but showed an augmented cocaine-seeking response following priming-induced reinstatement. This enhanced cocaine-seeking response was associated with increased levels of activity-regulated transcripts and prodynorphin. The primary reinforcing effects of cocaine were not altered in the mutant mice as they did not differ from wild-type in cocaine self-administration under a fixed ratio schedule at the training dose. Collectively, our data indicate that expression of a dominant-negative CREB variant exclusively in neurons expressing D1R is sufficient to recapitulate the previously reported behavioral phenotypes associated with virally expressed dominant-negative CREB. PMID:24966820

  5. Intravenous gestational cocaine in rats: effects on offspring development and weanling behavior.

    Science.gov (United States)

    Kunko, P M; Moyer, D; Robinson, S E

    1993-01-01

    Pregnant rats were injected with cocaine (CN; 6 mg/kg) or an equal volume of saline (SAL), via the tail vein, on gestation days 8-20. A third group was untreated (UT). Maternal weight gain was not affected by dam treatment despite slight differences in food intake. Litter characteristics (e.g., litter size, pup weight) did not differ among groups. Indices of fetal mortality were not affected by the treatments. Developmental tests, initiated on postnatal day (PND) 2, indicated slight delays in the negative geotaxic response and eye opening in cocaine-exposed pups. Open-field and tail-flick tests were performed on PND 21. Pups were acutely injected with cocaine (10 mg/kg, IP), saline, or received no treatment before placement in a novel open field; morphine (1.5 mg/kg, SC) or saline was injected prior to the tail flick test. Pups from CN dams exhibited a significant decrease in spontaneous exploratory behavior compared to both controls, and a time-dependent increase in rearing compared to pups from UT dams. The acute cocaine injection prior to placement in the open field did not alter locomotion or rearing among dam treatment groups. However, the acute cocaine injection did increase stereotypy ratings for female pups from CN dams compared to similarly treated males, and females from SAL and UT dams. No differences were observed among groups in the tail-flick test. These data suggest that the IV route of administration provides a viable method of cocaine delivery in pregnant rats, and provides further evidence of the developmental and behavioral teratogenicity of prenatal cocaine exposure.

  6. Chronic Inhibition of Dopamine β-Hydroxylase Facilitates Behavioral Responses to Cocaine in Mice

    Science.gov (United States)

    Gaval-Cruz, Meriem; Liles, Larry Cameron; Iuvone, Paul Michael; Weinshenker, David

    2012-01-01

    The anti-alcoholism medication, disulfiram (Antabuse), decreases cocaine use in humans regardless of concurrent alcohol consumption and facilitates cocaine sensitization in rats, but the functional targets are unknown. Disulfiram inhibits dopamine β-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. The goal of this study was to test the effects of chronic genetic or pharmacological DBH inhibition on behavioral responses to cocaine using DBH knockout (Dbh −/−) mice, disulfiram, and the selective DBH inhibitor, nepicastat. Locomotor activity was measured in control (Dbh +/−) and Dbh −/− mice during a 5 day regimen of saline+saline, disulfiram+saline, nepicastat+saline, saline+cocaine, disulfiram+cocaine, or nepicastat+cocaine. After a 10 day withdrawal period, all groups were administered cocaine, and locomotor activity and stereotypy were measured. Drug-naïve Dbh −/− mice were hypersensitive to cocaine-induced locomotion and resembled cocaine-sensitized Dbh +/− mice. Chronic disulfiram administration facilitated cocaine-induced locomotion in some mice and induced stereotypy in others during the development of sensitization, while cocaine-induced stereotypy was evident in all nepicastat-treated mice. Cocaine-induced stereotypy was profoundly increased in the disulfiram+cocaine, nepicastat+cocaine, and nepicastat+saline groups upon cocaine challenge after withdrawal in Dbh +/− mice. Disulfiram or nepicastat treatment had no effect on behavioral responses to cocaine in Dbh −/− mice. These results demonstrate that chronic DBH inhibition facilitates behavioral responses to cocaine, although different methods of inhibition (genetic vs. non-selective inhibitor vs. selective inhibitor) enhance qualitatively different cocaine-induced behaviors. PMID:23209785

  7. Chronic inhibition of dopamine β-hydroxylase facilitates behavioral responses to cocaine in mice.

    Directory of Open Access Journals (Sweden)

    Meriem Gaval-Cruz

    Full Text Available The anti-alcoholism medication, disulfiram (Antabuse, decreases cocaine use in humans regardless of concurrent alcohol consumption and facilitates cocaine sensitization in rats, but the functional targets are unknown. Disulfiram inhibits dopamine β-hydroxylase (DBH, the enzyme that converts dopamine (DA to norepinephrine (NE in noradrenergic neurons. The goal of this study was to test the effects of chronic genetic or pharmacological DBH inhibition on behavioral responses to cocaine using DBH knockout (Dbh -/- mice, disulfiram, and the selective DBH inhibitor, nepicastat. Locomotor activity was measured in control (Dbh +/- and Dbh -/- mice during a 5 day regimen of saline+saline, disulfiram+saline, nepicastat+saline, saline+cocaine, disulfiram+cocaine, or nepicastat+cocaine. After a 10 day withdrawal period, all groups were administered cocaine, and locomotor activity and stereotypy were measured. Drug-naïve Dbh -/- mice were hypersensitive to cocaine-induced locomotion and resembled cocaine-sensitized Dbh +/- mice. Chronic disulfiram administration facilitated cocaine-induced locomotion in some mice and induced stereotypy in others during the development of sensitization, while cocaine-induced stereotypy was evident in all nepicastat-treated mice. Cocaine-induced stereotypy was profoundly increased in the disulfiram+cocaine, nepicastat+cocaine, and nepicastat+saline groups upon cocaine challenge after withdrawal in Dbh +/- mice. Disulfiram or nepicastat treatment had no effect on behavioral responses to cocaine in Dbh -/- mice. These results demonstrate that chronic DBH inhibition facilitates behavioral responses to cocaine, although different methods of inhibition (genetic vs. non-selective inhibitor vs. selective inhibitor enhance qualitatively different cocaine-induced behaviors.

  8. The Effects of Oral d-Amphetamine on Impulsivity in Smoked and Intranasal Cocaine Users

    Science.gov (United States)

    Reed, Stephanie Collins; Evans, Suzette M.

    2016-01-01

    BACKGROUND Effective treatments for cocaine use disorders remain elusive. Two factors that may be related to treatment failures are route of cocaine used and impulsivity. Smoked cocaine users are more likely to have poorer treatment outcomes compared to intranasal cocaine users. Further, cocaine users are impulsive and impulsivity is associated with poor treatment outcomes. While stimulants are used to treat Attention Deficit Hyperactivity Disorder (ADHD) and attenuate certain cocaine-related behaviors, few studies have comprehensively examined whether stimulants can reduce behavioral impulsivity in cocaine users, and none examined route of cocaine use as a factor. METHODS The effects of immediate release oral d-amphetamine (AMPH) were examined in 34 cocaine users (13 intranasal, 21 smoked). Participants had three separate sessions where they were administered AMPH (0, 10, or 20 mg) and completed behavioral measures of impulsivity and risk-taking and subjective measures of abuse liability. RESULTS Smoked cocaine users were more impulsive on the Delayed Memory Task, the GoStop task and the Delay Discounting Task than intranasal cocaine users. Smoked cocaine users also reported more cocaine craving and negative mood than intranasal cocaine users. AMPH produced minimal increases on measures of abuse liability (e.g., Drug Liking). CONCLUSIONS Smoked cocaine users were more impulsive than intranasal cocaine users on measures of impulsivity that had a delay component. Additionally, although AMPH failed to attenuate impulsive responding, there was minimal evidence of abuse liability in cocaine users. These preliminary findings need to be confirmed in larger samples that control for route and duration of cocaine use. PMID:27114203

  9. COCAINE AND PAVLOVIAN FEAR CONDITIONING: DOSE-EFFECT ANALYSIS

    OpenAIRE

    Wood, Suzanne C.; Fay, Jonathon; Sage, Jennifer R.; Anagnostaras, Stephan G.

    2006-01-01

    Emerging evidence suggests that cocaine and other drugs of abuse can interfere with many aspects of cognitive functioning. The authors examined the effects of 0.1 – 15 mg/kg of cocaine on Pavlovian contextual and cued fear conditioning in mice. As expected, pre-training cocaine dose-dependently produced hyperactivity and disrupted freezing. Surprisingly, when the mice were tested off-drug later, the group pre-treated with a moderate dose of cocaine (15 mg/kg) displayed significantly less cont...

  10. Effects of inhibitory GABA-active neurosteroids on cocaine seeking and cocaine taking in rats.

    Science.gov (United States)

    Schmoutz, Christopher D; Runyon, Scott P; Goeders, Nicholas E

    2014-09-01

    Several compounds that potentiate GABA-induced inhibitory currents also decrease stress, anxiety and addiction-related behaviors. Because of the well-established connection between stress and addiction, compounds that reduce stress-induced responses might be efficacious in treating addiction. Since endogenous neurosteroids such as allopregnanolone may function in a manner similar to benzodiazepines to reduce HPA axis activation and anxiety following stressful stimuli, we hypothesized that exogenously applied neurosteroids would reduce cocaine reinforcement in two animal models. Male Wistar rats were trained to self-administer cocaine and food under a concurrent alternating operant schedule of reinforcement. Two separate groups of rats were trained to self-administer cocaine or food pellets and were then exposed to similar cue-induced reinstatement paradigms. Both groups of rats were pretreated with various doses of neurosteroids. Allopregnanolone and 3α-hydroxy-3β-methyl-17β-nitro-5α-androstane (R6305-7, a synthetic neurosteroid) were ineffective in selectively decreasing cocaine relative to food self-administration. On the other hand, both allopregnanolone and R6305-7 significantly decreased the cue-induced reinstatement of extinguished cocaine seeking, confirmed by one-way ANOVA. These results suggest that neurosteroids may be effective in reducing the relapse to cocaine use without affecting ongoing cocaine self-administration.

  11. Peripheral benzodiazepine receptors are decreased during cocaine withdrawal in humans.

    Science.gov (United States)

    Javaid, J I; Notorangelo, M P; Pandey, S C; Reddy, P L; Pandey, G N; Davis, J M

    1994-07-01

    In the present study, homovanillic acid in plasma (pHVA) and benzodiazepine receptors (3H-PK11195 binding) in neutrophil membranes were determined in blood obtained from cocaine-dependent (DSM-III-R) adult male inpatients at baseline-(within 72 hr of last cocaine use) and after 3 weeks of cocaine abstinence, and normal controls. The mean (+/- SEM) pHVA at baseline (10.3 ng/ml +/- 1.1) was similar to normals and did not change after 3 weeks of cocaine abstinence. Similarly, the binding indices of benzodiazepine receptors in cocaine-dependent subjects as a group were not significantly different than in normal controls. In 10 cocaine-dependent subjects, however, where both blood samples were available, the number of 3H-PK11195 binding sites was significantly (p < 0.05) decreased after 3 weeks of cocaine abstinence (mean +/- sem: Bmax = 6371 +/- 657 fmol/mg protein) compared with baseline (Bmax = 7553 +/- 925 fmol/mg protein), although there were no differences in the binding affinity (mean +/- sem: KD = 8.6 +/- 1.2 nmol/L after 3 weeks of abstinence compared with 8.1 +/- 1.0 nmol/L at baseline). These preliminary results suggest that peripheral benzodiazepine receptors may play an important role in the pathophysiology of cocaine withdrawal in cocaine-dependent human subjects.

  12. 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

  13. 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.

  14. Paternal cocaine taking elicits epigenetic remodeling and memory deficits in male progeny.

    Science.gov (United States)

    Wimmer, M E; Briand, L A; Fant, B; Guercio, L A; Arreola, A C; Schmidt, H D; Sidoli, S; Han, Y; Garcia, B A; Pierce, R C

    2017-11-01

    Paternal environmental perturbations including exposure to drugs of abuse can produce profound effects on the physiology and behavior of offspring via epigenetic modifications. Here we show that adult drug-naive male offspring of cocaine-exposed sires have memory formation deficits and associated reductions in NMDA receptor-mediated hippocampal synaptic plasticity. Reduced levels of the endogenous NMDA receptor co-agonist d-serine were accompanied by increased expression of the d-serine degrading enzyme d-amino acid oxidase (Dao1) in the hippocampus of cocaine-sired male progeny. Increased Dao1 transcription was associated with enrichment of permissive epigenetic marks on histone proteins in the hippocampus of male cocaine-sired progeny, some of which were enhanced near the Dao1 locus. Finally, hippocampal administration of d-serine reversed both the memory formation and synaptic plasticity deficits. Collectively, these results demonstrate that paternal cocaine exposure produces epigenetic remodeling in the hippocampus leading to NMDA receptor-dependent memory formation and synaptic plasticity impairments only in male progeny, which has significant implications for the male descendants of chronic cocaine users.

  15. Examining supply changes in Australia's cocaine market.

    Science.gov (United States)

    Hughes, Caitlin E; Chalmers, Jenny; Bright, David A; Matthew-Simmons, Francis; Sindicich, Natasha

    2012-05-01

    Media attention to cocaine use and supply has increased following some of the largest cocaine seizures in Australia's history. Whether there has been an expansion in supply remains unclear. This paper examines the evidence behind assertions of increased supply in Australia and the scale and nature of any apparent increase, using proxy indicators of cocaine importation, distribution and use. Eight proxies of cocaine importation, distribution and use were adopted, including amount of importation, mode of importation and supply flows to Australia. Each proxy indicator was sourced using publicly available and Australia-wide data, including information on the total weight of border seizures, mode of detection and country of embarkation of individual seizures. Data permitting, trends were examined for up to a 12 year period (1997-1998 to 2009-2010). Since 2006-2007 there was evidence of increased cocaine importation, albeit less than between 1998-1999 and 2001-2002. There were further signs that the 2006-2007 expansion coincided with a diversification of trafficking routes to and through Australia (beyond the traditional site of entry-Sydney) and shifts in the geographic distribution of use. The congruity between indicators suggests that there has been a recent expansion in cocaine supply to and distribution within Australia, but that the more notable shift has concerned the nature of supply, with an apparent growth in importation and distribution beyond New South Wales. The diversification of cocaine supply routes may increase risks of market entrenchment and organised crime throughout Australia. © 2011 Australasian Professional Society on Alcohol and other Drugs.

  16. Assessing the effect of patterns of cocaine and alcohol use on the risk of adverse acute cocaine intoxication.

    Science.gov (United States)

    Santos, Sara; Brugal, M Teresa; Barrio, Gregorio; Castellano, Yolanda; Domingo-Salvany, Antonia; Espelt, Albert; Bravo, M Jose; de la Fuente, Luis

    2012-06-01

    Although, in the laboratory, most acute adverse effects of cocaine are dose-dependent and alcohol potentiates some of these effects, there are few observational studies, and scarce awareness that the risk of acute cocaine intoxication (ACI) can increase as the amounts of cocaine and alcohol consumed increase. Our objectives were to assess if the risk of ACI increases with the level cocaine use, both in chronic and binge use; and also to determine whether it increases when a cocaine binge is combined with binge drinking or with regular excessive drinking. Hypotheses were evaluated using logistic regression and case-crossover analyses in a sample of 720 young regular cocaine users who did not regularly use heroin, recruited at drug scenes in 2004-2006. All data on ACI, predictor and confounding variables were obtained through a computer-assisted personal interview. The annual prevalence of ACI was 21%. In the last year 10.3% of the participants reported cocaine binges (≥ 0.5 g in 4 h). ACI risk increased considerably in the 4 h following a cocaine binge (odds ratio = 34.6; 95% confidence interval 11.5-170.8). Also, it increased with increases in the average level of cocaine used over a long period and when users regularly drank excessively. Finally, the results suggest that the high risk of ACI associated with cocaine binge may increase even more when combined with binge drinking. Awareness of the dose-dependent effect of cocaine on ACI risk, as well as the possible synergistic effect of alcohol, ought to be incorporated into preventive and care strategies. © 2012 Australasian Professional Society on Alcohol and other Drugs.

  17. Six-month trial of bupropion with contingency management for cocaine dependence in a methadone-maintained population.

    Science.gov (United States)

    Poling, James; Oliveto, Alison; Petry, Nancy; Sofuoglu, Mehmet; Gonsai, Kishorchandra; Gonzalez, Gerardo; Martell, Bridget; Kosten, Thomas R

    2006-02-01

    No effective pharmacotherapies exist for cocaine dependence, although contingency management (CM) has demonstrated efficacy. To compare the efficacy of bupropion hydrochloride and CM for reducing cocaine use in methadone hydrochloride-maintained individuals. This 25-week, placebo-controlled, double-blind trial randomly assigned participants to 1 of 4 treatment conditions: CM and placebo (CMP), CM and 300 mg/d of bupropion hydrochloride (CMB), voucher control and placebo (VCP), or voucher control and bupropion (VCB). Outpatient clinic at the Veterans Affairs Connecticut Healthcare System. A total of 106 opiate-dependent, cocaine-abusing individuals. All study participants received methadone hydrochloride (range, 60-120 mg). Participants receiving bupropion hydrochloride were given 300 mg/d beginning at week 3. In the CM conditions, each urine sample negative for both opioids and cocaine resulted in a monetary-based voucher that increased for consecutively drug-free urine samples during weeks 1 to 13. Completion of abstinence-related activities also resulted in a voucher. During weeks 14 to 25, only completion of activities was reinforced in the CM group, regardless of sample results. The voucher control groups received vouchers for submitting urine samples, regardless of results, throughout the study. Thrice-weekly urine toxicologic test results for cocaine and heroin. Groups did not differ in baseline characteristics or retention rates. Opiate use decreased significantly, with all treatment groups attaining equivalent amounts of opiate use at the end of the study. In the CMB group, the proportion of cocaine-positive samples significantly decreased during weeks 3 to 13 (P<.001) relative to week 3 and remained low during weeks 14 to 25. In the CMP group, cocaine use significantly increased during weeks 3 to 13 (P<.001) relative to week 3, but then cocaine use significantly decreased relative to the initial slope during weeks 14 to 25 (P<.001). In contrast, by

  18. 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 ...

  19. Safety of atomoxetine in combination with intravenous cocaine in cocaine-experienced participants.

    Science.gov (United States)

    Cantilena, Louis; Kahn, Roberta; Duncan, Connie C; Li, Shou-Hua; Anderson, Ann; Elkashef, Ahmed

    2012-12-01

    Atomoxetine has been considered as an agonist replacement therapy for cocaine. We investigated the safety of the interaction of atomoxetine with cocaine and also whether cognitive function was affected by atomoxetine during short-term administration. In a double-blind placebo-controlled inpatient study of 20 cocaine-dependent volunteers, participants received atomoxetine 80 mg daily followed by 100 mg daily for 5 days each. On the fourth and fifth day at each dose, cocaine (20 and 40 mg) was infused intravenously in sequential daily sessions. Preinfusion mean systolic pressures showed a small but statistically significant difference between placebo and both doses of atomoxetine. Preinfusion mean diastolic pressures were significant between placebo and atomoxetine 80 mg only. The diastolic pressure response to 40 mg cocaine was statistically significant only between the 80- and 100-mg atomoxetine doses. All electrocardiogram parameters were unchanged. Visual Analog Scale (VAS) scores for "bad effect" in the atomoxetine group were significantly higher at baseline, then declined, and for "likely to use" declined with atomoxetine treatment. On the Addiction Research Center Inventory, the atomoxetine group scored significantly lower on amphetamine, euphoria, and energy subscales (P affect cocaine pharmacokinetics. In tests of working memory, sustained attention, cognitive flexibility, and decision-making, atomoxetine improved performance on the visual n-back task. There were no differences in any pharmacokinetic parameters for cocaine with atomoxetine. Atomoxetine was tolerated safely by all participants. Certain cognitive improvements and a dampening effect on VAS scores after cocaine were observed, but should be weighed against small but significant differences in hemodynamic responses after atomoxetine.

  20. Safety of Atomoxetine in Combination with Intravenous Cocaine in Cocaine- Experienced Participants

    Science.gov (United States)

    Cantilena, Louis; Kahn, Roberta; Duncan, Connie C.; Li, Shou-Hua; Anderson, Ann; Elkashef, Ahmed

    2012-01-01

    Objectives Atomoxetine has been considered as an agonist replacement therapy for cocaine. We investigated the safety of the interaction of atomoxetine with cocaine, and also whether cognitive function was affected by atomoxetine during short-term administration. Methods In a double-blind placebo-controlled inpatient study of 20 cocaine-dependent volunteers, participants received atomoxetine 80 mg daily followed by 100 mg daily for 5 days each. On the fourth and fifth day at each dose, cocaine (20 mg and 40 mg) was infused intravenously in sequential daily sessions. Results Pre-infusion mean systolic pressures showed a small but statistically significant difference between placebo and both doses of atomoxetine. Pre-infusion mean diastolic pressures were significant between placebo and atomoxetine 80 mg only. The diastolic pressure response to 40 mg cocaine was statistically significant only between the 80 mg and 100 mg atomoxetine doses. All ECG parameters were unchanged. VAS scores for “bad effect” in the atomoxetine group were significantly higher at baseline, then declined, and for “likely to use” declined with atomoxetine treatment. On the ARCI the atomoxetine group scored significantly lower on amphetamine, euphoria and energy subscales (pAtomoxetine did not affect cocaine pharmacokinetics. In tests of working memory, sustained attention, cognitive flexibility, and decision-making, atomoxetine improved performance on the visual n-back task. There were no differences in any pharmacokinetic parameters for cocaine with atomoxetine. Conclusions Atomoxetine was tolerated safely by all participants. Certain cognitive improvements and a dampening effect on VAS scores after cocaine were observed, but should be weighed against small but significant differences in hemodynamic responses after atomoxetine. PMID:22987022

  1. Bupropion perceived as a stimulant by two patients with a previous history of cocaine misuse

    Directory of Open Access Journals (Sweden)

    Alessandro E. Vento

    2013-12-01

    Full Text Available BACKGROUND AND OBJECTIVE: Despite animal studies having shown a generalisation of the bupropion cue to cocaine, this drug has been used in cocaine abuse with mixed results. We here aimed at describing two cases which contradict current knowledge. CASE REPORTS: We describe two cases of former cocaine abusers who reported a cocaine-like sensation upon taking bupropion. Bupropion improved patients' depression without any increase in cocaine craving. One of the patients increased without doctor consultation his dose on an as needed basis. CONCLUSIONS: The issue of bupropion cue generalisation to cocaine needs further elucidation. People with past cocaine addiction need to be informed on the potential of bupropion to elicit cocaine-like cues and be invited to adhere to medical prescription, because bupropion has been associated with fatalities in some cases.

  2. Neurotensin Agonist Attenuates Nicotine Potentiation to Cocaine Sensitization

    Directory of Open Access Journals (Sweden)

    Paul Fredrickson

    2014-01-01

    Full Text Available Tobacco usage typically precedes illicit drug use in adolescent and young adult populations. Several animal studies suggest nicotine increases the risk for subsequent cocaine abuse, and may be a negative prognostic factor for treatment of cocaine addiction; i.e., a “gateway drug”. Neurotensin (NT is a 13-amino acid neuropeptide that modulates dopamine, acetylcholine, glutamate, and GABA neurotransmission in brain reward pathways. NT69L, a NT(8-13 analog, blocks behavioral sensitization (an animal model for psychostimulant addiction to nicotine, and nicotine self-administration in rats. The present study tested the effect of NT69L on the potentiating effects of nicotine on cocaine-induced locomotor sensitization. Male Wistar rats were injected daily for seven days with nicotine or saline (control followed by four daily injections of cocaine. NT69L was administered 30 min prior to the last cocaine injection. Behavior was recorded with the use of activity chambers. Subchronic administration of nicotine enhanced cocaine-induced behavioral sensitization in Wistar rats, consistent with an hypothesized gateway effect. These behavioral effects of cocaine were attenuated by pretreatment with NT69L. The effect of the neurotensin agonist on cocaine sensitization in the nicotine treated group indicated a possible therapeutic effect for cocaine addiction, even in the presence of enhanced behavioral sensitization induced by nicotine.

  3. Cocaine enhances resistance to extinction of responding for brain-stimulation reward in adult prenatally stressed rats.

    Science.gov (United States)

    Gao, Shuibo; Suenaga, Toshiko; Oki, Yutaka; Yukie, Masao; Nakahara, Daiichiro

    2011-10-01

    The present experiment assessed whether prenatal stress (PS) can alter the ability of acute and chronic cocaine administration to increase and decrease the rewarding effectiveness of the medial forebrain bundle (MFB) using intracranial self-stimulation (ICSS), and also whether PS can affect the extinction of the MFB stimulation response. Adult male offspring of female rats that received PS or no PS (nPS) were implanted with MFB stimulating electrodes, and were then tested in ICSS paradigms. In both nPS and PS offspring, acute cocaine injection decreased ICSS thresholds dose-dependently. However, the threshold-lowering effects at any dose were not significantly different between groups. There was also no group-difference in the threshold-elevating effects of chronic cocaine administration. Nevertheless, chronically drug-administered PS rats exhibited a resistance to the extinguishing of the response for brain-stimulation reward when acutely treated with cocaine, as compared to extinction without cocaine treatment. The results suggest that PS may weaken the ability for response inhibition under cocaine loading in male adult offspring. Copyright © 2011 Elsevier B.V. All rights reserved.

  4. Effects of phendimetrazine treatment on cocaine vs food choice and extended-access cocaine consumption in rhesus monkeys.

    Science.gov (United States)

    Banks, Matthew L; Blough, Bruce E; Fennell, Timothy R; Snyder, Rodney W; Negus, S Stevens

    2013-12-01

    There is currently no Food and Drug Administration-approved pharmacotherapy for cocaine addiction. Monoamine releasers such as d-amphetamine constitute one class of candidate medications, but clinical use and acceptance are hindered by their own high-abuse liability. Phendimetrazine (PDM) is a schedule III anorectic agent that functions as both a low-potency monoamine-uptake inhibitor and as a prodrug for the monoamine-releaser phenmetrazine (PM), and it may serve as a clinically available, effective, and safer alternative to d-amphetamine. This study determined efficacy of chronic PDM to reduce cocaine self-administration by rhesus monkeys (N=4) using a novel procedure that featured both daily assessments of cocaine vs food choice (to assess medication efficacy to reallocate behavior away from cocaine choice and toward choice of an alternative reinforcer) and 20 h/day cocaine access (to allow high-cocaine intake). Continuous 21-day treatment with ramping PDM doses (days 1-7: 0.32 mg/kg/h; days 8-21: 1.0 mg/kg/h) reduced cocaine choices, increased food choices, and nearly eliminated extended-access cocaine self-administration without affecting body weight. There was a trend for plasma PDM and PM levels to correlate with efficacy to decrease cocaine choice such that the monkey with the highest plasma PDM and PM levels also demonstrated the greatest reductions in cocaine choice. These results support further consideration of PDM as a candidate anti-cocaine addiction pharmacotherapy. Moreover, PDM may represent a novel pharmacotherapeutic approach for cocaine addiction because it may simultaneously function as both a monoamine-uptake inhibitor (via the parent drug PDM) and as a monoamine releaser (via the active metabolite PM).

  5. 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.

  6. Optogenetic Central Amygdala Stimulation Intensifies and Narrows Motivation for Cocaine.

    Science.gov (United States)

    Warlow, Shelley M; Robinson, Mike J F; Berridge, Kent C

    2017-08-30

    Addiction is often characterized by intense motivation for a drug, which may be narrowly focused at the expense of other rewards. Here, we examined the role of amygdala-related circuitry in the amplification and narrowing of motivation focus for intravenous cocaine. We paired optogenetic channelrhodopsin (ChR2) stimulation in either central nucleus of amygdala (CeA) or basolateral amygdala (BLA) of female rats with one particular nose-poke porthole option for earning cocaine infusions (0.3 mg/kg, i.v.). A second alternative porthole earned identical cocaine but without ChR2 stimulation. Consequently, CeA rats quickly came to pursue their CeA ChR2-paired cocaine option intensely and exclusively, elevating cocaine intake while ignoring their alternative cocaine alone option. By comparison, BLA ChR2 pairing failed to enhance cocaine motivation. CeA rats also emitted consummatory bites toward their laser-paired porthole, suggesting that higher incentive salience made that cue more attractive. A separate progressive ratio test of incentive motivation confirmed that CeA ChR2 amplified rats' motivation, raising their breakpoint effort price for cocaine by 10-fold. However, CeA ChR2 laser on its own lacked any reinforcement value: laser by itself was never self-stimulated, not even by the same rats in which it amplified motivation for cocaine. Conversely, CeA inhibition by muscimol/baclofen microinjections prevented acquisition of cocaine self-administration and laser preference, whereas CeA inhibition by optogenetic halorhodopsin suppressed cocaine intake, indicating that CeA circuitry is needed for ordinary cocaine motivation. We conclude that CeA ChR2 excitation paired with a cocaine option specifically focuses and amplifies motivation to produce intense pursuit and consumption focused on that single target. SIGNIFICANCE STATEMENT In addiction, intense incentive motivation often becomes narrowly focused on a particular drug of abuse. Here we show that pairing central

  7. Impact of food restriction and cocaine on locomotion in ghrelin- and ghrelin-receptor knockout mice.

    Science.gov (United States)

    Clifford, Shane; Zeckler, Rosie Albarran; Buckman, Sam; Thompson, Jeff; Hart, Nigel; Wellman, Paul J; Smith, Roy G

    2011-07-01

    Food restriction (FR) augments the behavioral and reinforcing effects of psychomotor stimulants such as cocaine or amphetamine; effects that may be related to the capacity of FR to increase plasma levels of ghrelin (GHR), a 28-amino acid orexigenenic peptide linked to activation of brain dopamine systems. The present study used wild-type (WT) mice or mutant mice sustaining knockout of either GHR [GHR((-/-)) ] or of the growth hormone secretagogue receptor [GHS-R((-/-)) ] and subjected to FR or not to evaluate the role of GHR and GHS-R in cocaine-stimulated locomotion. WT, GHR((-/-)) , and GHS-R((-/-)) mice were either restricted to 60% of baseline caloric intake or allowed to free-feed (FF). Mice were treated with 0, 1.25, 2.5 and 5.0 mg/kg cocaine on separate test days (in random dose order) and forward locomotion was recorded on each drug day for 45 minutes after drug dosing. Food (and water) was available immediately after (but not during) each activity test. For FF mice, there was no interaction between cocaine and GHR status on locomotion. FR-WT mice treated with saline exhibited significant increases in anticipatory locomotion (relative to FF-WT mice), whereas FR-GHS-R((-/-)) mice did not. Cocaine significantly increased locomotion in FR-GHR((-/-)) and FR-GHS-R((-/-)) mice to the levels noted in FR-WT mice. These results suggest that GHS-R activity, but not GHR activity, is required for FR to augment food-associated anticipatory locomotion, but do not support the contention that GHR pathways are required for the capacity of FR to augment the acute effect of cocaine on locomotion. © 2010 The Authors, Addiction Biology © 2010 Society for the Study of Addiction.

  8. 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.

  9. 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.

  10. Cocaine effects on pulsatile secretion of anterior pituitary, gonadal, and adrenal hormones.

    Science.gov (United States)

    Mendelson, J H; Mello, N K; Teoh, S K; Ellingboe, J; Cochin, J

    1989-12-01

    Pulse frequency analysis of LH, PRL, testosterone, and cortisol was carried out with the Cluster Analysis Program in eight male cocaine abusers and eight aged-matched normal men. Four of the eight cocaine abusers had hyperprolactinemia (range, 22.08-44.65 micrograms/L). Cocaine users as a group had significantly higher mean peak height (P less than 0.02) than control subjects. Cocaine users with hyperprolactinemia had higher mean peak height than control subjects or cocaine users with normal PRL levels (P less than 0.01). Cocaine users with hyperprolactinemia also had higher mean amplitude increments than control subjects (P less than 0.02). Cocaine users with hyperprolactinemia had a higher mean valley than controls (P less than 0.01) and cocaine users with normal PRL levels (P less than 0.03). However, there were no significant differences in PRL peak frequency, peak duration, or interpulse intervals between cocaine users with or without hyperprolactinemia and control subjects. There were minimal differences between cocaine users and control subjects in pulse frequency analysis of LH parameters; the small differences in mean LH levels and average interpulse interval were not in the abnormal range and were probably not biologically significant. No differences between cocaine users and controls were detected for pulse frequency analysis of testosterone or cortisol. Cocaine-induced hyperprolactinemia may contribute to disorders of sexual and reproductive function in men who abuse the drug, and recent reports that PRL modulates immune function suggest that cocaine-induced derangements of PRL secretion may also contribute to cocaine-related comorbidity in infectious disease. Since cocaine users with hyperprolactinemia had a higher mean valley as well as a higher peak pulse PRL height than control subjects, but did not have greater PRL pulse frequencies, we conclude that hyperprolactinemia in these men may be due to a cocaine-induced derangement of dopaminergic

  11. Recurrent myocardial infarction in a young cocaine abuser | Stiha ...

    African Journals Online (AJOL)

    Cocaine increases the risk of cardiovascular diseases, including myocardial infarction. We herein describe a case of a 22-year-old man with a long history of cocaine abuse. He presented at our institution because of acute coronary syndrome with ST segment elevation. Emergency coronary angiography revealed ostial ...

  12. [Rhabdomyolysis in acute cocaine poisoning. Presentation of 2 cases].

    LENUS (Irish Health Repository)

    Bernad, M

    1990-12-01

    Because the important increase of cocaine abuse and the frequent pathology associated, we present two cases of males who had a multiorganic failure cause by severe rabdomyolysis, renal failure with myoglobinuria and disseminated intravascular coagulation, after the cocaine consumption. In one case a pancreatitis associated was observed, this not being described before. Both cases are recovered.

  13. Sex differences in psychiatric comorbidity and plasma biomarkers for cocaine addiction in abstinent cocaine-addicted subjects in outpatient settings

    Directory of Open Access Journals (Sweden)

    MARIA ePEDRAZ

    2015-02-01

    Full Text Available There are sex differences in the progression of drug addiction, relapse and response to therapies. Because biological factors participate in these differences, they should be considered when using biomarkers for addiction. In the current study, we evaluated the sex differences in psychiatric comorbidity and the concentrations of plasma mediators that have been reported to be affected by cocaine.Fifty-five abstinent cocaine-addicted subjects diagnosed with lifetime cocaine use disorders (40 men and 15 women and 73 healthy controls (48 men and 25 women were clinically assessed with the diagnostic interview ‘Psychiatric Research Interview for Substance and Mental Disorders’. Plasma concentrations of chemokines, cytokines, N-acyl-ethanolamines and 2-acyl-glycerols were analyzed according to history of cocaine addiction and sex.The results showed that the chemokine concentrations of CCL2/MCP-1 and CXCL12/SDF-1 were only affected by history of cocaine addiction. The plasma concentrations of IL-1β, IL-6, IL-10 and TNFα were higher in control women relative to men, but these concentrations were reduced in cocaine-addicted women. Cytokine concentrations were unaltered in addicted men. Regarding fatty acid derivatives, history of cocaine addiction had a main effect on the concentration of each acyl derivative; whereas N-acyl-ethanolamines were increased overall in the cocaine group, 2-acyl-glycerols were decreased. Interestingly, POEA was only increased in cocaine-addicted women.Regarding psychiatric comorbidity in the cocaine group, women had lower incidence rates of comorbid substance use disorders than did men. For example, alcohol use disorders were found in 80% of men and 40% of women. In contrast, the addicted women had increased prevalences of comorbid psychiatric disorders (mood, anxiety and psychosis disorders.These results demonstrate the existence of a sex influence on plasma biomarkers for cocaine addiction and on the presence of

  14. Perceived parenting behavior in the childhood of cocaine users: relationship with genotype and personality traits.

    Science.gov (United States)

    Gerra, G; Zaimovic, A; Garofano, L; Ciusa, F; Moi, G; Avanzini, P; Talarico, E; Gardini, F; Brambilla, F; Manfredini, M; Donnini, C

    2007-01-05

    Low parental care during childhood, a pattern characteristic of an "affectionless control" rearing style was frequently reported in the history of addicted individuals. Parents' childrearing regimes and children's genetic predispositions, with their own behavioral characteristics, have been seen to be closely interwoven, probably affecting children's development and addictive behavior susceptibility. In the present study, parents care perception, aggressive personality traits, and genotype (serotonin transporter promoter gene--5-HTTLPR) have been investigated in cocaine users and healthy control subjects. PBI scores (maternal and paternal care) were lower and BDHI scores (aggressiveness) higher in cocaine users in comparison with controls and significant differences in the perception of either paternal or maternal care were observed between cocaine users and non-users. The short-short (SS) genotype frequency was significantly higher among cocaine users compared with control subjects (P = 0.04). Logistic regression proves that persons bearing the SS genotype have a risk of becoming cocaine user almost three times higher than those having the LL genotype. Estimations of the effects of other factors potentially affecting the risk of being cocaine addicted clearly prove the significant impact of aggressiveness: the highest the score, the highest the risk of becoming cocaine user. Moreover, paternal and maternal care perception significantly improve the fit of the model (the log likelihood decreases passing from -105.9 to -89.8, LR test = 32.17, P-value = 0.0000). Each unit increase in the PBI score yields a significant 12% and 10% decrease of the risk of becoming cocaine user, respectively for paternal and maternal care. Interestingly, once controlled for the PBI score, the relative risk associated to the SS genotype drops strikingly and becomes no longer statistically significant. On the whole, our preliminary data suggest that the association between 5-HT transporter

  15. Spontaneous locomotor activity correlates with the degranulation of mast cells in the meninges rather than in the thalamus: disruptive effect of cocaine.

    Science.gov (United States)

    Larson, Alice A; Thomas, Mark J; McElhose, Alex; Kovács, Katalin J

    2011-06-13

    Mast cells are located in the central nervous system (CNS) of many mammals and stress induces their degranulation. We postulated that mast cells are associated with wakefulness and stimulatory tone in the CNS, as reflected by spontaneous motor activity. Because stress also precipitates drug-seeking behavior in cocaine addicts, we also postulated that cocaine manifests its effects through this relationship. We investigated the influence of single and repeated injections of cocaine on circulating corticosterone, motor activity and degranulation of mast cells in both the thalamus and meninges of mice. Mice were subjected to 5 consecutive days of cocaine or saline followed by a single injection of cocaine or saline 11 days later. Spontaneous locomotor activity was measure for 1h after the final injection before death. Neither a single injection nor prior treatment with cocaine increased motor activity compared to saline-injected controls, however, repeated administration of cocaine induced a significant sensitization to its behavioral effect when delivered 11 days later. In mice that received only saline, motor activity correlated positively with mast cell degranulation in the meninges but not in the thalamus. Cocaine, regardless of the treatment schedule, disrupted this correlation. The concentration of corticosterone did not differ amongst groups and did not correlate with either behavior or mast cell parameters in any group. The correlation between behavioral activity and the mast cell degranulation in the meninges suggests that these parameters are linked. The disruptive effect of cocaine on this relationship indicates a role downstream from mast cells in the regulation of motor activity. Copyright © 2011 Elsevier B.V. All rights reserved.

  16. Cocaine and Pavlovian fear conditioning: dose-effect analysis.

    Science.gov (United States)

    Wood, Suzanne C; Fay, Jonathan; Sage, Jennifer R; Anagnostaras, Stephan G

    2007-01-25

    Emerging evidence suggests that cocaine and other drugs of abuse can interfere with many aspects of cognitive functioning. The authors examined the effects of 0.1-15mg/kg of cocaine on Pavlovian contextual and cued fear conditioning in mice. As expected, pre-training cocaine dose-dependently produced hyperactivity and disrupted freezing. Surprisingly, when the mice were tested off-drug later, the group pre-treated with a moderate dose of cocaine (15mg/kg) displayed significantly less contextual and cued memory, compared to saline control animals. Conversely, mice pre-treated with a very low dose of cocaine (0.1mg/kg) showed significantly enhanced fear memory for both context and tone, compared to controls. These results were not due to cocaine's anesthetic effects, as shock reactivity was unaffected by cocaine. The data suggest that despite cocaine's reputation as a performance-enhancing and anxiogenic drug, this effect is seen only at very low doses, whereas a moderate dose disrupts hippocampus and amygdala-dependent fear conditioning.

  17. Polysomnographic Sleep Dysregulation in Cocaine Dependence

    Directory of Open Access Journals (Sweden)

    Edwin M. Valladares

    2007-01-01

    Full Text Available Insomnia and sleep disturbance are associated with declines in health functioning, alongwith increases in mortality risk. Given the prominence of reported sleep disturbance incocaine-dependent subjects and persistence into recovery, understanding the natureand severity of these disturbances in this population may help to identify relevantpathways that contribute to the increased mortality in cocaine dependence. Polysomnography provides a means of objectively characterizing sleep and, in turn, sleep disturbances. Few studies have used polysomnography to evaluate sleep incocaine-dependent persons, yet these studies have the potential to advance treatmentsthat will ultimately reduce morbidity in cocaine-dependent subjects.

  18. [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.

  19. Dehydroepiandrosterone Attenuates Cocaine-Seeking Behaviour Independently of Corticosterone Fluctuations.

    Science.gov (United States)

    Maayan, R; Hirsh, L; Yadid, G; Weizman, A

    2015-11-01

    The neurosteroid dehydroepiandrosterone (DHEA) is involved in the pathophysiology of several psychiatric disorders, including cocaine addiction. We have previously shown that DHEA attenuates cocaine-seeking behaviour, and also that DHEA decreases corticosterone (CORT) levels in plasma and the prefrontal cortex. Previous studies have found that rats demonstrate cocaine-seeking behaviour only when the level of CORT reaches a minimum threshold. In the present study, we investigated whether the attenuating effect of DHEA on cocaine seeking is a result of it reducing CORT levels rather than a result of any unique neurosteroid properties. Rats received either daily DHEA injections (2 mg/kg, i.p.) alone, daily DHEA (2 mg/kg, i.p.) with CORT infusion (to maintain stable basal levels of CORT; 15 mg/kg, s.c.) or vehicle (i.p.) as control, throughout self-administration training and extinction sessions. We found that both DHEA-treated and DHEA + CORT-treated groups showed a significantly lower number of active lever presses compared to controls throughout training and extinction sessions, as well as at cocaine-primed reinstatement. DHEA-treated rats showed lower CORT levels throughout the experimental phases compared to DHEA + CORT-treated and control rats. Additionally, we show that DHEA administered to cocaine-trained rats throughout extinction sessions, or immediately before reinstatement, attenuated cocaine seeking. These findings indicate that DHEA attenuates cocaine-seeking behaviour independently of fluctuations in CORT levels. © 2015 British Society for Neuroendocrinology.

  20. Chronic cocaine administration induces opposite changes in dopamine receptors in the striatum and nucleus accumbens

    International Nuclear Information System (INIS)

    Goeders, N.E.; Kuhar, M.J.

    1987-01-01

    A variety of clinical and animal data suggest that the repeated administration of cocaine and related psychomotor stimulants may be associated with a behavioral sensitization whereby the same dose of the drug results in increasing behavioral pathology. This investigation was designed to determine the effects of chronic cocaine administration on the binding of [ 3 H]sulpiride, a relatively specific ligand for D2 dopaminergic receptors, in the rat brain using in vitro homogenate binding and light microscopic quantitative autoradiographic methodologies. Chronic daily injections of cocaine (10 mg/kg, i.p.) for 15 days resulted in a significant decrease in the maximum concentration of sulpiride binding sites in the striatum and a significant increase in the maximum number of these binding sites in the nucleus accumbens. No significant differences in binding affinity were observed in either brain region. These data suggest that chronic cocaine administration may result in differential effects on D2 receptors in the nigro-striatal and mesolimbic dopaminergic systems

  1. Retrieval-induced NMDA receptor-dependent Arc expression in two models of cocaine-cue memory.

    Science.gov (United States)

    Alaghband, Yasaman; O'Dell, Steven J; Azarnia, Siavash; Khalaj, Anna J; Guzowski, John F; Marshall, John F

    2014-12-01

    The association of environmental cues with drugs of abuse results in persistent drug-cue memories. These memories contribute significantly to relapse among addicts. While conditioned place preference (CPP) is a well-established paradigm frequently used to examine the modulation of drug-cue memories, very few studies have used the non-preference-based model conditioned activity (CA) for this purpose. Here, we used both experimental approaches to investigate the neural substrates of cocaine-cue memories. First, we directly compared, in a consistent setting, the involvement of cortical and subcortical brain regions in cocaine-cue memory retrieval by quantifying activity-regulated cytoskeletal-associated (Arc) protein expression in both the CPP and CA models. Second, because NMDA receptor activation is required for Arc expression, we investigated the NMDA receptor dependency of memory persistence using the CA model. In both the CPP and CA models, drug-paired animals showed significant increases in Arc immunoreactivity in regions of the frontal cortex and amygdala compared to unpaired controls. Additionally, administration of a NMDA receptor antagonist (MK-801 or memantine) immediately after cocaine-CA memory reactivation impaired the subsequent conditioned locomotion associated with the cocaine-paired environment. The enhanced Arc expression evident in a subset of corticolimbic regions after retrieval of a cocaine-context memory, observed in both the CPP and CA paradigms, likely signifies that these regions: (i) are activated during retrieval of these memories irrespective of preference-based decisions, and (ii) undergo neuroplasticity in order to update information about cues previously associated with cocaine. This study also establishes the involvement of NMDA receptors in maintaining memories established using the CA model, a characteristic previously demonstrated using CPP. Overall, these results demonstrate the utility of the CA model for studies of cocaine

  2. Extinction of conditioned cues attenuates incubation of cocaine craving in adolescent and adult rats.

    Science.gov (United States)

    Madsen, Heather B; Zbukvic, Isabel C; Luikinga, Sophia J; Lawrence, Andrew J; Kim, Jee Hyun

    2017-09-01

    Relapse to drug use is often precipitated by exposure to drug associated cues that evoke craving. Cue-induced drug craving has been observed in both animals and humans to increase over the first few weeks of abstinence and remain high over extended periods, a phenomenon known as 'incubation of craving'. As adolescence represents a period of vulnerability to developing drug addiction, potentially due to persistent reactivity to drug associated cues, we first compared incubation of cocaine craving in adolescent and adult rats. Adolescent (P35) and adult (P70) rats were trained to lever press to obtain intravenous cocaine, with each drug delivery accompanied by a light cue that served as the conditioned stimulus (CS). Following acquisition of stable responding, rats were tested for cue-induced cocaine-seeking after either 1 or 30days of abstinence. Additional groups of rats were also tested after 30days of abstinence, however these rats were subjected to a cue extinction session 1week into the abstinence period. Rats were injected with aripiprazole, a dopamine 2 receptor (D2R)-like partial agonist, or vehicle, 30min prior to cue extinction. We found that adolescent and adult rats acquired and maintained a similar level of cocaine self-administration, and rats of both ages exhibited a higher level of cue-induced cocaine-seeking if they were tested after 30days of abstinence compared to 1day. Incubation of cocaine craving was significantly reduced to 1day levels in both adults and adolescents that received cue extinction training. Administration of aripiprazole prior to cue extinction did not further reduce cue-induced drug-seeking. These results indicate that cue extinction training during abstinence may effectively reduce cue-induced relapse at a time when cue-induced drug craving is usually high. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Continuous background light significantly increases flashing-light enhancement of photosynthesis and growth of microalgae.

    Science.gov (United States)

    Abu-Ghosh, Said; Fixler, Dror; Dubinsky, Zvy; Iluz, David

    2015-01-01

    Under specific conditions, flashing light enhances the photosynthesis rate in comparison to continuous illumination. Here we show that a combination of flashing light and continuous background light with the same integrated photon dose as continuous or flashing light alone can be used to significantly enhance photosynthesis and increase microalgae growth. To test this hypothesis, the green microalga Dunaliella salina was exposed to three different light regimes: continuous light, flashing light, and concomitant application of both. Algal growth was compared under three different integrated light quantities; low, intermediate, and moderately high. Under the combined light regime, there was a substantial increase in all algal growth parameters, with an enhanced photosynthesis rate, within 3days. Our strategy demonstrates a hitherto undescribed significant increase in photosynthesis and algal growth rates, which is beyond the increase by flashing light alone. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. St. John's wort significantly increased the systemic exposure and toxicity of methotrexate in rats

    International Nuclear Information System (INIS)

    Yang, Shih-Ying; Juang, Shin-Hun; Tsai, Shang-Yuan; Chao, Pei-Dawn Lee; Hou, Yu-Chi

    2012-01-01

    St. John's wort (SJW, Hypericum perforatum) is one of the popular nutraceuticals for treating depression. Methotrexate (MTX) is an immunosuppressant with narrow therapeutic window. This study investigated the effect of SJW on MTX pharmacokinetics in rats. Rats were orally given MTX alone and coadministered with 300 and 150 mg/kg of SJW, and 25 mg/kg of diclofenac, respectively. Blood was withdrawn at specific time points and serum MTX concentrations were assayed by a specific monoclonal fluorescence polarization immunoassay method. The results showed that 300 mg/kg of SJW significantly increased the AUC 0−t and C max of MTX by 163% and 60%, respectively, and 150 mg/kg of SJW significantly increased the AUC 0−t of MTX by 55%. In addition, diclofenac enhanced the C max of MTX by 110%. The mortality of rats treated with SJW was higher than that of controls. In conclusion, coadministration of SJW significantly increased the systemic exposure and toxicity of MTX. The combined use of MTX with SJW would need to be with caution. -- Highlights: ► St. John's wort significantly increased the AUC 0−t and C max of methotrexate. ► Coadministration of St. John's wort increased the exposure and toxicity of methotrexate. ► The combined use of methotrexate with St. John's wort will need to be with caution.

  5. 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.

  6. Increased frequency of retinopathy of prematurity over the last decade and significant regional differences.

    Science.gov (United States)

    Holmström, Gerd; Tornqvist, Kristina; Al-Hawasi, Abbas; Nilsson, Åsa; Wallin, Agneta; Hellström, Ann

    2018-03-01

    Retinopathy of prematurity (ROP) causes childhood blindness globally in prematurely born infants. Although increased levels of oxygen supply lead to increased survival and reduced frequency of cerebral palsy, increased incidence of ROP is reported. With the help of a Swedish register for ROP, SWEDROP, national and regional incidences of ROP and frequencies of treatment were evaluated from 2008 to 2015 (n = 5734), as well as before and after targets of provided oxygen changed from 85-89% to 91-95% in 2014. Retinopathy of prematurity (ROP) was found in 31.9% (1829/5734) of all infants with a gestational age (GA) of <31 weeks at birth and 5.7% of the infants (329/5734) had been treated for ROP. Analyses of the national data revealed an increased incidence of ROP during the 8-year study period (p = 0.003), but there was no significant increase in the frequency of treatment. There were significant differences between the seven health regions of Sweden, regarding both incidence of ROP and frequency of treatment (p < 0.001). Comparison of regional data before and after the new oxygen targets revealed a significant increase in treated ROP in one region [OR: 2.24 (CI: 1.11-4.49), p = 0.024] and a borderline increase in one other [OR: 3.08 (CI: 0.99-9.60), p = 0.052]. The Swedish national ROP register revealed an increased incidence of ROP during an 8-year period and significant regional differences regarding the incidence of ROP and frequency of treatment. © 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  7. Cocaine smuggling from Bolivia to Atlantic ports may exploit commercial trade on Mercosur Hidrovia, lacking a waterways management strategy

    Science.gov (United States)

    1997-10-01

    Bolivian cocaine production has been increasing and Argentine traffickers are playing a greater role in direct exportation of Bolivian cocaine to the United States and Europe. Development of the Paraguay-Parana river system (Hidrovia) into an efficie...

  8. THE SMALL BUT SIGNIFICANT AND NONTRANSITORY INCREASE IN PRICES (SSNIP TEST

    Directory of Open Access Journals (Sweden)

    Liviana Niminet

    2008-12-01

    Full Text Available The Small but Significant Nontransitory Increase in Price Test was designed to define the relevant market by concepts of product, geographical area and time. This test, also called the ,,hypothetical monopolistic test” is the subject of many researches both economical and legal as it deals with economic concepts as well as with legally aspects.

  9. The effects of exogenous progesterone on drug craving and stress arousal in cocaine dependence: impact of gender and cue type.

    Science.gov (United States)

    Fox, Helen C; Sofuoglu, Mehmet; Morgan, Peter T; Tuit, Keri L; Sinha, Rajita

    2013-09-01

    Exogenous progesterone has been shown to attenuate the rewarding effects of cocaine. However, its effects on provoked drug craving, stress arousal and cognitive performance has not been systematically investigated in cocaine dependent men and women. Thus, we conducted a double-blind placebo-controlled study assessing the efficacy of progesterone in reducing provoked drug craving, stress system arousal and improving cognitive performance in cocaine dependent men and women. Forty-two early abstinent treatment-seeking cocaine dependent individuals were randomly assigned to either daily doses of placebo (12M/9F) or micronized progesterone (12M/9F) (400 mg/day), for 7 days. Under experimental conditions, all subjects were exposed to three 5-min personalized guided imagery conditions (stress, cocaine cue, relaxing), one per day, consecutively in a random, counterbalanced order. Subjective craving, mood, hypothalamic-pituitary-adrenal (HPA) and cardiovascular output, and a cognitive measure of inhibitory control (Stroop Color Word Task) were assessed pre- and post imagery. Progesterone relative to placebo significantly decreased cue-induced craving and cortisol responses and increased cue-induced ACTH. In addition, women but not men receiving progesterone reported lower ratings of negative emotion and higher ratings of relaxed mood following stress exposure. Improved Stroop performance was observed in all participants receiving progesterone, across all conditions. Progesterone was selectively effective in reducing cocaine cue-induced but not stress-related cocaine craving as well as specific measures of the provoked arousal state. Findings suggest that progesterone's effects on drug craving and arousal are moderated by both the type of environmental cue exposure and gender. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. 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 ...

  11. 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 ...

  12. The selective dopamine uptake inhibitor, D-84, suppresses cocaine self-administration, but does not occasion cocaine-like levels of generalization.

    Science.gov (United States)

    Batman, Angela M; Dutta, Aloke K; Reith, Maarten E A; Beardsley, Patrick M

    2010-12-01

    A successful replacement pharmacotherapy for treating cocaine dependency would likely reduce cocaine's abuse, support a low abuse liability, overlap cocaine's subjective effects, and have a long duration of action. Inhibitors with varying selectivity at the dopamine transporter (DAT) have approximated these properties. The objective of the present study was to characterize the behavioural effects of an extremely selective DAT inhibitor, (+) trans-4-(2-Benzhydryloxyethyl)-1-(4-fluorobenzyl) piperadin-3-ol (D-84), a 3-hydroxy substituted piperidine derivative of GBR-12935, for its cocaine-like discriminative stimulus effects, its effects on cocaine self-administration, and for its own self-administration. During cocaine discrimination tests, cocaine occasioned the 10 mg/kg cocaine training stimulus with an ED(50) value of 3.13 (1.54-6.34) mg/kg, and reduced response rates with an ED(50) value of 20.39 (7.24-57.44) mg/kg. D-84 incompletely generalized to the cocaine stimulus occasioning a maximal 76% cocaine-lever responding, while reducing response rates with lower potency than cocaine (ED(50)=30.94 (12.34-77.60) mg/kg). Pretreatment with D-84 (9.6-30.4 mg/kg) significantly (P<0.05) reduced cocaine intake at 17.1 mg/kg D-84 when cocaine was self-administered at 0.5 mg/kg/infusion, and at 30.4 mg/kg D-84 when cocaine was self-administered at 0.1, 0.5 .and 1.0 mg/kg/infusion. During self-administration tests with D-84 (0.1-1 mg/kg/infusion), numbers of infusions significantly exceeded vehicle levels at 0.3 mg/kg/infusion. These results show that D-84 pretreatment can decrease cocaine intake especially when high doses of cocaine are being self-administered. This observation, combined with its incomplete generalization to the cocaine discriminative stimulus and its reported long duration of action, provides a profile consistent with a potential replacement therapy for treating cocaine-abusing patients. Copyright © 2010 Elsevier B.V. All rights reserved.

  13. Salivary buffer capacity, pH, and stimulated flow rate of crack cocaine users.

    Science.gov (United States)

    Woyceichoski, Iverson Ernani Cogo; Costa, Carlos Henrique; de Araújo, Cristiano Miranda; Brancher, João Armando; Resende, Luciane Grochocki; Vieira, Iran; de Lima, Antonio Adilson Soares

    2013-08-01

    Crack cocaine is the freebase form of cocaine that can be smoked. The use of this drug has been considered a public health problem in many countries. The aim of this study was to assess the stimulated salivary flow rate (SSFR), pH, and the buffer capacity of saliva in crack cocaine users. Stimulated whole saliva was collected from 54 selected crack cocaine users and 40 non-users. All samples were analyzed for SSFR, pH, and buffer capacity. SSFR was analyzed by gravimetric method. The buffer capacity and pH were determined using a digital pH meter. The crack cocaine users demonstrated higher buffer capacity than the control group (P > 0.05). Salivary pH was lower in crack cocaine users (P 0.05). Crack cocaine users might exhibit a significant decrease in salivary pH, but not in salivary flow rate or buffer capacity. © 2012 Blackwell Publishing Asia Pty Ltd.

  14. Evaluation of Significance of Diffusely Increased Bilateral Renal Uptake on Bone Scan

    Energy Technology Data Exchange (ETDEWEB)

    Sung, Mi Sook; Yang, Woo Jin; Byun, Jae Young; Park, Jung Mi; Shinn, Kyung Sub; Bahk, Yong Whee [Catholic University College of Medicine, Seoul (Korea, Republic of)

    1990-03-15

    Unexpected renal abnormality can be detected on bone scan using {sup 99m}Tc-MDP. The purpose of the study is to evaluate the diagnostic significance of diffusely increased bilateral renal uptake on bone scan. 1,500 bone scan were reviewed and 43 scans which showed diffusely increased bilateral renal uptake were selected for analysis. Laboratory findings for renal and liver function tests including routine urinalysis were reviewed in 43 patients. 26 of 43 case showed abnormality in urinalysis and renal function study. 20 of 43 cases showed abnormal liver function study and 3 of these cases were diagnosed as hepatorenal syndrome later. 13 of those 20 cases had liver cirrhosis with or without hepatoma. 12 of 43 cases showed abnormality both in renal and liver function studies. 2 of 43 cases showed diffusely increased bilateral renal uptake after chemotherapy for cancer but not on previous scans before chemotherapy. 2 of 43 cases showed hypercalcaemia and 8 of 43 cases had multifocal bone uptake due to metastasis or benign bone lesion. But the latter showed no hypercalcaemia at all. There was no significant correlation between increased renal uptake and MDP uptake in soft tissue other than kidneys. This study raised the possibility that the impaired liver and/or renal function may result in diffuse increase of bilateral renal uptake of MDP of unknown mechanism. It seems to need further study on this correlation.

  15. Evaluation of Significance of Diffusely Increased Bilateral Renal Uptake on Bone Scan

    International Nuclear Information System (INIS)

    Sung, Mi Sook; Yang, Woo Jin; Byun, Jae Young; Park, Jung Mi; Shinn, Kyung Sub; Bahk, Yong Whee

    1990-01-01

    Unexpected renal abnormality can be detected on bone scan using 99m Tc-MDP. The purpose of the study is to evaluate the diagnostic significance of diffusely increased bilateral renal uptake on bone scan. 1,500 bone scan were reviewed and 43 scans which showed diffusely increased bilateral renal uptake were selected for analysis. Laboratory findings for renal and liver function tests including routine urinalysis were reviewed in 43 patients. 26 of 43 case showed abnormality in urinalysis and renal function study. 20 of 43 cases showed abnormal liver function study and 3 of these cases were diagnosed as hepatorenal syndrome later. 13 of those 20 cases had liver cirrhosis with or without hepatoma. 12 of 43 cases showed abnormality both in renal and liver function studies. 2 of 43 cases showed diffusely increased bilateral renal uptake after chemotherapy for cancer but not on previous scans before chemotherapy. 2 of 43 cases showed hypercalcaemia and 8 of 43 cases had multifocal bone uptake due to metastasis or benign bone lesion. But the latter showed no hypercalcaemia at all. There was no significant correlation between increased renal uptake and MDP uptake in soft tissue other than kidneys. This study raised the possibility that the impaired liver and/or renal function may result in diffuse increase of bilateral renal uptake of MDP of unknown mechanism. It seems to need further study on this correlation.

  16. 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

  17. 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

  18. Drivers under the influence of drugs of abuse: quantification of cocaine and impaired driving.

    Science.gov (United States)

    Arroyo, Amparo; Sánchez, Marta; Barberia, Eneko; Barbal, Maria; Marrón, M Teresa; Mora, Agustí

    2013-01-01

    In recent years, the interest in oral fluid as a biological matrix has significantly increased, particularly for detecting driving under the influence of drugs. In this study, the concentration of cocaine and its relationship with clinical symptoms in drivers suspected of driving under the influence of drugs was evaluated. A total of 154 samples of oral fluid, which tested positive for cocaine in previous immunoassay screening, Cozart Drug Detector System, were confirmed using gas chromatography/mass spectrometry method. In Catalonia, during 2007-2010, there were 1791 samples positive for cocaine among a total of 3468 samples taken from drivers who tested positive for any drug of abuse. The evaluation of clinical symptoms was through a questionnaire that was filled in by the police officers who collected the samples. The mean concentration of cocaine was 4.11 mg/l and median concentration was 0.38 mg/l (range 0.01-345.64 mg/l). Clinical impairment symptoms such as motor coordination, walking, speech, mood and state of pupils were not significant. The testing of oral fluids presents fewer ethical problems than blood or urine.

  19. Introducing extra NADPH consumption ability significantly increases the photosynthetic efficiency and biomass production of cyanobacteria.

    Science.gov (United States)

    Zhou, Jie; Zhang, Fuliang; Meng, Hengkai; Zhang, Yanping; Li, Yin

    2016-11-01

    Increasing photosynthetic efficiency is crucial to increasing biomass production to meet the growing demands for food and energy. Previous theoretical arithmetic analysis suggests that the light reactions and dark reactions are imperfectly coupled due to shortage of ATP supply, or accumulation of NADPH. Here we hypothesized that solely increasing NADPH consumption might improve the coupling of light reactions and dark reactions, thereby increasing the photosynthetic efficiency and biomass production. To test this hypothesis, an NADPH consumption pathway was constructed in cyanobacterium Synechocystis sp. PCC 6803. The resulting extra NADPH-consuming mutant grew much faster and achieved a higher biomass concentration. Analyses of photosynthesis characteristics showed the activities of photosystem II and photosystem I and the light saturation point of the NADPH-consuming mutant all significantly increased. Thus, we demonstrated that introducing extra NADPH consumption ability is a promising strategy to increase photosynthetic efficiency and to enable utilization of high-intensity lights. Copyright © 2016 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

  20. Cocaine promotes oxidative stress and microglial-macrophage activation in rat cerebellum

    Directory of Open Access Journals (Sweden)

    Rosa M López-Pedrajas

    2015-07-01

    Full Text Available Different mechanisms have been suggested for cocaine neurotoxicity, including oxidative stress alterations. Nuclear factor kappa B (NF-κB, considered a sensor of oxidative stress and inflammation, is involved in drug toxicity and addiction. NF-κB is a key mediator for immune responses that induces microglial/macrophage activation under inflammatory processes and neuronal injury/degeneration. Although cerebellum is commonly associated to motor control, muscular tone and balance. Its relation with addiction is getting relevance, being associated to compulsive and perseverative behaviors. Some reports indicate that cerebellar microglial activation induced by cannabis or ethanol, promote cerebellar alterations and these alterations could be associated to addictive-related behaviors. After considering the effects of some drugs on cerebellum, the aim of the present work analyzes pro-inflammatory changes after cocaine exposure. Rats received daily 15 mg/kg cocaine i.p. for 18 days. Reduced and oxidized forms of glutathione (GSH and GSSG, glutathione peroxidase (GPx activity and glutamate were determined in cerebellar homogenates. NF-κB activity, CD68 and GFAP expression were determined.Cerebellar GPx activity and GSH/GSSG ratio are significantly decreased after cocaine exposure. A significant increase of glutamate concentration is also observed. Interestingly, increased NF-κB activity is also accompanied by an increased expression of the lysosomal mononuclear phagocytic marker ED1 without GFAP alterations.Current trends in addiction biology are focusing on the role of cerebellum on addictive behaviors. Cocaine-induced cerebellar changes described herein fit with previosus data showing cerebellar alterations on addict subjects and support the proposed role of cerebelum in addiction.

  1. Hydrologic effects of large southwestern USA wildfires significantly increase regional water supply: fact or fiction?

    Science.gov (United States)

    Wine, M. L.; Cadol, D.

    2016-08-01

    In recent years climate change and historic fire suppression have increased the frequency of large wildfires in the southwestern USA, motivating study of the hydrological consequences of these wildfires at point and watershed scales, typically over short periods of time. These studies have revealed that reduced soil infiltration capacity and reduced transpiration due to tree canopy combustion increase streamflow at the watershed scale. However, the degree to which these local increases in runoff propagate to larger scales—relevant to urban and agricultural water supply—remains largely unknown, particularly in semi-arid mountainous watersheds co-dominated by winter snowmelt and the North American monsoon. To address this question, we selected three New Mexico watersheds—the Jemez (1223 km2), Mogollon (191 km2), and Gila (4807 km2)—that together have been affected by over 100 wildfires since 1982. We then applied climate-driven linear models to test for effects of fire on streamflow metrics after controlling for climatic variability. Here we show that, after controlling for climatic and snowpack variability, significantly more streamflow discharged from the Gila watershed for three to five years following wildfires, consistent with increased regional water yield due to enhanced infiltration-excess overland flow and groundwater recharge at the large watershed scale. In contrast, we observed no such increase in discharge from the Jemez watershed following wildfires. Fire regimes represent a key difference between the contrasting responses of the Jemez and Gila watersheds with the latter experiencing more frequent wildfires, many caused by lightning strikes. While hydrologic dynamics at the scale of large watersheds were previously thought to be climatically dominated, these results suggest that if one fifth or more of a large watershed has been burned in the previous three to five years, significant increases in water yield can be expected.

  2. 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.

  3. 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.

  4. Cocaine Administration and Its Withdrawal Enhance the Expression of Genes Encoding Histone-Modifying Enzymes and Histone Acetylation in the Rat Prefrontal Cortex.

    Science.gov (United States)

    Sadakierska-Chudy, Anna; Frankowska, Małgorzata; Jastrzębska, Joanna; Wydra, Karolina; Miszkiel, Joanna; Sanak, Marek; Filip, Małgorzata

    2017-07-01

    Chronic exposure to cocaine, craving, and relapse are attributed to long-lasting changes in gene expression arising through epigenetic and transcriptional mechanisms. Although several brain regions are involved in these processes, the prefrontal cortex seems to play a crucial role not only in motivation and decision-making but also in extinction and seeking behavior. In this study, we applied cocaine self-administration and extinction training procedures in rats with a yoked triad to determine differentially expressed genes in prefrontal cortex. Microarray analysis showed significant upregulation of several genes encoding histone modification enzymes during early extinction training. Subsequent real-time PCR testing of these genes following cocaine self-administration or early (third day) and late (tenth day) extinction revealed elevated levels of their transcripts. Interestingly, we found the enrichment of Brd1 messenger RNA in rats self-administering cocaine that lasted until extinction training during cocaine withdrawal with concomitant increased acetylation of H3K9 and H4K8. However, despite elevated levels of methyl- and demethyltransferase-encoded transcripts, no changes in global di- and tri-methylation of histone H3 at lysine 4, 9, 27, and 79 were observed. Surprisingly, at the end of extinction training (10 days of cocaine withdrawal), most of the analyzed genes in the rats actively and passively administering cocaine returned to the control level. Together, the alterations identified in the rat prefrontal cortex may suggest enhanced chromatin remodeling and transcriptional activity induced by early cocaine abstinence; however, to know whether they are beneficial or not for the extinction of drug-seeking behavior, further in vivo evaluation is required.

  5. Breast-cancer-associated metastasis is significantly increased in a model of autoimmune arthritis.

    Science.gov (United States)

    Das Roy, Lopamudra; Pathangey, Latha B; Tinder, Teresa L; Schettini, Jorge L; Gruber, Helen E; Mukherjee, Pinku

    2009-01-01

    Sites of chronic inflammation are often associated with the establishment and growth of various malignancies including breast cancer. A common inflammatory condition in humans is autoimmune arthritis (AA) that causes inflammation and deformity of the joints. Other systemic effects associated with arthritis include increased cellular infiltration and inflammation of the lungs. Several studies have reported statistically significant risk ratios between AA and breast cancer. Despite this knowledge, available for a decade, it has never been questioned if the site of chronic inflammation linked to AA creates a milieu that attracts tumor cells to home and grow in the inflamed bones and lungs which are frequent sites of breast cancer metastasis. To determine if chronic inflammation induced by autoimmune arthritis contributes to increased breast cancer-associated metastasis, we generated mammary gland tumors in SKG mice that were genetically prone to develop AA. Two breast cancer cell lines, one highly metastatic (4T1) and the other non-metastatic (TUBO) were used to generate the tumors in the mammary fat pad. Lung and bone metastasis and the associated inflammatory milieu were evaluated in the arthritic versus the non-arthritic mice. We report a three-fold increase in lung metastasis and a significant increase in the incidence of bone metastasis in the pro-arthritic and arthritic mice compared to non-arthritic control mice. We also report that the metastatic breast cancer cells augment the severity of arthritis resulting in a vicious cycle that increases both bone destruction and metastasis. Enhanced neutrophilic and granulocytic infiltration in lungs and bone of the pro-arthritic and arthritic mice and subsequent increase in circulating levels of proinflammatory cytokines, such as macrophage colony stimulating factor (M-CSF), interleukin-17 (IL-17), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and tumor necrosis factor-alpha (TNF-alpha) may contribute

  6. Breast cancer-associated metastasis is significantly increased in a model of autoimmune arthritis

    Science.gov (United States)

    Das Roy, Lopamudra; Pathangey, Latha B; Tinder, Teresa L; Schettini, Jorge L; Gruber, Helen E; Mukherjee, Pinku

    2009-01-01

    Introduction Sites of chronic inflammation are often associated with the establishment and growth of various malignancies including breast cancer. A common inflammatory condition in humans is autoimmune arthritis (AA) that causes inflammation and deformity of the joints. Other systemic effects associated with arthritis include increased cellular infiltration and inflammation of the lungs. Several studies have reported statistically significant risk ratios between AA and breast cancer. Despite this knowledge, available for a decade, it has never been questioned if the site of chronic inflammation linked to AA creates a milieu that attracts tumor cells to home and grow in the inflamed bones and lungs which are frequent sites of breast cancer metastasis. Methods To determine if chronic inflammation induced by autoimmune arthritis contributes to increased breast cancer-associated metastasis, we generated mammary gland tumors in SKG mice that were genetically prone to develop AA. Two breast cancer cell lines, one highly metastatic (4T1) and the other non-metastatic (TUBO) were used to generate the tumors in the mammary fat pad. Lung and bone metastasis and the associated inflammatory milieu were evaluated in the arthritic versus the non-arthritic mice. Results We report a three-fold increase in lung metastasis and a significant increase in the incidence of bone metastasis in the pro-arthritic and arthritic mice compared to non-arthritic control mice. We also report that the metastatic breast cancer cells augment the severity of arthritis resulting in a vicious cycle that increases both bone destruction and metastasis. Enhanced neutrophilic and granulocytic infiltration in lungs and bone of the pro-arthritic and arthritic mice and subsequent increase in circulating levels of proinflammatory cytokines, such as macrophage colony stimulating factor (M-CSF), interleukin-17 (IL-17), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and tumor necrosis factor

  7. Initial validation of a proxy indicator of functioning as a potential tool for establishing a clinically meaningful cocaine use outcome.

    Science.gov (United States)

    Kiluk, Brian D; Babuscio, Theresa A; Nich, Charla; Carroll, Kathleen M

    2017-10-01

    Establishing a non-abstinence cocaine use outcome as clinically meaningful has been elusive, in part due to the lack of association between cocaine use outcomes and meaningful indicators of long-term functioning. Using data pooled across 7 clinical trials evaluating treatments for cocaine (N=718), a dichotomous indicator of functioning was created to represent a meaningful outcome ('problem-free functioning' - PFF), defined as the absence of problems across non-substance-related domains on the Addiction Severity Index. Its validity was evaluated at multiple time points (baseline, end-of-treatment, terminal follow-up) and used to explore associations with cocaine use. The percentage of participants meeting PFF criteria increased over time (baseline=18%; end-of-treatment=32%; terminal follow-up=37%). At each time point, ANOVAs indicated those who met PFF criteria reported significantly less distress on the Brief Symptom Inventory and less perceived stress on the Perceived Stress Scale. Generalized linear models indicated categorical indices of self-reported cocaine use at the end of treatment were predictive of the probability of meeting PFF criteria during follow-up (β=-0.01, pcocaine use in the final month of treatment was associated with PFF during follow-up, with strongest associations between PFF and abstinence or 'occasional' use. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Changes in brain-derived neurotrophic factor (BDNF) during abstinence could be associated with relapse in cocaine-dependent patients.

    Science.gov (United States)

    Corominas-Roso, Margarida; Roncero, Carlos; Daigre, Constanza; Grau-Lopez, Lara; Ros-Cucurull, Elena; Rodríguez-Cintas, Laia; Sanchez-Mora, Cristina; Lopez, Maria Victoria; Ribases, Marta; Casas, Miguel

    2015-02-28

    Brain-derived neurotrophic factor (BDNF) is involved in cocaine craving in humans and drug seeking in rodents. Based on this, the aim of this study was to explore the possible role of serum BDNF in cocaine relapse in abstinent addicts. Forty cocaine dependent subjects (DSM-IV criteria) were included in an inpatient 2 weeks abstinence program. Organic and psychiatric co-morbidities were excluded. Two serum samples were collected for each subject at baseline and at after 14 abstinence days. After discharge, all cocaine addicts underwent a 22 weeks follow-up, after which they were classified into early relapsers (ER) (resumed during the first 14 days after discharge,) or late relapsers (LR) (resumed beyond 14 days after discharge). The only clinical differences between groups were the number of consumption days during the last month before detoxification. Serum BDNF levels increased significantly across the 12 days of abstinence in the LR group (p=0.02), whereas in the ER group BDNF remained unchanged. In the ER group, the change of serum BDNF during abstinence negatively correlated with the improvement in depressive symptoms (p=0.02). These results suggest that BDNF has a role in relapse to cocaine consumption in abstinent addicts, although the underlying neurobiological mechanisms remain to be clarified. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  9. Selective alterations in cerebral metabolism within the mesocorticolimbic dopaminergic system produced by acute cocaine administration in rats

    Energy Technology Data Exchange (ETDEWEB)

    Porrino, L.J.; Domer, F.R.; Crane, A.M.; Sokoloff, L.

    1988-05-01

    The 2-(/sup 14/C)deoxyglucose method was used to examine the effects of acute intravenous administration of cocaine on local cerebral glucose utilization in rats. These effects were correlated with the effects of cocaine on locomotor activity assessed simultaneously in the same animals. At the lowest dose of cocaine, 0.5 mg/kg (1.47 mumol/kg), alterations in glucose utilization were restricted to the medial prefrontal cortex and nucleus accumbens. Metabolic activity at 1.0 mg/kg (2.9 mumol/kg) was altered in these structures, but in the substantia nigra reticulata and lateral habenula as well. The selectivity of cocaine's effects at low doses demonstrates the particular sensitivity of these structures to cocaine's actions in the brain. In contrast, 5.0 mg/kg (14.7 mumol/kg) produced widespread changes in glucose utilization, particularly in the extrapyramidal system. Only this dose significantly increased locomotor activity above levels in vehicle-treated controls. Rates of glucose utilization were positively correlated with locomotor activity in the globus pallidus, substantia nigra reticulata, and subthalamic nucleus, and negatively correlated in the lateral habenula.

  10. High Suicide Risk after the Development of Cognitive and Working Memory Deficits Caused by Cannabis, Cocaine and Ecstasy Use

    Science.gov (United States)

    Pompili, Maurizio; Lester, David; Girardi, Paolo; Tatarelli, Roberto

    2007-01-01

    We report the case of attempted suicide by a 30-year-old man who had significant cognitive deficits that developed after at least three years of polysubstance use with cannabis, methylenedioxymethamphetamine (MDMA, "ecstasy") and cocaine. The patient reported increasing difficulties in his professional and interpersonal life which may have been…

  11. Hypocretin 1/orexin A in the ventral tegmental area enhances dopamine responses to cocaine and promotes cocaine self-administration.

    Science.gov (United States)

    España, Rodrigo A; Melchior, James R; Roberts, David C S; Jones, Sara R

    2011-03-01

    Recent evidence indicates that the hypocretin/orexin system participates in the regulation of reinforcement and addiction processes. For example, manipulations that decrease hypocretin neurotransmission result in disruptions of neurochemical and behavioral responses to cocaine. To further assess the relationship between the hypocretin system and cocaine reinforcement, the current studies used microdialysis and in vivo voltammetry to examine the effects of hypocretin 1 on cocaine-induced enhancement of dopamine signaling in the nucleus accumbens core. Fixed ratio, discrete trials, and progressive ratio self-administration procedures were also used to assess whether hypocretin 1 promotes cocaine self-administration behavior. Infusions of hypocretin 1 into the ventral tegmental area increased the effects of cocaine on tonic and phasic dopamine signaling and increased the motivation to self-administer cocaine on the discrete trials and progressive ratio schedules. Together with previous observations demonstrating that a hypocretin 1 receptor antagonist disrupts dopamine signaling and reduces self-administration of cocaine, the current observations further indicate that the hypocretin system participates in reinforcement processes likely through modulation of the mesolimbic dopamine system.

  12. A fibre optic chemical sensor for the detection of cocaine

    Science.gov (United States)

    Nguyen, T. Hien; Sun, Tong; Grattan, Kenneth T. V.; Hardwick, S. A.

    2010-09-01

    A fibre-optic chemical sensor for the detection of cocaine has been developed, based on a molecularly imprinted polymer (MIP) containing a fluorescein moiety as the signalling group. The fluorescent MIP was formed and covalently attached to the distal end of an optical fibre. The sensor exhibited an increase in fluorescence intensity in response to cocaine in the concentration range of 0 - 500 μM in aqueous acetonitrile mixtures with good reproducibility over 24 h. Selectivity for cocaine over others drugs has also been demonstrated.

  13. 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.

  14. Structural analysis of thermostabilizing mutations of cocaine esterase

    Energy Technology Data Exchange (ETDEWEB)

    Narasimhan, Diwahar; Nance, Mark R.; Gao, Daquan; Ko, Mei-Chuan; Macdonald, Joanne; Tamburi, Patricia; Yoon, Dan; Landry, Donald M.; Woods, James H.; Zhan, Chang-Guo; Tesmer, John J.G.; Sunahara, Roger K. (Michigan); (Columbia); (Kentucky)

    2010-09-03

    Cocaine is considered to be the most addictive of all substances of abuse and mediates its effects by inhibiting monoamine transporters, primarily the dopamine transporters. There are currently no small molecules that can be used to combat its toxic and addictive properties, in part because of the difficulty of developing compounds that inhibit cocaine binding without having intrinsic effects on dopamine transport. Most of the effective cocaine inhibitors also display addictive properties. We have recently reported the use of cocaine esterase (CocE) to accelerate the removal of systemic cocaine and to prevent cocaine-induced lethality. However, wild-type CocE is relatively unstable at physiological temperatures ({tau}{sub 1/2} {approx} 13 min at 37 C), presenting challenges for its development as a viable therapeutic agent. We applied computational approaches to predict mutations to stabilize CocE and showed that several of these have increased stability both in vitro and in vivo, with the most efficacious mutant (T172R/G173Q) extending half-life up to 370 min. Here we present novel X-ray crystallographic data on these mutants that provide a plausible model for the observed enhanced stability. We also more extensively characterize the previously reported variants and report on a new stabilizing mutant, L169K. The improved stability of these engineered CocE enzymes will have a profound influence on the use of this protein to combat cocaine-induced toxicity and addiction in humans.

  15. Significant increase of surface ozone at a rural site, north of eastern China

    Directory of Open Access Journals (Sweden)

    Z. Ma

    2016-03-01

    Full Text Available Ozone pollution in eastern China has become one of the top environmental issues. Quantifying the temporal trend of surface ozone helps to assess the impacts of the anthropogenic precursor reductions and the likely effects of emission control strategies implemented. In this paper, ozone data collected at the Shangdianzi (SDZ regional atmospheric background station from 2003 to 2015 are presented and analyzed to obtain the variation in the trend of surface ozone in the most polluted region of China, north of eastern China or the North China Plain. A modified Kolmogorov–Zurbenko (KZ filter method was performed on the maximum daily average 8 h (MDA8 concentrations of ozone to separate the contributions of different factors from the variation of surface ozone and remove the influence of meteorological fluctuations on surface ozone. Results reveal that the short-term, seasonal and long-term components of ozone account for 36.4, 57.6 and 2.2 % of the total variance, respectively. The long-term trend indicates that the MDA8 has undergone a significant increase in the period of 2003–2015, with an average rate of 1.13 ± 0.01 ppb year−1 (R2 = 0.92. It is found that meteorological factors did not significantly influence the long-term variation of ozone and the increase may be completely attributed to changes in emissions. Furthermore, there is no significant correlation between the long-term O3 and NO2 trends. This study suggests that emission changes in VOCs might have played a more important role in the observed increase of surface ozone at SDZ.

  16. 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.

  17. Stable self-serving personality traits in recreational and dependent cocaine users.

    Directory of Open Access Journals (Sweden)

    Boris B Quednow

    Full Text Available Chronic cocaine use has been associated with impairments in social cognition, self-serving and antisocial behavior, and socially relevant personality disorders (PD. Despite the apparent relationship between Machiavellianism and stimulant use, no study has explicitly examined this personality concept in cocaine users so far. In the frame of the longitudinal Zurich Cocaine Cognition Study, the Machiavellianism Questionnaire (MACH-IV was assessed in 68 recreational and 30 dependent cocaine users as well as in 68 psychostimulant-naïve controls at baseline. Additionally, three closely related personality dimensions from the Temperament and Character Inventory (TCI-cooperativeness, (social reward dependence, and self-directedness-and the screening questionnaire of the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II were acquired. At the one-year follow-up, 57 cocaine users and 48 controls were reassessed with the MACH-IV. Finally, MACH-IV scores were correlated with measures of social cognition and interaction (cognitive/emotional empathy, Theory-of-Mind, prosocial behavior and with SCID-II PD scores assessed at baseline. Both recreational and dependent cocaine users showed significantly higher Machiavellianism than controls, while dependent cocaine users additionally displayed significantly lower levels of TCI cooperativeness and self-directedness. During the one-year interval, MACH-IV scores showed high test-retest reliability and also the significant gap between cocaine users and controls remained. Moreover, in cocaine users, higher Machiavellianism correlated significantly with lower levels of cooperativeness and self-directedness, with less prosocial behavior, and with higher cluster B PD scores. However, Machiavellianism was not correlated with measures of cocaine use severity (r<-.15. Both recreational and dependent cocaine users display pronounced and stable Machiavellian personality traits. The lack of

  18. 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.

  19. Methaemoglobinaemia associated with the use of cocaine and volatile nitrites as recreational drugs: a review

    Science.gov (United States)

    Hunter, Laura; Gordge, Laura; Dargan, Paul I; Wood, David M

    2011-01-01

    Methaemoglobinaemia can cause significant tissue hypoxia, leading to severe, potentially life-threatening clinical features and/or death. Over recent years there have been increasing reports of methaemoglobinaemia related to recreational drug use. There have been 25 articles describing methaemoglobinaemia related to recreational use of volatile nitrites (poppers) and more recently, four reports of methaemoglobinaemia in association with recreational cocaine use. In this article we discuss the mechanisms by which methaemoglobinaemia occurs in relation to the use of both volatile nitrites and cocaine, and summarize the published cases of recreational drug-related methaemoglobinaemia. The volatile nitrites can cause methaemoglobinaemia directly through their activity as oxidizing agents. However, with cocaine, methaemoglobinaemia is related to adulterants such as local anaesthetics or phenacetin, rather than to the cocaine itself. Clinicians managing patients with acute recreational drug toxicity should be aware of the potential for methaemoglobinaemia in these patients, particularly in patients with cyanosis or unexplained low oxygen saturations on pulse oximetry, and ensure that appropriate and timely management is provided, including, where appropriate, the use of methylthioninium chloride (methylene blue). PMID:21352269

  20. Electrochemical aptasensor for highly sensitive determination of cocaine using a supramolecular aptamer and rolling circle amplification

    International Nuclear Information System (INIS)

    Shen, Bo; Yan, Yurong; Tang, Renkuan; Li, Yongguo; Li, Jianbo; Cheng, Wei; Ju, Huangxian; Ding, Shijia

    2015-01-01

    We report on a novel strategy for the electrochemical detection of cocaine. It is based on the use of a supramolecular aptamer, rolling circle amplification (RCA), and multiplex binding of a biotin-strepavidin system. The aptamer fragments were assembled to a supramolecular aptamer which, in the presence of cocaine, conjugates to streptavidin for anchoring of biotinylated circular DNA. This initiates RCA and enables sensitive electrochemical-enzymatic readout. A significant signal amplification was obtained by using streptavidin linked to alkaline phosphatase that binds to the remaining biotinylated detection probes and catalyzes the hydrolysis of the synthetic enzyme substrate α-naphthylphosphate. This dual amplification strategy tremendously increases the detection limit of the aptasensor. Under optimal conditions and using differential pulse voltammetry, cocaine can be detected in the concentration range between 2 and 500 nM with a detection limit as low as 1.3 nM (at S/N = 3). The method is specific and acceptably reproducible. It was successfully applied to the detection of cocaine in (spiked) urine samples. The data were in good agreement with those obtained by the GC-MS reference method. (author)

  1. Cocaine Use and Risk of Ischemic Stroke in Young Adults.

    Science.gov (United States)

    Cheng, Yu-Ching; Ryan, Kathleen A; Qadwai, Saad A; Shah, Jay; Sparks, Mary J; Wozniak, Marcella A; Stern, Barney J; Phipps, Michael S; Cronin, Carolyn A; Magder, Laurence S; Cole, John W; Kittner, Steven J

    2016-04-01

    Although case reports have long identified a temporal association between cocaine use and ischemic stroke (IS), few epidemiological studies have examined the association of cocaine use with IS in young adults, by timing, route, and frequency of use. A population-based case-control study design with 1090 cases and 1154 controls was used to investigate the relationship of cocaine use and young-onset IS. Stroke cases were between the ages of 15 and 49 years. Logistic regression analysis was used to evaluate the association between cocaine use and IS with and without adjustment for potential confounders. Ever use of cocaine was not associated with stroke with 28% of cases and 26% of controls reporting ever use. In contrast, acute cocaine use in the previous 24 hours was strongly associated with increased risk of stroke (age-sex-race adjusted odds ratio, 6.4; 95% confidence interval, 2.2-18.6). Among acute users, the smoking route had an adjusted odds ratio of 7.9 (95% confidence interval, 1.8-35.0), whereas the inhalation route had an adjusted odds ratio of 3.5 (95% confidence interval, 0.7-16.9). After additional adjustment for current alcohol, smoking use, and hypertension, the odds ratio for acute cocaine use by any route was 5.7 (95% confidence interval, 1.7-19.7). Of the 26 patients with cocaine use within 24 hours of their stroke, 14 reported use within 6 hours of their event. Our data are consistent with a causal association between acute cocaine use and risk of early-onset IS. © 2016 American Heart Association, Inc.

  2. 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

  3. 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...

  4. 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.

  5. 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.

  6. Neural correlates of stress-induced and cue-induced drug craving: influences of sex and cocaine dependence.

    Science.gov (United States)

    Potenza, Marc N; Hong, Kwang-ik Adam; Lacadie, Cheryl M; Fulbright, Robert K; Tuit, Keri L; Sinha, Rajita

    2012-04-01

    Although stress and drug cue exposure each increase drug craving and contribute to relapse in cocaine dependence, no previous research has directly examined the neural correlates of stress-induced and drug cue-induced craving in cocaine-dependent women and men relative to comparison subjects. Functional MRI was used to assess responses to individualized scripts for stress, drug/alcohol cue and neutral-relaxing-imagery conditions in 30 abstinent cocaine-dependent individuals (16 women, 14 men) and 36 healthy recreational-drinking comparison subjects (18 women, 18 men). Significant three-way interactions between diagnostic group, sex, and script condition were observed in multiple brain regions including the striatum, insula, and anterior and posterior cingulate. Within women, group-by-condition interactions were observed involving these regions and were attributable to relatively increased regional activations in cocaine-dependent women during the stress and, to a lesser extent, neutral-relaxing conditions. Within men, group main effects were observed involving these same regions, with cocaine-dependent men demonstrating relatively increased activation across conditions, with the main contributions from the drug and neutral-relaxing conditions. In men and women, subjective drug-induced craving measures correlated positively with corticostriatal-limbic activations. In cocaine dependence, corticostriatal-limbic hyperactivity appears to be linked to stress cues in women, drug cues in men, and neutral-relaxing conditions in both. These findings suggest that sex should be taken into account in the selection of therapies in the treatment of addiction, particularly those targeting stress reduction.

  7. Cocaine affects foraging behaviour and biogenic amine modulated behavioural reflexes in honey bees

    Directory of Open Access Journals (Sweden)

    Eirik Søvik

    2014-11-01

    Full Text Available In humans and other mammals, drugs of abuse alter the function of biogenic amine pathways in the brain leading to the subjective experience of reward and euphoria. Biogenic amine pathways are involved in reward processing across diverse animal phyla, however whether cocaine acts on these neurochemical pathways to cause similar rewarding behavioural effects in animal phyla other than mammals is unclear. Previously, it has been shown that bees are more likely to dance (a signal of perceived reward when returning from a sucrose feeder after cocaine treatment. Here we examined more broadly whether cocaine altered reward-related behaviour, and biogenic amine modulated behavioural responses in bees. Bees developed a preference for locations at which they received cocaine, and when foraging at low quality sucrose feeders increase their foraging rate in response to cocaine treatment. Cocaine also increased reflexive proboscis extension to sucrose, and sting extension to electric shock. Both of these simple reflexes are modulated by biogenic amines. This shows that systemic cocaine treatment alters behavioural responses that are modulated by biogenic amines in insects. Since insect reward responses involve both octopamine and dopamine signalling, we conclude that cocaine treatment altered diverse reward-related aspects of behaviour in bees. We discuss the implications of these results for understanding the ecology of cocaine as a plant defence compound. Our findings further validate the honey bee as a model system for understanding the behavioural impacts of cocaine, and potentially other drugs of abuse.

  8. Application of Bioorganic Fertilizer Significantly Increased Apple Yields and Shaped Bacterial Community Structure in Orchard Soil.

    Science.gov (United States)

    Wang, Lei; Li, Jing; Yang, Fang; E, Yaoyao; Raza, Waseem; Huang, Qiwei; Shen, Qirong

    2017-02-01

    and Rhodospirillaceae, were found to be the significantly increased by the BOF addition and the genus Lysobacter may identify members of this group effective in biological control-based plant disease management and the members of family Rhodospirillaceae had an important role in fixing molecular nitrogen. These results strengthen the understanding of responses to the BOF and possible interactions within bacterial communities in soil that can be associated with disease suppression and the accumulation of carbon and nitrogen. The increase of apple yields after the application of BOF might be attributed to the fact that the application of BOF increased SOM, and soil total nitrogen, and changed the bacterial community by enriching Rhodospirillaceae, Alphaprotreobateria, and Proteobacteria.

  9. ProSAAS-derived peptides are regulated by cocaine and are required for sensitization to the locomotor effects of cocaine.

    Science.gov (United States)

    Berezniuk, Iryna; Rodriguiz, Ramona M; Zee, Michael L; Marcus, David J; Pintar, John; Morgan, Daniel J; Wetsel, William C; Fricker, Lloyd D

    2017-11-01

    To identify neuropeptides that are regulated by cocaine, we used a quantitative peptidomic technique to examine the relative levels of neuropeptides in several regions of mouse brain following daily intraperitoneal administration of 10 mg/kg cocaine or saline for 7 days. A total of 102 distinct peptides were identified in one or more of the following brain regions: nucleus accumbens, caudate putamen, frontal cortex, and ventral tegmental area. None of the peptides detected in the caudate putamen or frontal cortex were altered by cocaine administration. Three peptides in the nucleus accumbens and seven peptides in the ventral tegmental area were significantly decreased in cocaine-treated mice. Five of these ten peptides are derived from proSAAS, a secretory pathway protein and neuropeptide precursor. To investigate whether proSAAS peptides contribute to the physiological effects of psychostimulants, we examined acute responses to cocaine and amphetamine in the open field with wild-type (WT) and proSAAS knockout (KO) mice. Locomotion was stimulated more robustly in the WT compared to mutant mice for both psychostimulants. Behavioral sensitization to amphetamine was not maintained in proSAAS KO mice and these mutants failed to sensitize to cocaine. To determine whether the rewarding effects of cocaine were altered, mice were tested in conditioned place preference (CPP). Both WT and proSAAS KO mice showed dose-dependent CPP to cocaine that was not distinguished by genotype. Taken together, these results suggest that proSAAS-derived peptides contribute differentially to the behavioral sensitization to psychostimulants, while the rewarding effects of cocaine appear intact in mice lacking proSAAS. © 2017 International Society for Neurochemistry.

  10. Motivated attention to cocaine and emotional cues in abstinent and current cocaine users--an ERP study.

    Science.gov (United States)

    Dunning, Jonathan P; Parvaz, Muhammad A; Hajcak, Greg; Maloney, Thomas; Alia-Klein, Nelly; Woicik, Patricia A; Telang, Frank; Wang, Gene-Jack; Volkow, Nora D; Goldstein, Rita Z

    2011-05-01

    Event-related potentials (ERPs) are a direct measure of neural activity and are ideally suited to study the time-course of attentional engagement with emotional and drug-related stimuli in addiction. In particular, the late positive potential (LPP) appears to be enhanced following cocaine-related compared with neutral stimuli in human participants with cocaine use disorders (CUD). However, previous studies have not directly compared cocaine-related with emotional stimuli while examining potential differences between abstinent and current cocaine users. The present study examined ERPs in 55 CUD (27 abstinent and 28 current users) and 29 matched healthy controls while they passively viewed pleasant, unpleasant, neutral and cocaine-related pictures. To examine the time-course of attention to these stimuli, we analysed both an early and later window in the LPP as well as the early posterior negativity (EPN), established in assessing motivated attention. Cocaine pictures elicited increased electrocortical measures of motivated attention in ways similar to affectively pleasant and unpleasant pictures in all CUD, an effect that was no longer discernible during the late LPP window for the current users. This group also exhibited deficient processing of the other emotional stimuli (early LPP window - pleasant pictures; late LPP window - pleasant and unpleasant pictures). Results were unique to the LPP and not EPN. Taken together, results support a relatively early attention bias to cocaine stimuli in cocaine-addicted individuals, further suggesting that recent cocaine use decreases such attention bias during later stages of processing but at the expense of deficient processing of other emotional stimuli. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd. No claim to original US government works.

  11. One stone, two birds: silica nanospheres significantly increase photocatalytic activity and colloidal stability of photocatalysts

    Science.gov (United States)

    Rasamani, Kowsalya D.; Foley, Jonathan J., IV; Sun, Yugang

    2018-03-01

    Silver-doped silver chloride [AgCl(Ag)] nanoparticles represent a unique class of visible-light-driven photocatalysts, in which the silver dopants introduce electron-abundant mid-gap energy levels to lower the bandgap of AgCl. However, free-standing AgCl(Ag) nanoparticles, particularly those with small sizes and large surface areas, exhibit low colloidal stability and low compositional stability upon exposure to light irradiation, leading to easy aggregation and conversion to metallic silver and thus a loss of photocatalytic activity. These problems could be eliminated by attaching the small AgCl(Ag) nanoparticles to the surfaces of spherical dielectric silica particles with submicrometer sizes. The high optical transparency in the visible spectral region (400-800 nm), colloidal stability, and chemical/electronic inertness displayed by the silica spheres make them ideal for supporting photocatalysts and significantly improving their stability. The spherical morphology of the dielectric silica particles can support light scattering resonances to generate significantly enhanced electric fields near the silica particle surfaces, on which the optical absorption cross-section of the AgCl(Ag) nanoparticles is dramatically increased to promote their photocatalytic activity. The hybrid silica/AgCl(Ag) structures exhibit superior photocatalytic activity and stability, suitable for supporting photocatalysis sustainably; for instance, their efficiency in the photocatalytic decomposition of methylene blue decreases by only ˜9% even after ten cycles of operation.

  12. Effects of nalbuphine on anterior pituitary and adrenal hormones and subjective responses in male cocaine abusers.

    Science.gov (United States)

    Goletiani, Nathalie V; Mendelson, Jack H; Sholar, Michelle B; Siegel, Arthur J; Skupny, Alicja; Mello, Nancy K

    2007-04-01

    Nalbuphine (Nubain) is a mixed action mu-kappa agonist used clinically for the management of pain. Nalbuphine and other mu-kappa agonists decreased cocaine self-administration in preclinical models. Cocaine stimulates the hypothalamic-pituitary-adrenal (HPA) axis, but the effects of nalbuphine on the HPA axis are unknown. Analgesic doses (5 and 10 mg/70 kg) of IV nalbuphine were administered to healthy male cocaine abusers, and plasma levels of PRL, ACTH and cortisol were measured before and at 10, 17, 19, 23, 27, 31, 35, 40, 45, 60, 75, 105, and 135 min after nalbuphine administration. Subjective effects were measured on a Visual Analog Scale (VAS). Prolactin (PRL) increased significantly within 17 min (P=.04) and reached peak levels of 22.1+/-7.1 ng/ml and 54.1+/-11.3 at 60 min after low and high dose nalbuphine administration, respectively. VAS reports of "Sick," "Bad" and "Dizzy" were significantly higher after 10 mg/70 kg than after 5 mg/70 kg nalbuphine (P=.05-.0001), and were significantly correlated with increases in PRL (P=.05-.0003). However, sedation and emesis were observed only after a 10 mg/70 kg dose of nalbuphine. Interestingly, ACTH and cortisol levels did not change significantly after administration of either dose of nalbuphine. Taken together, these data suggest that nalbuphine had both mu- and kappa-like effects on PRL (PRL increase) but did not increase ACTH and cortisol.

  13. Phytohormone supplementation significantly increases growth of Chlamydomonas reinhardtii cultivated for biodiesel production.

    Science.gov (United States)

    Park, Won-Kun; Yoo, Gursong; Moon, Myounghoon; Kim, Chul Woong; Choi, Yoon-E; Yang, Ji-Won

    2013-11-01

    Cultivation is the most expensive step in the production of biodiesel from microalgae, and substantial research has been devoted to developing more cost-effective cultivation methods. Plant hormones (phytohormones) are chemical messengers that regulate various aspects of growth and development and are typically active at very low concentrations. In this study, we investigated the effect of different phytohormones on microalgal growth and biodiesel production in Chlamydomonas reinhardtii and their potential to lower the overall cost of commercial biofuel production. The results indicated that all five of the tested phytohormones (indole-3-acetic acid, gibberellic acid, kinetin, 1-triacontanol, and abscisic acid) promoted microalgal growth. In particular, hormone treatment increased biomass production by 54 to 69 % relative to the control growth medium (Tris-acetate-phosphate, TAP). Phytohormone treatments also affected microalgal cell morphology but had no effect on the yields of fatty acid methyl esters (FAMEs) as a percent of biomass. We also tested the effect of these phytohormones on microalgal growth in nitrogen-limited media by supplementation in the early stationary phase. Maximum cell densities after addition of phytohormones were higher than in TAP medium, even when the nitrogen source was reduced to 40 % of that in TAP medium. Taken together, our results indicate that phytohormones significantly increased microalgal growth, particularly in nitrogen-limited media, and have potential for use in the development of efficient microalgal cultivation for biofuel production.

  14. [Significant increase in the colonisation of Staphylococcus aureus among medical students during their hospital practices].

    Science.gov (United States)

    Rodríguez-Avial, Carmen; Alvarez-Novoa, Andrea; Losa, Azucena; Picazo, Juan J

    2013-10-01

    Staphylococcus aureus is a pathogen of major concern. The emergence of methicillin-resistant S. aureus (MRSA) has increasingly complicated the therapeutic approach of hospital-acquired infections. Surveillance of MRSA and control measures must be implemented in different healthcare settings, including screening programs for carriers. Our first aim was to determine the prevalence of methicillin-susceptible S. aureus (MSSA) and MRSA nasal carriage in medical students from the Clínico San Carlos Hospital (Madrid). As the MRSA carrier rate in healthcare workers is higher than in the general population, we hypothesised that carrier rate could be increased during their clinical practice in their last three years. We performed an epidemiologic al study of the prevalence of S. aureus colonisation among a group of medical students, who were sampled in 2008 in their third-year, and in 2012 when this class was in its sixth year. We have found a significant increase in MSSA carriage, from 27% to 46%. There were no MRSA colonisations in the third-year, but one was found in the sixth-year group. The large majority of strains (89%) of strains were resistant to penicillin, and 27% to erythromycin and clindamycin. As 19 coagulase-negative Staphylococcus MR were also identified, a horizontal transfer of genes, such as mecA gene to S. aureus, could have occurred. Medical students are both, at risk for acquiring, and a potential source of nosocomial pathogens, mainly MSSA. Therefore, they should take special care for hygienic precautions, such as frequent and proper hand washing, while working in the hospital. Copyright © 2012 Elsevier España, S.L. All rights reserved.

  15. Race/Ethnic-Specific Homicide Rates in New York City: Evaluating the Impact of Broken Windows Policing and Crack Cocaine Markets

    Science.gov (United States)

    Chauhan, Preeti; Cerdá, Magdalena; Messner, Steven F.; Tracy, Melissa; Tardiff, Kenneth; Galea, Sandro

    2012-01-01

    The current study evaluated a range of social influences including misdemeanor arrests, drug arrests, cocaine consumption, alcohol consumption, firearm availability, and incarceration that may be associated with changes in gun-related homicides by racial/ethnic group in New York City (NYC) from 1990 to 1999. Using police precincts as the unit of analysis, we used cross-sectional, time series data to examine changes in Black, White, and Hispanic homicides, separately. Bayesian hierarchical models with a spatial error term indicated that an increase in cocaine consumption was associated with an increase in Black homicides. An increase in firearm availability was associated with an increase in Hispanic homicides. Last, there were no significant predictors for White homicides. Support was found for the crack cocaine hypotheses but not for the broken windows hypothesis. Examining racially/ethnically disaggregated data can shed light on group-sensitive mechanisms that may explain changes in homicide over time. PMID:22328820

  16. 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.

  17. Skipping one or more dialysis sessions significantly increases mortality: measuring the impact of non-adherence

    Directory of Open Access Journals (Sweden)

    Eduardo Gottlieb

    2014-06-01

    Full Text Available Introduction: Non-adherence to the prescribed dialysis sessions frequency ranges from 2% to 50% of patients. The objective of this study was to evaluate the impact of detecting and measuring the non-adherence to the prescribed dialysis frequency and to determine the importance of a multidisciplinary approach with the aim of improving adherence. Methods: longitudinal cohort study including 8,164 prevalent hemodialysis patients in April 2010, with more than 90 days of treatment, in Fresenius Medical Care Argentina units that were monitored for 3 years. The survey evaluated: interruption of at least one dialysis session in a month or reduction at least 10 minutes of a dialysis session in a month, during 6 months prior to the survey. Relative mortality risks were evaluated among groups. Results: 648 patients (7.9% interrupted dialysis sessions: 320 (3.9% interrupted one session per month and 328 (4.01% interrupted more than one session per month. After 3 years monitoring, 349 patients (53.8 % remained active in hemodialysis and 299 were inactive due to different reasons: 206 deceased (31.8 %, 47 transfers or monitoring losses (7.25 %, 36 transplanted (5.55 %, 8 changes to PD modality (1.2% and 2 recovered their kidney function (0.3 %.Interrupting one session per month significantly increased the mortality risk comparing both groups (interrupters and non-interrupters: RR 2.65 (IC 95% 2.24 – 3.14. Interrupting more than one dialysis session also increased significantly mortality risk comparing to the non-interrupters: RR 2.8 (IC 95% 2.39 – 3.28. After 3 years monitoring, 41.6 % of interrupters at the beginning had improved their adherence through a multidisciplinary program of quality improvement. Conclusion: Global mortality was greater among patients who interrupted dialysis sessions. A considerable proportion of interrupter patients at the beginning modified their behavior through the implementation of a multidisciplinary program of quality

  18. Maternal undernutrition significantly impacts ovarian follicle number and increases ovarian oxidative stress in adult rat offspring.

    Directory of Open Access Journals (Sweden)

    Angelica B Bernal

    Full Text Available BACKGROUND: We have shown recently that maternal undernutrition (UN advanced female pubertal onset in a manner that is dependent upon the timing of UN. The long-term consequence of this accelerated puberty on ovarian function is unknown. Recent findings suggest that oxidative stress may be one mechanism whereby early life events impact on later physiological functioning. Therefore, using an established rodent model of maternal UN at critical windows of development, we examined maternal UN-induced changes in offspring ovarian function and determined whether these changes were underpinned by ovarian oxidative stress. METHODOLOGY/PRINCIPAL FINDINGS: Our study is the first to show that maternal UN significantly reduced primordial and secondary follicle number in offspring in a manner that was dependent upon the timing of maternal UN. Specifically, a reduction in these early stage follicles was observed in offspring born to mothers undernourished throughout both pregnancy and lactation. Additionally, antral follicle number was reduced in offspring born to all mothers that were UN regardless of whether the period of UN was restricted to pregnancy or lactation or both. These reductions were associated with decreased mRNA levels of genes critical for follicle maturation and ovulation. Increased ovarian protein carbonyls were observed in offspring born to mothers UN during pregnancy and/or lactation and this was associated with peroxiredoxin 3 hyperoxidation and reduced mRNA levels; suggesting compromised antioxidant defence. This was not observed in offspring of mothers UN during lactation alone. CONCLUSIONS: We propose that maternal UN, particularly at a time-point that includes pregnancy, results in reduced offspring ovarian follicle numbers and mRNA levels of regulatory genes and may be mediated by increased ovarian oxidative stress coupled with a decreased ability to repair the resultant oxidative damage. Together these data are suggestive of

  19. Free ammonia pre-treatment of secondary sludge significantly increases anaerobic methane production.

    Science.gov (United States)

    Wei, Wei; Zhou, Xu; Wang, Dongbo; Sun, Jing; Wang, Qilin

    2017-07-01

    Energy recovery in the form of methane from sludge/wastewater is restricted by the poor and slow biodegradability of secondary sludge. An innovative pre-treatment technology using free ammonia (FA, i.e. NH 3 ) was proposed in this study to increase anaerobic methane production. The solubilisation of secondary sludge was significantly increased after FA pre-treatment at up to 680 mg NH 3 -N/L for 1 day, under which the solubilisation (i.e. 0.4 mg SCOD/mg VS; SCOD: soluble chemical oxygen demand; VS: volatile solids) was >10 times higher than that without FA pre-treatment (i.e. 0.03 mg SCOD/mg VS). Biochemical methane potential assays showed that FA pre-treatment at above 250 mg NH 3 -N/L is effective in improving anaerobic methane production. The highest improvement in biochemical methane potential (B 0 ) and hydrolysis rate (k) was achieved at FA concentrations of 420-680 mg NH 3 -N/L, and was determined as approximately 22% (from 160 to 195 L CH 4 /kg VS added) and 140% (from 0.22 to 0.53 d -1 ) compared to the secondary sludge without pre-treatment. More analysis revealed that the FA induced improvement in B 0 and k could be attributed to the rapidly biodegradable substances rather than the slowly biodegradable substances. Economic and environmental analyses showed that the FA-based technology is economically favourable and environmentally friendly. Since this FA technology aims to use the wastewater treatment plants (WWTPs) waste (i.e. anaerobic digestion liquor) to enhance methane production from the WWTPs, it will set an example for the paradigm shift of the WWTPs from 'linear economy' to 'circular economy'. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Myriocin significantly increases the mortality of a non-mammalian model host during Candida pathogenesis.

    Directory of Open Access Journals (Sweden)

    Nadja Rodrigues de Melo

    Full Text Available Candida albicans is a major human pathogen whose treatment is challenging due to antifungal drug toxicity, drug resistance and paucity of antifungal agents available. Myrocin (MYR inhibits sphingosine synthesis, a precursor of sphingolipids, an important cell membrane and signaling molecule component. MYR also has dual immune suppressive and antifungal properties, potentially modulating mammalian immunity and simultaneously reducing fungal infection risk. Wax moth (Galleria mellonella larvae, alternatives to mice, were used to establish if MYR suppressed insect immunity and increased survival of C. albicans-infected insects. MYR effects were studied in vivo and in vitro, and compared alone and combined with those of approved antifungal drugs, fluconazole (FLC and amphotericin B (AMPH. Insect immune defenses failed to inhibit C. albicans with high mortalities. In insects pretreated with the drug followed by C. albicans inoculation, MYR+C. albicans significantly increased mortality to 93% from 67% with C. albicans alone 48 h post-infection whilst AMPH+C. albicans and FLC+C. albicans only showed 26% and 0% mortalities, respectively. MYR combinations with other antifungal drugs in vivo also enhanced larval mortalities, contrasting the synergistic antifungal effect of the MYR+AMPH combination in vitro. MYR treatment influenced immunity and stress management gene expression during C. albicans pathogenesis, modulating transcripts putatively associated with signal transduction/regulation of cytokines, I-kappaB kinase/NF-kappaB cascade, G-protein coupled receptor and inflammation. In contrast, all stress management gene expression was down-regulated in FLC and AMPH pretreated C. albicans-infected insects. Results are discussed with their implications for clinical use of MYR to treat sphingolipid-associated disorders.

  1. Rats classified as low or high cocaine locomotor responders: A unique model involving striatal dopamine transporters that predicts cocaine addiction-like behaviors

    Science.gov (United States)

    Yamamoto, Dorothy J.; Nelson, Anna M.; Mandt, Bruce H.; Larson, Gaynor A.; Rorabaugh, Jacki M.; Ng, Christopher M.C.; Barcomb, Kelsey M.; Richards, Toni L.; Allen, Richard M.; Zahniser, Nancy R.

    2013-01-01

    Individual differences are a hallmark of drug addiction. Here, we describe a rat model based on differential initial responsiveness to low dose cocaine. Despite similar brain cocaine levels, individual outbred Sprague-Dawley rats exhibit markedly different magnitudes of acute cocaine-induced locomotor activity and, thereby, can be classified as low or high cocaine responders (LCRs or HCRs). LCRs and HCRs differ in drug-induced, but not novelty-associated, hyperactivity. LCRs have higher basal numbers of striatal dopamine transporters (DATs) than HCRs and exhibit marginal cocaine inhibition of in vivo DAT activity and cocaine-induced increases in extracellular DA. Importantly, lower initial cocaine response predicts greater locomotor sensitization, conditioned place preference and greater motivation to self-administer cocaine following low dose acquisition. Further, outbred Long-Evans rats classified as LCRs, versus HCRs, are more sensitive to cocaine’s discriminative stimulus effects. Overall, results to date with the LCR/HCR model underscore the contribution of striatal DATs to individual differences in initial cocaine responsiveness and the value of assessing the influence of initial drug response on subsequent expression of addiction-like behaviors. PMID:23850581

  2. Significantly increased risk of carotid atherosclerosis with arsenic exposure and polymorphisms in arsenic metabolism genes

    International Nuclear Information System (INIS)

    Hsieh, Yi-Chen; Lien, Li-Ming; Chung, Wen-Ting; Hsieh, Fang-I; Hsieh, Pei-Fan; Wu, Meei-Maan; Tseng, Hung-Pin; Chiou, Hung-Yi; Chen, Chien-Jen

    2011-01-01

    Individual susceptibility to arsenic-induced carotid atherosclerosis might be associated with genetic variations in arsenic metabolism. The purpose of this study is to explore the interaction effect on risk of carotid atherosclerosis between arsenic exposure and risk genotypes of purine nucleoside phosphorylase (PNP), arsenic (+3) methyltransferase (As3MT), and glutathione S-transferase omega 1 (GSTO1) and omega 2 (GSTO2). A community-based case-control study was conducted in northeastern Taiwan to investigate the arsenic metabolic-related genetic susceptibility to carotid atherosclerosis. In total, 863 subjects, who had been genotyped and for whom the severity of carotid atherosclerosis had been determined, were included in the present study. Individual well water was collected and arsenic concentration determined using hydride generation combined with flame atomic absorption spectrometry. The result showed that a significant dose-response trend (P=0.04) of carotid atherosclerosis risk associated with increasing arsenic concentration. Non-significant association between genetic polymorphisms of PNP Gly51Ser, Pro57Pro, As3MT Met287Thr, GSTO1 Ala140Asp, and GSTO2 A-183G and the risk for development of carotid atherosclerosis were observed. However, the significant interaction effect on carotid atherosclerosis risk was found for arsenic exposure (>50 μg/l) and the haplotypes of PNP (p=0.0115). A marked elevated risk of carotid atherosclerosis was observed in subjects with arsenic exposure of >50 μg/l in drinking water and those who carried the PNP A-T haplotype and at least either of the As3MT risk polymorphism or GSTO risk haplotypes (OR, 6.43; 95% CI, 1.79-23.19). In conclusion, arsenic metabolic genes, PNP, As3MT, and GSTO, may exacerbate the formation of atherosclerosis in individuals with high levels of arsenic concentration in well water (>50 μg/l). - Highlights: →Arsenic metabolic genes might be associated with carotid atherosclerosis. → A case

  3. Significantly increased risk of carotid atherosclerosis with arsenic exposure and polymorphisms in arsenic metabolism genes

    Energy Technology Data Exchange (ETDEWEB)

    Hsieh, Yi-Chen [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, 250 Wusing St., Taipei 11031, Taiwan (China); Lien, Li-Ming [Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); School of Medicine, Taipei Medical University, Taipei, Taiwan (China); Department of Neurology, Shin Kong WHS Memorial Hospital, Taipei, Taiwan (China); Chung, Wen-Ting [Department of Neurology, Wanfang Hospital, Taipei Medical University, Taipei, Taiwan (China); Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan (China); Hsieh, Fang-I; Hsieh, Pei-Fan [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, 250 Wusing St., Taipei 11031, Taiwan (China); Wu, Meei-Maan [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, 250 Wusing St., Taipei 11031, Taiwan (China); Graduate Institute of Basic Medicine, College of Medicine, Fu-Jen Catholic University, Taipei, Taiwan (China); Tseng, Hung-Pin [Department of Neurology, Lotung Poh-Ai Hospital, I-Lan, Taiwan (China); Chiou, Hung-Yi, E-mail: hychiou@tmu.edu.tw [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, 250 Wusing St., Taipei 11031, Taiwan (China); Chen, Chien-Jen [Genomics Research Center, Academia Sinica, Taipei, Taiwan (China)

    2011-08-15

    Individual susceptibility to arsenic-induced carotid atherosclerosis might be associated with genetic variations in arsenic metabolism. The purpose of this study is to explore the interaction effect on risk of carotid atherosclerosis between arsenic exposure and risk genotypes of purine nucleoside phosphorylase (PNP), arsenic (+3) methyltransferase (As3MT), and glutathione S-transferase omega 1 (GSTO1) and omega 2 (GSTO2). A community-based case-control study was conducted in northeastern Taiwan to investigate the arsenic metabolic-related genetic susceptibility to carotid atherosclerosis. In total, 863 subjects, who had been genotyped and for whom the severity of carotid atherosclerosis had been determined, were included in the present study. Individual well water was collected and arsenic concentration determined using hydride generation combined with flame atomic absorption spectrometry. The result showed that a significant dose-response trend (P=0.04) of carotid atherosclerosis risk associated with increasing arsenic concentration. Non-significant association between genetic polymorphisms of PNP Gly51Ser, Pro57Pro, As3MT Met287Thr, GSTO1 Ala140Asp, and GSTO2 A-183G and the risk for development of carotid atherosclerosis were observed. However, the significant interaction effect on carotid atherosclerosis risk was found for arsenic exposure (>50 {mu}g/l) and the haplotypes of PNP (p=0.0115). A marked elevated risk of carotid atherosclerosis was observed in subjects with arsenic exposure of >50 {mu}g/l in drinking water and those who carried the PNP A-T haplotype and at least either of the As3MT risk polymorphism or GSTO risk haplotypes (OR, 6.43; 95% CI, 1.79-23.19). In conclusion, arsenic metabolic genes, PNP, As3MT, and GSTO, may exacerbate the formation of atherosclerosis in individuals with high levels of arsenic concentration in well water (>50 {mu}g/l). - Highlights: {yields}Arsenic metabolic genes might be associated with carotid atherosclerosis. {yields

  4. 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

  5. Effects of L-methamphetamine treatment on cocaine- and food-maintained behavior in rhesus monkeys.

    Science.gov (United States)

    Kohut, Stephen J; Bergman, Jack; Blough, Bruce E

    2016-03-01

    Monoamine releasers with prominent dopaminergic actions, e.g., D-methamphetamine (D-MA), significantly reduce cocaine use and craving in clinical and preclinical laboratory studies. However, D-MA and related drugs also display high abuse potential, which limits their acceptability as agonist replacement medications for the management of Cocaine Use Disorder. The L-isomer of methamphetamine (L-MA), unlike D-MA, has preferential noradrenergic actions and is used medicinally with low, if any, abuse liability. The present study was conducted to determine whether L-MA could serve as an agonist replacement medication by both mimicking interoceptive effects of cocaine and decreasing intravenous (IV) cocaine self-administration. Separate groups (N = 4-5) of rhesus monkeys were studied to determine whether L-MA could (1) substitute for cocaine in subjects that discriminated intramuscular (IM) cocaine (0.4 mg/kg) from saline and (2) decrease IV cocaine self-administration under a second-order FR2(VR16:S) schedule of reinforcement. L-MA, like D-MA but with approximately 5-fold lesser potency, substituted for cocaine in drug discrimination experiments in a dose-dependent manner. In IV self-administration studies, 5-10-day treatments with continuously infused L-MA (0.032-0.32 mg/kg/h, IV) dose-dependently decreased cocaine-maintained responding; the highest dosage reduced cocaine intake to levels of saline self-administration without appreciable effects on food-maintained responding. These results indicate that L-MA both shares discriminative stimulus effects with cocaine and reduces cocaine self-administration in a behaviorally selective manner. L-MA and other compounds with a similar pharmacological profile deserve further evaluation for the management of Cocaine Use Disorder.

  6. Effects of Acute and Chronic Treatments with Dopamine D2 and D3 Receptor Ligands on Cocaine versus Food Choice in Rats.

    Science.gov (United States)

    Thomsen, Morgane; Barrett, Andrew C; Butler, Paul; Negus, S Stevens; Caine, S Barak

    2017-07-01

    Dopamine D 3 receptor ligands are potential medications for psychostimulant addiction. Medication assessment may benefit from preclinical studies that evaluate chronic medication effects on choice between an abused drug and an alternative, nondrug reinforcer. This study compared acute and chronic effects of dopamine D 2 - and D 3 -preferring ligands on choice between intravenous cocaine and palatable food in rats. Under baseline conditions, cocaine maintained dose-dependent increases in cocaine choice and reciprocal decreases in food choice. Acutely, the D 2 agonist R -(-)-norpropylapomorphine (NPA) and antagonist L-741,626 [3-[[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1 H -indole] produced leftward and rightward shifts in cocaine dose-effect curves, respectively, whereas the partial agonist terguride had no effect. All three drugs dose-dependently decreased food-maintained responding. Chronically, the effects of R -(-)-norpropylapomorphine and L-741,626 on cocaine self-administration showed marked tolerance, whereas suppression of food-reinforced behavior persisted. Acute effects of the D 3 ligands were less systematic and most consistent with nonselective decreases in cocaine- and food-maintained responding. Chronically, the D 3 agonist PF-592,379 [5-[(2 R ,5 S )-5-methyl-4-propylmorpholin-2-yl]pyridin-2-amine] increased cocaine choice, whereas an intermediate dose of the D 3 antagonist PG01037 [ N -[( E )-4-[4-(2,3-dichlorophenyl)piperazin-1-yl]but-2-enyl]-4-pyridin-2-ylbenzamide] produced a therapeutically desirable decrease in cocaine choice early in treatment; however, tolerance to this effect developed, and lower and higher doses were ineffective. D 3 ligands failed to significantly modify total cocaine intake but caused persistent decreases in food intake. Thus, D 2 -and D 3 -preferring ligands showed distinct profiles, consistent with different pharmacological actions. In addition, these results highlight the role of acute versus chronic treatment

  7. Cocaine-induced agitated delirium: a case report and review.

    Science.gov (United States)

    Plush, Theodore; Shakespeare, Walter; Jacobs, Dorian; Ladi, Larry; Sethi, Sheeba; Gasperino, James

    2015-01-01

    Cocaine use continues to be a major public health problem in the United States. Although many of the initial signs and symptoms of cocaine intoxication result from increased stimulation of the sympathetic nervous system, this condition can present as a spectrum of acuity from hypertension and tachycardia to multiorgan system failure. Classic features of acute intoxication include tachycardia, arterial vasoconstriction, enhanced thrombus formation, mydriasis, psychomotor agitation, and altered level of consciousness. At the extreme end of this toxidrome is a rare condition known as cocaine-induced agitated delirium. This syndrome is characterized by severe cardiopulmonary dysfunction, hyperthermia, and acute neurologic changes frequently leading to death. We report a case of cocaine-induced agitated delirium in a man who presented to our institution in a paradoxical form of circulatory shock. Rapid evaluation, recognition, and proper management enabled our patient not only to survive but also to leave the hospital without neurologic sequelae. © The Author(s) 2013.

  8. Templated assembly of photoswitches significantly increases the energy-storage capacity of solar thermal fuels.

    Science.gov (United States)

    Kucharski, Timothy J; Ferralis, Nicola; Kolpak, Alexie M; Zheng, Jennie O; Nocera, Daniel G; Grossman, Jeffrey C

    2014-05-01

    Large-scale utilization of solar-energy resources will require considerable advances in energy-storage technologies to meet ever-increasing global energy demands. Other than liquid fuels, existing energy-storage materials do not provide the requisite combination of high energy density, high stability, easy handling, transportability and low cost. New hybrid solar thermal fuels, composed of photoswitchable molecules on rigid, low-mass nanostructures, transcend the physical limitations of molecular solar thermal fuels by introducing local sterically constrained environments in which interactions between chromophores can be tuned. We demonstrate this principle of a hybrid solar thermal fuel using azobenzene-functionalized carbon nanotubes. We show that, on composite bundling, the amount of energy stored per azobenzene more than doubles from 58 to 120 kJ mol(-1), and the material also maintains robust cyclability and stability. Our results demonstrate that solar thermal fuels composed of molecule-nanostructure hybrids can exhibit significantly enhanced energy-storage capabilities through the generation of template-enforced steric strain.

  9. Increased Mortality in Diabetic Foot Ulcer Patients: The Significance of Ulcer Type

    Science.gov (United States)

    Chammas, N. K.; Hill, R. L. R.; Edmonds, M. E.

    2016-01-01

    Diabetic foot ulcer (DFU) patients have a greater than twofold increase in mortality compared with nonulcerated diabetic patients. We investigated (a) cause of death in DFU patients, (b) age at death, and (c) relationship between cause of death and ulcer type. This was an eleven-year retrospective study on DFU patients who attended King's College Hospital Foot Clinic and subsequently died. A control group of nonulcerated diabetic patients was matched for age and type of diabetes mellitus. The cause of death was identified from death certificates (DC) and postmortem (PM) examinations. There were 243 DFU patient deaths during this period. Ischaemic heart disease (IHD) was the major cause of death in 62.5% on PM compared to 45.7% on DC. Mean age at death from IHD on PM was 5 years lower in DFU patients compared to controls (68.2 ± 8.7 years versus 73.1 ± 8.0 years, P = 0.015). IHD as a cause of death at PM was significantly linked to neuropathic foot ulcers (OR 3.064, 95% CI 1.003–9.366, and P = 0.049). Conclusions. IHD is the major cause of premature mortality in DFU patients with the neuropathic foot ulcer patients being at a greater risk. PMID:27213157

  10. Factors associated with an increased risk of vertebral fracture in monoclonal gammopathies of undetermined significance

    International Nuclear Information System (INIS)

    Piot, J M; Royer, M; Schmidt-Tanguy, A; Hoppé, E; Gardembas, M; Bourrée, T; Hunault, M; François, S; Boyer, F; Ifrah, N; Renier, G; Chevailler, A; Audran, M; Chappard, D; Libouban, H; Mabilleau, G; Legrand, E; Bouvard, B

    2015-01-01

    Monoclonal gammopathies of undetermined significance (MGUS) have been shown to be associated with an increased risk of fractures. This study describes prospectively the bone status of MGUS patients and determines the factors associated with vertebral fracture. We included prospectively 201 patients with MGUS, incidentally discovered, and with no known history of osteoporosis: mean age 66.6±12.5 years, 48.3% women, 51.7% immunoglobulin G (IgG), 33.3% IgM and 10.4% IgA. Light chain was kappa in 64.2% patients. All patients had spinal radiographs and bone mineral density measurement in addition to gammopathy assessment. At least one prevalent non-traumatic vertebral fracture was discovered in 18.4% patients and equally distributed between men and women. Fractured patients were older, had a lower bone density and had also more frequently a lambda light chain isotype. Compared with patients with κ light chain, the odds ratio of being fractured for patients with λ light chain was 4.32 (95% confidence interval 1.80–11.16; P=0.002). These results suggest a high prevalence of non-traumatic vertebral fractures in MGUS associated with lambda light chain isotype and not only explained by low bone density

  11. 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.

  12. Narco-scapes: Cocaine Trafficking and Deforestation in Central America

    Science.gov (United States)

    Wrathall, D.; McSweeney, K.; Nielsen, E.; Pearson, Z.

    2015-12-01

    Narcotics trafficking and drug interdiction efforts have resulted in a well-documented social crisis in Central America, but more recently, has been tightly linked to environmental catastrophe and accelerated deforestation in transit zones. This talk will outline synthesis findings from multi-country, interdisciplinary research on cocaine trafficking as an engine of forest loss in Central America. During the "narco-boom" of the mid-2000s, we observed a geographical evolution of cocaine flows into Central America, and the transit of cocaine through new spaces, accompanied by specific patterns of social and environmental change in new nodes of transit. We coarsely estimated that the total amount of cocaine flowing through Central America increased from 70 metric tons in 2000 to 350 mt in 2012, implying that total cocaine trafficking revenue in the region increased from roughly 600 million dollars to 3.5 billion in that time. We describe the mechanism by which these locally captured cocaine rents resulted in a rapid conversion of forest into cattle pasture. Narco-traffickers are drawn to invest in the cattle economy, as a direct means of laundering and formalizing proceeds. Ranching is a land intensive activity, and new narco-enriched cattle pastures can be isolated from other forms forest loss solely by their spatial and temporal change characteristics. A preliminary forest change study in Honduras, for example, indicated that areas of accelerated deforestation were in close proximity to known narcotics trafficking routes and were thirteen times more extensive on average than other forest clearings. Deforested areas commonly appeared in isolated and biodiverse lowland tropical rainforest regions that often intersected with protected areas and indigenous reserves. We find that narco-deforestation is a readily identifiable signal of the extent and health of the cocaine economy. This talk will feature summaries of both ethnographic and land cover change we have observed

  13. The Impact of Disulfiram Treatment on the Reinforcing Effects of Cocaine: A Randomized Clinical Trial

    Science.gov (United States)

    Haile, Colin N.; De La Garza, Richard; Mahoney, James J.; Nielsen, David A.; Kosten, Thomas R.; Newton, Thomas F.

    2012-01-01

    Background Clinical trials indicate that disulfiram (250 mg/d) reduces cocaine use, though one study found that treatment with lower doses of disulfiram (62.5 and 125 mg/d) increased cocaine use. We conducted the present study to better understand how disulfiram alters the reinforcing effects of cocaine in cocaine users. Methods Seventeen non-treatment seeking, cocaine-dependent volunteers participated in this double-blind, placebo-controlled, laboratory-based study. A cross-over design was utilized in which participants received placebo in one phase and disulfiram (250 mg/d) in the other. Following three days of study medication participants completed two choice sessions. In one they made 10 choices between receiving an intravenous infusion of saline or money that increased in value (US$ 0.05–16) and in the other cocaine (20 mg) or money. Results Participants chose cocaine more than saline under both disulfiram and placebo conditions (p<0.05). Unexpectedly, disulfiram increased both the number of cocaine and saline infusion choices (p<0.05). We next examined the relationship between disulfiram dose and cocaine choices. Disulfiram dose (mg/kg bodyweight) was negatively correlated with number of choices for cocaine (p<0.05). Disulfiram also enhanced cocaine-induced increases in cardiovascular measures (p's<0.05–0.01). Conclusions Disulfiram's impact on the reinforcing effects of cocaine depends on dose relative to body weight. Our results suggest that the use of weight-based medication doses would produce more reliable effects, consistent with weight-based dosing used in pediatrics and in preclinical research. Trial Registration Clinicaltrials.gov NCT00729300 PMID:23144826

  14. Constrained parameterisation of photosynthetic capacity causes significant increase of modelled tropical vegetation surface temperature

    Science.gov (United States)

    Kattge, J.; Knorr, W.; Raddatz, T.; Wirth, C.

    2009-04-01

    Photosynthetic capacity is one of the most sensitive parameters of terrestrial biosphere models whose representation in global scale simulations has been severely hampered by a lack of systematic analyses using a sufficiently broad database. Due to its coupling to stomatal conductance changes in the parameterisation of photosynthetic capacity may potentially influence transpiration rates and vegetation surface temperature. Here, we provide a constrained parameterisation of photosynthetic capacity for different plant functional types in the context of the photosynthesis model proposed by Farquhar et al. (1980), based on a comprehensive compilation of leaf photosynthesis rates and leaf nitrogen content. Mean values of photosynthetic capacity were implemented into the coupled climate-vegetation model ECHAM5/JSBACH and modelled gross primary production (GPP) is compared to a compilation of independent observations on stand scale. Compared to the current standard parameterisation the root-mean-squared difference between modelled and observed GPP is substantially reduced for almost all PFTs by the new parameterisation of photosynthetic capacity. We find a systematic depression of NUE (photosynthetic capacity divided by leaf nitrogen content) on certain tropical soils that are known to be deficient in phosphorus. Photosynthetic capacity of tropical trees derived by this study is substantially lower than standard estimates currently used in terrestrial biosphere models. This causes a decrease of modelled GPP while it significantly increases modelled tropical vegetation surface temperatures, up to 0.8°C. These results emphasise the importance of a constrained parameterisation of photosynthetic capacity not only for the carbon cycle, but also for the climate system.

  15. Significant yield increases from control of leaf diseases in maize - an overlooked problem?!

    DEFF Research Database (Denmark)

    Jørgensen, Lise Nistrup

    2012-01-01

    The area of maize has increased in several European countries in recent years. In Denmark, the area has increased from 10,000 ha in 1980 to 185,000 ha in 2011. Initially only silage maize was cultivated in Denmark, but in more recent years the area of grain maize has also increased. Farms growing...

  16. Cocaine treatment admissions at three sentinel sites in South Africa (1997–2006: findings and implications for policy, practice and research

    Directory of Open Access Journals (Sweden)

    Plüddemann Andreas

    2007-12-01

    Full Text Available Abstract Background Accurate prevalence data on cocaine use, that points to where problems exist and the extent of these problems, is necessary to guide the formulation of effective substance abuse policy and practice. The purpose of this study was to provide surveillance information about the nature and extent of problematic cocaine use in South Africa. Methods Data were collected between January 1997 and December 2006 on admissions for drug abuse treatment through a regular monitoring system involving 56 drug treatment centres and programmes in Cape Town, Gauteng Province (Johannesburg and Pretoria and the Eastern Cape every six months as part of the South African Community Epidemiology Network on Drug Use (SACENDU. A one-page form was completed by treatment centre personnel to obtain demographic data, the patients' primary and secondary substances of abuse, the mode, frequency and age of first use of substance, and information on prior treatment. Results Treatment indicators point to a significant increase in cocaine related admissions over time in all sites, but with substantial inter-site variation, particularly in recent years. The data indicate high levels of crack cocaine use and high levels of daily usage among patients, most of whom were first time admissions. Patients with cocaine related problems continue to be predominantly male, with a mean age of around 30 years. Substantial changes in the racial profile of patients have occurred over time. Poly drug use is high with cocaine often used with alcohol, cannabis and other drugs. Conclusion These trends point to the possibility of cocaine use becoming a serious health and social issue in South Africa and demonstrate the utility of continued monitoring of cocaine treatment admissions in the future. They also highlight the need to address cocaine use in national and provincial policy planning and intervention efforts. In terms of treatment, the findings highlight the need to ensure that

  17. Aerobic exercise decreases the positive-reinforcing effects of cocaine.

    Science.gov (United States)

    Smith, Mark A; Schmidt, Karl T; Iordanou, Jordan C; Mustroph, Martina L

    2008-11-01

    Aerobic exercise can serve as an alternative, non-drug reinforcer in laboratory animals and has been recommended as a potential intervention for substance abusing populations. Unfortunately, relatively little empirical data have been collected that specifically address the possible protective effects of voluntary, long-term exercise on measures of drug self-administration. The purpose of the present study was to examine the effects of chronic exercise on sensitivity to the positive-reinforcing effects of cocaine in the drug self-administration procedure. Female rats were obtained at weaning and immediately divided into two groups. Sedentary rats were housed individually in standard laboratory cages that permitted no exercise beyond normal cage ambulation; exercising rats were housed individually in modified cages equipped with a running wheel. After 6 weeks under these conditions, rats were surgically implanted with venous catheters and trained to self-administer cocaine on a fixed-ratio schedule of reinforcement. Once self-administration was acquired, cocaine was made available on a progressive ratio schedule and breakpoints were obtained for various doses of cocaine. Sedentary and exercising rats did not differ in the time to acquire cocaine self-administration or responding on the fixed-ratio schedule of reinforcement. However, on the progressive ratio schedule, breakpoints were significantly lower in exercising rats than sedentary rats when responding was maintained by both low (0.3mg/kg/infusion) and high (1.0mg/kg/infusion) doses of cocaine. In exercising rats, greater exercise output prior to catheter implantation was associated with lower breakpoints at the high dose of cocaine. These data indicate that chronic exercise decreases the positive-reinforcing effects of cocaine and support the possibility that exercise may be an effective intervention in drug abuse prevention and treatment programs.

  18. Measuring Outcome in the Treatment of Cocaine Dependence

    Science.gov (United States)

    Crits-Christoph, Paul; Gallop, Robert; Gibbons, Mary Beth Connolly; Sadicario, Jaclyn S.; Woody, George

    2015-01-01

    Background Little in known about the extent to which outcome measures used in studies of the treatment of cocaine dependence are associated with longer-term use and with broader measures of clinical improvement. The current study examined reductions in use, and abstinence-oriented measures, in relation to functioning and longer-term clinical benefits in the treatment of cocaine dependence. Methods Overall drug use, cocaine use, and functioning in a number of addiction-related domains for 487 patients diagnosed with DSM-IV cocaine dependence and treated with one of four psychosocial interventions in the NIDA Cocaine Collaborative Treatment Study were assessed monthly during 6 months of treatment and at 9, 12, 15, and 18 month follow-up. Results Measures of during-treatment reduction in use were moderately correlated with drug and cocaine use measures 12 months, but showed non-significant or small correlations with measures of functioning at 12 months. Highest correlations were evident for abstinence measures (maximum consecutive days abstinence and completely abstinent) during treatment in relation to sustained (3 month) abstinence at 12 months. Latent class analysis of patterns of change over time revealed that most patients initially (months 1 to 4 of treatment) either became abstinent immediately or continued to use every month. Over the couse of follow-up, patients either maintained abstinence or used regularly – intermittent use was less common. Conclusions There were generally small associations between various measures of cocaine use and longer-term clinical benefits, other than abstinence was associated with continued abstinence. No one method of measuring outcome of treatment of cocaine dependence appears superior to others. PMID:26366427

  19. A spatio-temporal analysis of forest loss related to cocaine trafficking in Central America

    Science.gov (United States)

    Sesnie, Steven E.; Tellman, Beth; Wrathall, David; McSweeney, Kendra; Nielsen, Erik; Benessaiah, Karina; Wang, Ophelia; Rey, Luis

    2017-05-01

    A growing body of evidence suggests that criminal activities associated with drug trafficking networks are a progressively important driver of forest loss in Central America. However, the scale at which drug trafficking represents a driver of forest loss is not presently known. We estimated the degree to which narcotics trafficking may contribute to forest loss using an unsupervised spatial clustering of 15 spatial and temporal forest loss patch metrics developed from global forest change data. We distinguished anomalous forest loss from background loss patches for each country exhibiting potential ‘narco-capitalized’ signatures which showed a statistically significant dissimilarity from other patches in terms of size, timing, and rate of forest loss. We also compared annual anomalous forest loss with the number of cocaine shipments and volume of cocaine seized, lost, or delivered at country- and department-level. For Honduras, results from linear mixed effects models showed a highly significant relationship between anomalous forest loss and the timing of increased drug trafficking (F = 9.90, p = 0.009) that also differed significantly from temporal patterns of background forest loss (t-ratio = 2.98, p = 0.004). Other locations of high forest loss in Central America showed mixed results. The timing of increased trafficking was not significantly related to anomalous forest loss in Guatemala and Nicaragua, but significantly differed in patch size compared to background losses. We estimated that cocaine trafficking could account for between 15% and 30% of annual national forest loss in these three countries over the past decade, and 30% to 60% of loss occurred within nationally and internationally designated protected areas. Cocaine trafficking is likely to have severe and lasting consequences in terms of maintaining moist tropical forest cover in Central America. Addressing forest loss in these and other tropical locations will require a stronger

  20. Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity

    International Nuclear Information System (INIS)

    Vilela, Luciano R.; Gobira, Pedro H.; Viana, Thercia G.; Medeiros, Daniel C.; Ferreira-Vieira, Talita H.; Doria, Juliana G.; Rodrigues, Flávia; Aguiar, Daniele C.; Pereira, Grace S.; Massessini, André R.; Ribeiro, Fabíola M.; Oliveira, Antonio Carlos P. de; Moraes, Marcio F.D.; Moreira, Fabricio A.

    2015-01-01

    Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB 1 receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB 1 receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity. - Highlights: • Cocaine toxicity is characterized by seizures and hippocampal cell death. • The endocannabinoid anandamide acts as a brain protective mechanism. • Inhibition of anandamide hydrolysis attenuates

  1. Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Vilela, Luciano R. [Graduate Program in Neuroscience, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Gobira, Pedro H.; Viana, Thercia G. [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Medeiros, Daniel C.; Ferreira-Vieira, Talita H. [Department of Physiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Doria, Juliana G. [Graduate Program in Neuroscience, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Rodrigues, Flávia [Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Aguiar, Daniele C. [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Pereira, Grace S.; Massessini, André R. [Department of Physiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Ribeiro, Fabíola M. [Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Oliveira, Antonio Carlos P. de [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Moraes, Marcio F.D., E-mail: mfdm@icb.ufmg.br [Department of Physiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Moreira, Fabricio A., E-mail: fabriciomoreira@icb.ufmg.br [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil)

    2015-08-01

    Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB{sub 1} receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB{sub 1} receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity. - Highlights: • Cocaine toxicity is characterized by seizures and hippocampal cell death. • The endocannabinoid anandamide acts as a brain protective mechanism. • Inhibition of anandamide hydrolysis

  2. Ultraviolet resonance Raman spectroscopy for the detection of cocaine in oral fluid

    Science.gov (United States)

    D'Elia, Valentina; Montalvo, Gemma; Ruiz, Carmen García; Ermolenkov, Vladimir V.; Ahmed, Yasmine; Lednev, Igor K.

    2018-01-01

    Detecting and quantifying cocaine in oral fluid is of significant importance for practical forensics. Up to date, mainly destructive methods or biochemical tests have been used, while spectroscopic methods were only applied to pretreated samples. In this work, the possibility of using resonance Raman spectroscopy to detect cocaine in oral fluid without pretreating samples was tested. It was found that ultraviolet resonance Raman spectroscopy with 239-nm excitation allows for the detection of cocaine in oral fluid at 10 μg/mL level. Further method development will be needed for reaching the practically useful levels of cocaine detection.

  3. 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.

  4. Brain activation to cocaine cues and motivation/treatment status.

    Science.gov (United States)

    Prisciandaro, James J; McRae-Clark, Aimee L; Myrick, Hugh; Henderson, Scott; Brady, Kathleen T

    2014-03-01

    Motivation to change is believed to be a key factor in therapeutic success in substance use disorders; however, the neurobiological mechanisms through which motivation to change impacts decreased substance use remain unclear. Existing research is conflicting, with some investigations supporting decreased and others reporting increased frontal activation to drug cues in individuals seeking treatment for substance use disorders. The present study investigated the relationship between motivation to change cocaine use and cue-elicited brain activity in cocaine-dependent individuals using two conceptualizations of 'motivation to change': (1) current treatment status (i.e. currently receiving versus not receiving outpatient treatment for cocaine dependence) and (2) self-reported motivation to change substance use, using the Stages of Change Readiness and Treatment Eagerness Scale. Thirty-eight cocaine-dependent individuals (14 currently in treatment) completed a diagnostic assessment and an fMRI cocaine cue-reactivity task. Whole-brain analyses demonstrated that both treatment-seeking and motivated participants had lower activation to cocaine cues in a wide variety of brain regions in the frontal, occipital, temporal and cingulate cortices relative to non-treatment-seeking and less motivated participants. Future research is needed to explain the mechanism by which treatment and/or motivation impacts neural cue reactivity, as such work could potentially aid in the development of more effective therapeutic techniques for substance-dependent patients. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.

  5. Evaluation of the Reinforcing Effect of Quetiapine, Alone and in Combination with Cocaine, in Rhesus Monkeys.

    Science.gov (United States)

    Brutcher, Robert E; Nader, Susan H; Nader, Michael A

    2016-02-01

    There are several case reports of nonmedicinal quetiapine abuse, yet there are very limited preclinical studies investigating quetiapine self-administration. The goal of this study was to investigate the reinforcing effects of quetiapine alone and in combination with intravenous cocaine in monkeys. In experiment 1, cocaine-experienced female monkeys (N = 4) responded under a fixed-ratio (FR) 30 schedule of food reinforcement (1.0-g banana-flavored pellets), and when responding was stable, quetiapine (0.003-0.1 mg/kg per injection) or saline was substituted for a minimum of five sessions; there was a return to food-maintained responding between doses. Next, monkeys were treated with quetiapine (25 mg, by mouth, twice a day) for approximately 30 days, and then the quetiapine self-administration dose-response curve was redetermined. In experiment 2, male monkeys (N = 6) self-administered cocaine under a concurrent FR schedule with food reinforcement (three food pellets) as the alternative to cocaine (0.003-0.3 mg/kg per injection) presentation. Once choice responding was stable, the effects of adding quetiapine (0.03 or 0.1 mg/kg per injection) to the cocaine solution were examined. In experiment 1, quetiapine did not function as a reinforcer, and chronic quetiapine treatment did not alter these effects. In experiment 2, cocaine choice increased in a dose-dependent fashion. The addition of quetiapine to cocaine resulted in increases in low-dose cocaine choice and number of cocaine injections in four monkeys, while not affecting high-dose cocaine preference. Thus, although quetiapine alone does not have abuse potential, there was evidence of enhancement of the reinforcing potency of cocaine. These results suggest that the use of quetiapine in cocaine-addicted patients should be monitored. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  6. Suppression of cocaine self-administration in monkeys: effects of delayed punishment.

    Science.gov (United States)

    Woolverton, William L; Freeman, Kevin B; Myerson, Joel; Green, Leonard

    2012-04-01

    Delaying presentation of a drug can decrease its effectiveness as a reinforcer, but the effect of delaying punishment of drug self-administration is unknown. This study examined whether a histamine injection could punish cocaine self-administration in a drug-drug choice, whether delaying histamine would decrease its effectiveness, and whether the effects of delay could be described within a delay discounting framework. Monkeys were implanted with double-lumen catheters to allow separate injection of cocaine and histamine. In discrete trials, subjects first chose between cocaine (50 or 100 μg/kg/inj) alone and an injection of the same dose of cocaine followed immediately by an injection of histamine (0.37-50 μg/kg). Next, they chose between cocaine followed immediately by histamine and cocaine followed by an equal but delayed dose of histamine. When choosing between cocaine alone and cocaine followed immediately by histamine, preference increased with histamine dose from indifference to >80% choice of cocaine alone. When choosing between cocaine followed by immediate histamine and cocaine followed by delayed histamine, monkeys showed strong position preferences. When delayed histamine was associated with the nonpreferred position, preference for that option increased with delay from ≤30% to >85%. The corresponding decrease in choice of the preferred position was well described by a hyperboloid discounting function. Histamine can function as a punisher in the choice between injections of cocaine and delay can decrease its effectiveness as a punisher. The effects of delaying punishment of drug self-administration can be conceptualized within the delay discounting framework.

  7. Possible addiction transference from cocaine insufflation to oral bupropion in bipolar patient.

    Science.gov (United States)

    Costa, Carolina; Araujo, Alberto; Brasil, Marco; Cruz, Marcelo

    2015-01-01

    Alert for the risk of oral bupropion addiction in patients with cocaine dependence. Single-case study. After a period of cocaine and alcohol abstinence, a 42-year-old patient started taking oral bupropion to relieve the symptoms of cocaine craving. He increased the bupropion dose up to 2250 mg/d without seizures. This case highlights the possibility of oral bupropion addiction after cocaine dependence. To our knowledge, it is the first case in the literature and emphasizes the risk of bupropion's misuse. Therefore, physicians should carefully examine the patient's profile before prescribing it, as well as follow appropriate measures.

  8. 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.

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

    Science.gov (United States)

    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.

  10. Differential vulnerability to the punishment of cocaine related behaviours: effects of locus of punishment, cocaine taking history and alternative reinforcer availability.

    Science.gov (United States)

    Pelloux, Yann; Murray, Jennifer E; Everitt, Barry J

    2015-01-01

    The availability of alternative reinforcement has been shown to reduce drug use, but it remains unclear whether it facilitates a reduction or cessation of drug seeking or taking. We compared the effects of punishment of cocaine seeking or taking behaviour after brief or extended cocaine-taking histories when behavioural reallocation was facilitated or not by making available an alternative ingestive reinforcer (sucrose). In the first experiment, punishment of either seeking or taking responses was introduced immediately after training on the seeking-taking chained schedule. In the second experiment, punishment of cocaine seeking was introduced after 12 additional days of either 1 or 6 h daily access to cocaine self-administration. In both experiments, beginning 1 week before the introduction of punishment, a subset of rats had concurrent nose poke access to sucrose while seeking or taking cocaine. The presence of an alternative source of reinforcement markedly facilitated behavioural reallocation from punished cocaine taking after acquisition. It also facilitated punishment-induced suppression of cocaine seeking after an extensive cocaine self-administration history likely by prompting goal-directed motivational control over drug use. However, a significant proportion of rats were deemed compulsive-maintaining drug use after an extensive cocaine history despite the presence of abstinence-promoting positive and negative incentives. Making available an alternative reinforcer facilitates disengagement from punished cocaine use through at least two different processes but remains ineffective in a subpopulation of vulnerable animals, which continued to seek cocaine despite the aversive consequence of punishment and the presence of the alternative positive reinforcer.

  11. Laboratory measures of methylphenidate effects in cocaine-dependent patients receiving treatment.

    Science.gov (United States)

    Roache, J D; Grabowski, J; Schmitz, J M; Creson, D L; Rhoades, H M

    2000-02-01

    Two experiments examined the effects of methylphenidate in male and female patients enrolled in an outpatient treatment program for primary cocaine dependence. The first study was a component of a double-blind efficacy trial wherein 57 patients were first tested in a human laboratory for their initial responsiveness to medication. Patients were randomly assigned to receive either placebo or methylphenidate treatment and received their first dose in the human laboratory environment before continuing in outpatient treatment. Methylphenidate was given as a 20-mg sustained-release dose (twice daily) plus an additional 5-mg immediate-release dose combined with the morning dose. Methylphenidate increased heart rate and subjective ratings; however, the subjective effects were primarily of a "dysphoric" nature, and significant effects were limited to increases in anxiety, depression, and anger on the Profile of Mood States; shaky/jittery ratings on a visual analog scale; and dysphoria on the lysergic acid diethylamide (LSD) scale of the Addiction Research Center Inventory. Methylphenidate did not increase cocaine craving nor ratings suggesting abuse potential (i.e., Morphine-Benzedrine Group or drug-liking scores, etc.). None of the drug effects observed in the human laboratory was of clinical concern, and no subject was precluded from continuing in the outpatient study. After outpatient treatment completion, 12 patients were brought back into a second double-blind human laboratory study in which three doses (15, 30, and 60 mg) of immediate-release methylphenidate were administered in an ascending series preceded and followed by placebo. Methylphenidate produced dose-related increases in heart rate, subjective ratings of shaky/jittery, and LSD/dysphoria without significantly altering cocaine craving or stimulant euphoria ratings. These results suggest that stimulant substitution-type approaches to the treatment of cocaine dependence are not necessarily contraindicated

  12. PI3 kinase is involved in cocaine behavioral sensitization and its reversal with brain area specificity

    International Nuclear Information System (INIS)

    Zhang Xiuwu; Mi Jing; Wetsel, William C.; Davidson, Colin; Xiong Xieying; Chen Qiang; Ellinwood, Everett H.; Lee, Tong H.

    2006-01-01

    Phosphatidylinositol 3-kinase (PI3K) is an important signaling molecule involved in cell differentiation, proliferation, survival, and phagocytosis, and may participate in various brain functions. To determine whether it is also involved in cocaine sensitization, we measured the p85α/p110 PI3K activity in the nuclear accumbens (NAc) shell, NAc core, and prefrontal cortex (PFC) following establishment of cocaine sensitization and its subsequent reversal. Naive rats were rank-ordered and split into either daily cocaine or saline pretreatment group based on their locomotor responses to an acute cocaine injection (7.5 mg/kg, i.p.). These two groups were then injected with cocaine (40 mg/kg, s.c.) or saline for 4 consecutive days followed by 9-day withdrawal. Cocaine sensitization was subsequently reversed by 5 daily injections of the D 1 /D 2 agonist pergolide (0.1 mg/kg, s.c.) in combination with the 5-HT 3 antagonist ondansetron (0.2 mg/kg, s.c., 3.5 h after pergolide injection). After another 9-day withdrawal, behavioral cocaine sensitization and its reversal were confirmed with an acute cocaine challenge (7.5 mg/kg, i.p.), and animals were sacrificed the next day for measurement of p85α/p110 PI3K activity. Cocaine-sensitized animals exhibited increased PI3K activity in the NAc shell, and this increase was reversed by combined pergolide/ondansetron treatment, which also reversed behavioral sensitization. In the NAc core and PFC, cocaine sensitization decreased and increased the PI3K activity, respectively. These changes, in contrast to that in the NAc shell, were not normalized following the reversal of cocaine-sensitization. Interestingly, daily injections of pergolide alone in saline-pretreated animals induced PI3K changes that were similar to the cocaine sensitization-associated changes in the NAc core and PFC but not the NAc shell; furthermore, these changes in saline-pretreated animals were prevented by ondansetron given 3.5 h after pergolide. The present

  13. 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.

  14. 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.

  15. 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.

  16. Presence of gingivitis and periodontitis significantly increases hospital charges in patients undergoing heart valve surgery.

    Science.gov (United States)

    Allareddy, Veerasathpurush; Elangovan, Satheesh; Rampa, Sankeerth; Shin, Kyungsup; Nalliah, Romesh P; Allareddy, Veerajalandhar

    2015-01-01

    To examine the prevalence and impact of gingivitis and periodontitis in patients having heart valve surgical procedures. Nationwide Inpatient Sample for the years 2004-2010 was used. All patients who had heart valve surgical procedures were selected. Prevalence of gingivitis/periodontitis was examined in these patients. Impact of gingivitis/periodontitis on hospital charges, length of stay, and infectious complications was examined. 596,190 patients had heart valve surgical procedures. Gingivitis/periodontitis was present in 0.2 percent. Outcomes included: median hospital charges ($175,418 with gingivitis/ periodontitis versus $149,353 without gingivitis/periodontitis) and median length of stay (14 days with gingivitis/periodontitis versus 8 days without gingivitis/periodontitis). After adjusting for the effects of patient- and hospital-level confounding factors, hospital charges and length of stay were significantly higher (p gingivitis/periodontitis compared to their counterparts. Further, patients with gingivitis/periodontitis had significantly higher odds for having bacterial infections (OR = 3.41, 95% CI = 2.33-4.98, p gingivitis/periodontitis. Presence of gingivitis and periodontitis is associated with higher risk for bacterial infections and significant hospital resource utilization.

  17. Cocaine use is associated with a higher prevalence of elevated ST2 concentrations.

    Science.gov (United States)

    van Wijk, Xander M R; Vittinghoff, Eric; Wu, Alan H B; Lynch, Kara L; Riley, Elise D

    2017-09-01

    Cocaine is a well-known risk factor for acute cardiac events, but the effects in users outside of acute events are less clear. We investigated a possible association between cocaine use and the concentration of a novel biomarker for cardiac stress and heart failure, ST2. A case-control study was conducted to compare ST2 concentrations by the presence of cocaine in patients presenting for care, but not cardiac care, at an urban safety net hospital. In samples taken from 100 cocaine-positive and 100 cocaine-negative patients, the presence of cocaine was associated with ST2 concentrations>35ng/mL. Serum concentrations of benzoylecgonine, a major cocaine metabolite, were significantly correlated with ST2 concentrations. Cocaine use is associated with subclinical cardiac stress and damage outside of acute cardiac events. This information could add to better stratification of cocaine users with elevated ST2 concentrations who may be at higher risk for developing heart failure and other cardiac complications. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  18. Differential sensitivity of long-sleep and short-sleep mice to high doses of cocaine.

    Science.gov (United States)

    de Fiebre, C M; Ruth, J A; Collins, A C

    1989-12-01

    The cocaine sensitivity of male and female long-sleep (LS) and short-sleep (SS) mice, which have been selectively bred for differential ethanol-induced "sleep-time," was examined in a battery of behavioral and physiological tests. Differences between these two mouse lines were subtle and were seen primarily at high doses. At high doses, SS mice were more sensitive than LS mice, particularly to cocaine-induced hypothermia; however, significant hypothermia was not seen except at doses which were very near to the seizure threshold. During a 60-min test of locomotor activity, LS mice showed greater stimulation of Y-maze activity by 20 mg/kg cocaine than SS mice. Consistent with the finding of subtle differences in sensitivity to low doses of cocaine. LS and SS mice did not differ in sensitivity to cocaine inhibition of synaptosomal uptake of [3H]-dopamine, [3H]-norepinephrine or [3H]-5-hydroxytryptamine. However, consistent with the finding of differential sensitivity to high doses of cocaine, SS mice were more sensitive to the seizure-producing effects of the cocaine and lidocaine, a local anesthetic. It is hypothesized that the differential sensitivity of these mouse lines to high doses of cocaine is due to differential sensitivity to cocaine's actions on systems that regulate local anesthetic effects. Selective breeding for differential duration of alcohol-induced "sleep-time" may have resulted in differential ion channel structure or function in these mice.

  19. Transabdominal cerclage: the significance of dual pathology and increased preterm delivery.

    Science.gov (United States)

    Farquharson, Roy G; Topping, Joanne; Quenby, Siobhan M

    2005-10-01

    Transabdominal cerclage is a recognised treatment for cervical weakness with a history of recurrent mid-trimester loss and a failed elective vaginal suture. The emergence of dual pathology, such as antiphospholipid syndrome and bacterial vaginosis, is associated with an increased risk of preterm delivery (RR 2.34, 95% CI 1.15-5.8). The first 40 cases are described where strict adherence to an investigation protocol and consistent treatment plan has been implemented.

  20. Employment-based abstinence reinforcement promotes opiate and cocaine abstinence in out-of-treatment injection drug users.

    Science.gov (United States)

    Holtyn, August F; Koffarnus, Mikhail N; DeFulio, Anthony; Sigurdsson, Sigurdur O; Strain, Eric C; Schwartz, Robert P; Silverman, Kenneth

    2014-01-01

    We examined the use of employment-based abstinence reinforcement in out-of-treatment injection drug users, in this secondary analysis of a previously reported trial. Participants (N = 33) could work in the therapeutic workplace, a model employment-based program for drug addiction, for 30 weeks and could earn approximately $10 per hr. During a 4-week induction, participants only had to work to earn pay. After induction, access to the workplace was contingent on enrollment in methadone treatment. After participants met the methadone contingency for 3 weeks, they had to provide opiate-negative urine samples to maintain maximum pay. After participants met those contingencies for 3 weeks, they had to provide opiate- and cocaine-negative urine samples to maintain maximum pay. The percentage of drug-negative urine samples remained stable until the abstinence reinforcement contingency for each drug was applied. The percentage of opiate- and cocaine-negative urine samples increased abruptly and significantly after the opiate- and cocaine-abstinence contingencies, respectively, were applied. These results demonstrate that the sequential administration of employment-based abstinence reinforcement can increase opiate and cocaine abstinence among out-of-treatment injection drug users. © Society for the Experimental Analysis of Behavior.

  1. The role of progestins in the behavioral effects of cocaine and other drugs of abuse: human and animal research.

    Science.gov (United States)

    Anker, Justin J; Carroll, Marilyn E

    2010-11-01

    This review summarizes findings from human and animal research investigating the influence of progesterone and its metabolites allopreganolone and pregnanolone (progestins) on the effects of cocaine and other drugs of abuse. Since a majority of these studies have used cocaine, this will be the primary focus; however, the influence of progestins on other drugs of abuse will also be discussed. Collectively, findings from these studies support a role for progestins in (1) attenuating the subjective and physiological effects of cocaine in humans, (2) blocking the reinforcing and other behavioral effects of cocaine in animal models of drug abuse, and (3) influencing behavioral responses to other drugs of abuse such as alcohol and nicotine in animals. Administration of several drugs of abuse in both human and nonhuman animals significantly increased progestin levels, and this is explained in terms of progestins acting as homeostatic regulators that decrease and normalize heightened stress and reward responses which lead to increased drug craving and relapse. The findings discussed here highlight the complexity of progestin-drug interactions, and they suggest a possible use for these agents in understanding the etiology of and developing treatments for drug abuse. Copyright © 2010 Elsevier Ltd. All rights reserved.

  2. Granulocyte-colony stimulating factor controls neural and behavioral plasticity in response to cocaine.

    Science.gov (United States)

    Calipari, Erin S; Godino, Arthur; Peck, Emily G; Salery, Marine; Mervosh, Nicholas L; Landry, Joseph A; Russo, Scott J; Hurd, Yasmin L; Nestler, Eric J; Kiraly, Drew D

    2018-01-16

    Cocaine addiction is characterized by dysfunction in reward-related brain circuits, leading to maladaptive motivation to seek and take the drug. There are currently no clinically available pharmacotherapies to treat cocaine addiction. Through a broad screen of innate immune mediators, we identify granulocyte-colony stimulating factor (G-CSF) as a potent mediator of cocaine-induced adaptations. Here we report that G-CSF potentiates cocaine-induced increases in neural activity in the nucleus accumbens (NAc) and prefrontal cortex. In addition, G-CSF injections potentiate cocaine place preference and enhance motivation to self-administer cocaine, while not affecting responses to natural rewards. Infusion of G-CSF neutralizing antibody into NAc blocks the ability of G-CSF to modulate cocaine's behavioral effects, providing a direct link between central G-CSF action in NAc and cocaine reward. These results demonstrate that manipulating G-CSF is sufficient to alter the motivation for cocaine, but not natural rewards, providing a pharmacotherapeutic avenue to manipulate addictive behaviors without abuse potential.

  3. Norepinephrine signaling through beta-adrenergic receptors is critical for expression of cocaine-induced anxiety.

    Science.gov (United States)

    Schank, Jesse R; Liles, L Cameron; Weinshenker, David

    2008-06-01

    Cocaine is a widely abused psychostimulant that has both rewarding and aversive properties. While the mechanisms underlying cocaine's rewarding effects have been studied extensively, less attention has been paid to the unpleasant behavioral states induced by cocaine, such as anxiety. In this study, we evaluated the performance of dopamine beta-hydroxylase knockout (Dbh -/-) mice, which lack norepinephrine (NE), in the elevated plus maze (EPM) to examine the contribution of noradrenergic signaling to cocaine-induced anxiety. We found that cocaine dose-dependently increased anxiety-like behavior in control (Dbh +/-) mice, as measured by a decrease in open arm exploration. The Dbh -/- mice had normal baseline performance in the EPM but were completely resistant to the anxiogenic effects of cocaine. Cocaine-induced anxiety was also attenuated in Dbh +/- mice following administration of disulfiram, a dopamine beta-hydroxylase (DBH) inhibitor. In experiments using specific adrenergic antagonists, we found that pretreatment with the beta-adrenergic receptor antagonist propranolol blocked cocaine-induced anxiety-like behavior in Dbh +/- and wild-type C57BL6/J mice, while the alpha(1) antagonist prazosin and the alpha(2) antagonist yohimbine had no effect. These results indicate that noradrenergic signaling via beta-adrenergic receptors is required for cocaine-induced anxiety in mice.

  4. Pair housing differentially affects motivation to self-administer cocaine in male and female rats.

    Science.gov (United States)

    Westenbroek, Christel; Perry, Adam N; Becker, Jill B

    2013-09-01

    Female rats exhibit greater intake and motivation to self-administer cocaine. In females but not males, isolation by itself is a stressor, which could lead to increased drug intake. Therefore, we hypothesized that social housing would buffer against stress and reduce the motivation to self-administer cocaine primarily in females. Male and female Sprague-Dawley rats were housed individually or in same-sex pairs. The individually housed rats and one of each pair were allowed to self-administer (SA) a low dose of cocaine (0.2 mg/kg/inf) on a fixed ratio (FR1) schedule for one week. Motivation for cocaine SA was measured for an additional 2 weeks on a progressive ratio schedule. Isolated females had greater cocaine-intake on the FR1 schedule and greater motivation to take cocaine than males. Pair-housing in females, but not males, attenuated the motivation to take cocaine. Isolated females, but not males, showed escalation of their motivation to take cocaine, which was attenuated by pair housing of females. Concluding, the motivation to take cocaine escalates in females but not males, and pair-housing of females attenuates this escalation. Copyright © 2013 Elsevier B.V. All rights reserved.

  5. Clinical significance of increased lung/heart ratio in 210Tl stress myocardial image

    International Nuclear Information System (INIS)

    Liu Zaoli; Chang Fengqin; Zhang Fengge; Wang Xiaoyuan; Liu Liuhua

    1990-01-01

    230 cases were studied with 201 Tl stress image. The results showed that the lung/heart ratio closely correlated with the presence and severity of coronary heart disease (CHD). Among them, 18 cases (7.8%) showed significantly elevated lung/heart ratio (> 0.50). It was confirmed that all of the 18 cases have severe CHD with left ventricular insufficiency. The author emphasizes that measurement of the lung/heart ratio during 201 Tl stress myocardial image may be useful for the assessment of the severity, evalation of the left ventricular function and judgement of prognosis in CHD

  6. Strong Selection Significantly Increases Epistatic Interactions in the Long-Term Evolution of a Protein.

    Directory of Open Access Journals (Sweden)

    Aditi Gupta

    2016-03-01

    Full Text Available Epistatic interactions between residues determine a protein's adaptability and shape its evolutionary trajectory. When a protein experiences a changed environment, it is under strong selection to find a peak in the new fitness landscape. It has been shown that strong selection increases epistatic interactions as well as the ruggedness of the fitness landscape, but little is known about how the epistatic interactions change under selection in the long-term evolution of a protein. Here we analyze the evolution of epistasis in the protease of the human immunodeficiency virus type 1 (HIV-1 using protease sequences collected for almost a decade from both treated and untreated patients, to understand how epistasis changes and how those changes impact the long-term evolvability of a protein. We use an information-theoretic proxy for epistasis that quantifies the co-variation between sites, and show that positive information is a necessary (but not sufficient condition that detects epistasis in most cases. We analyze the "fossils" of the evolutionary trajectories of the protein contained in the sequence data, and show that epistasis continues to enrich under strong selection, but not for proteins whose environment is unchanged. The increase in epistasis compensates for the information loss due to sequence variability brought about by treatment, and facilitates adaptation in the increasingly rugged fitness landscape of treatment. While epistasis is thought to enhance evolvability via valley-crossing early-on in adaptation, it can hinder adaptation later when the landscape has turned rugged. However, we find no evidence that the HIV-1 protease has reached its potential for evolution after 9 years of adapting to a drug environment that itself is constantly changing. We suggest that the mechanism of encoding new information into pairwise interactions is central to protein evolution not just in HIV-1 protease, but for any protein adapting to a changing

  7. Corruption Significantly Increases the Capital Cost of Power Plants in Developing Contexts

    Directory of Open Access Journals (Sweden)

    Kumar Biswajit Debnath

    2018-03-01

    Full Text Available Emerging economies with rapidly growing population and energy demand, own some of the most expensive power plants in the world. We hypothesized that corruption has a relationship with the capital cost of power plants in developing countries such as Bangladesh. For this study, we analyzed the capital cost of 61 operational and planned power plants in Bangladesh. Initial comparison study revealed that the mean capital cost of a power plant in Bangladesh is twice than that of the global average. Then, the statistical analysis revealed a significant correlation between corruption and the cost of power plants, indicating that higher corruption leads to greater capital cost. The high up-front cost can be a significant burden on the economy, at present and in the future, as most are financed through international loans with extended repayment terms. There is, therefore, an urgent need for the review of the procurement and due diligence process of establishing power plants, and for the implementation of a more transparent system to mitigate adverse effects of corruption on megaprojects.

  8. Modern environmental health hazards: a public health issue of increasing significance in Africa.

    Science.gov (United States)

    Nweke, Onyemaechi C; Sanders, William H

    2009-06-01

    Traditional hazards such as poor sanitation currently account for most of Africa's environmentally related disease burden. However, with rapid development absent appropriate safeguards for environment and health, modern environmental health hazards (MEHHs) may emerge as critical contributors to the continent's disease burden. We review recent evidence of human exposure to and health effects from MEHHs, and their occurrence in environmental media and consumer products. Our purpose is to highlight the growing significance of these hazards as African countries experience urbanization, industrial growth, and development. We reviewed published epidemiologic, exposure, and environmental studies of chemical agents such as heavy metals and pesticides. The body of evidence demonstrates ongoing environmental releases of MEHHs and human exposures sometimes at toxicologically relevant levels. Several sources of MEHHs in environmental media have been identified, including natural resource mining and processing and automobile exhaust. Biomonitoring studies provided direct evidence of human exposure to metals such as mercury and lead and pesticides such as p,p'-dichlorodiphenyltrichloroethane (DDT) and organophosphates. Land and water resource pollution and industrial air toxics are areas of significant data gaps, notwithstanding the presence of several emitting sources. Unmitigated MEHH releases and human exposure have implications for Africa's disease burden. For Africans encumbered by conditions such as malnutrition that impair resilience to toxicologic challenges, the burden may be higher. A shift in public health policy toward accommodating the emerging diversity in Africa's environmental health issues is necessary to successfully alleviate the burden of avoidable ill health and premature death for all its communities now and in the future.

  9. Cocaine induces astrocytosis through ER stress-mediated activation of autophagy

    Science.gov (United States)

    Periyasamy, Palsamy; Guo, Ming-Lei; Buch, Shilpa

    2016-01-01

    ABSTRACT Cocaine is known to induce inflammation, thereby contributing in part, to the pathogenesis of neurodegeneration. A recent study from our lab has revealed a link between macroautophagy/autophagy and microglial activation. The current study was aimed at investigating whether cocaine could also mediate activation of astrocytes and, whether this process involved induction of autophagy. Our findings demonstrated that cocaine mediated the activation of astrocytes by altering the levels of autophagy markers, such as BECN1, ATG5, MAP1LC3B-II, and SQSTM1 in both human A172 astrocytoma cells and primary human astrocytes. Furthermore, cocaine treatment resulted in increased formation of endogenous MAP1LC3B puncta in human astrocytes. Additionally, astrocytes transfected with the GFP-MAP1LC3B plasmid also demonstrated cocaine-mediated upregulation of the green fluorescent MAP1LC3B puncta. Cocaine-mediated induction of autophagy involved upstream activation of ER stress proteins such as EIF2AK3, ERN1, ATF6 since blockage of autophagy using either pharmacological or gene-silencing approaches, had no effect on cocaine-mediated induction of ER stress. Using both pharmacological and gene-silencing approaches to block either ER stress or autophagy, our findings demonstrated that cocaine-induced activation of astrocytes (measured by increased levels of GFAP) involved sequential activation of ER stress and autophagy. Cocaine-mediated-increased upregulation of GFAP correlated with increased expression of proinflammatory mediators such as TNF, IL1B, and IL6. In conclusion, these findings reveal an association between ER stress-mediated autophagy and astrogliosis in cocaine-treated astrocytes. Intervention of ER stress and/or autophagy signaling would thus be promising therapeutic targets for abrogating cocaine-mediated neuroinflammation. PMID:27337297

  10. Combining modularity, conservation, and interactions of proteins significantly increases precision and coverage of protein function prediction

    Directory of Open Access Journals (Sweden)

    Sers Christine T

    2010-12-01

    Full Text Available Abstract Background While the number of newly sequenced genomes and genes is constantly increasing, elucidation of their function still is a laborious and time-consuming task. This has led to the development of a wide range of methods for predicting protein functions in silico. We report on a new method that predicts function based on a combination of information about protein interactions, orthology, and the conservation of protein networks in different species. Results We show that aggregation of these independent sources of evidence leads to a drastic increase in number and quality of predictions when compared to baselines and other methods reported in the literature. For instance, our method generates more than 12,000 novel protein functions for human with an estimated precision of ~76%, among which are 7,500 new functional annotations for 1,973 human proteins that previously had zero or only one function annotated. We also verified our predictions on a set of genes that play an important role in colorectal cancer (MLH1, PMS2, EPHB4 and could confirm more than 73% of them based on evidence in the literature. Conclusions The combination of different methods into a single, comprehensive prediction method infers thousands of protein functions for every species included in the analysis at varying, yet always high levels of precision and very good coverage.

  11. Increased Body Mass Index during Therapy for Childhood Acute Lymphoblastic Leukemia: A Significant and Underestimated Complication

    Directory of Open Access Journals (Sweden)

    Helen C. Atkinson

    2015-01-01

    Full Text Available Objective & Design. We undertook a retrospective review of children diagnosed with acute lymphoblastic leukemia (ALL and treated with modern COG protocols (n=80 to determine longitudinal changes in body mass index (BMI and the prevalence of obesity compared with a healthy reference population. Results. At diagnosis, the majority of patients (77.5% were in the healthy weight category. During treatment, increases in BMI z-scores were greater for females than males; the prevalence of obesity increased from 10.3% to 44.8% (P<0.004 for females but remained relatively unchanged for males (9.8% to 13.7%, P=0.7. Longitudinal analysis using linear mixed-effects identified associations between BMI z-scores and time-dependent interactions with sex (P=0.0005, disease risk (P<0.0001, age (P=0.0001, and BMI z-score (P<0.0001 at diagnosis and total dose of steroid during maintenance (P=0.01. Predicted mean BMI z-scores at the end of therapy were greater for females with standard risk ALL irrespective of age at diagnosis and for males younger than 4 years of age at diagnosis with standard risk ALL. Conclusion. Females treated on standard risk protocols and younger males may be at greatest risk of becoming obese during treatment for ALL. These subgroups may benefit from intervention strategies to manage BMI during treatment for ALL.

  12. Big data integration shows Australian bush-fire frequency is increasing significantly.

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    Dutta, Ritaban; Das, Aruneema; Aryal, Jagannath

    2016-02-01

    Increasing Australian bush-fire frequencies over the last decade has indicated a major climatic change in coming future. Understanding such climatic change for Australian bush-fire is limited and there is an urgent need of scientific research, which is capable enough to contribute to Australian society. Frequency of bush-fire carries information on spatial, temporal and climatic aspects of bush-fire events and provides contextual information to model various climate data for accurately predicting future bush-fire hot spots. In this study, we develop an ensemble method based on a two-layered machine learning model to establish relationship between fire incidence and climatic data. In a 336 week data trial, we demonstrate that the model provides highly accurate bush-fire incidence hot-spot estimation (91% global accuracy) from the weekly climatic surfaces. Our analysis also indicates that Australian weekly bush-fire frequencies increased by 40% over the last 5 years, particularly during summer months, implicating a serious climatic shift.

  13. Significantly Increased Extreme Precipitation Expected in Europe and North America from Extratropical Storms

    Science.gov (United States)

    Hawcroft, M.; Hodges, K.; Walsh, E.; Zappa, G.

    2017-12-01

    For the Northern Hemisphere extratropics, changes in circulation are key to determining the impacts of climate warming. The mechanisms governing these circulation changes are complex, leading to the well documented uncertainty in projections of the future location of the mid-latitude storm tracks simulated by climate models. These storms are the primary source of precipitation for North America and Europe and generate many of the large-scale precipitation extremes associated with flooding and severe economic loss. Here, we show that in spite of the uncertainty in circulation changes, by analysing the behaviour of the storms themselves, we find entirely consistent and robust projections across an ensemble of climate models. In particular, we find that projections of change in the most intensely precipitating storms (above the present day 99th percentile) in the Northern Hemisphere are substantial and consistent across models, with large increases in the frequency of both summer (June-August, +226±68%) and winter (December-February, +186±34%) extreme storms by the end of the century. Regionally, both North America (summer +202±129%, winter +232±135%) and Europe (summer +390±148%, winter +318±114%) are projected to experience large increases in the frequency of intensely precipitating storms. These changes are thermodynamic and driven by surface warming, rather than by changes in the dynamical behaviour of the storms. Such changes in storm behaviour have the potential to have major impacts on society given intensely precipitating storms are responsible for many large-scale flooding events.

  14. Circulatory nucleosome levels are significantly increased in early and late-onset preeclampsia.

    Science.gov (United States)

    Zhong, Xiao Yan; Gebhardt, Stefan; Hillermann, Renate; Tofa, Kashefa Carelse; Holzgreve, Wolfgang; Hahn, Sinuhe

    2005-08-01

    Elevations in circulatory DNA, as measured by real-time PCR, have been observed in pregnancies with manifest preeclampsia. Recent reports have indicated that circulatory nucleosome levels are elevated in the periphery of cancer patients. We have now examined whether circulatory nucleosome levels are similarly elevated in cases with preeclampsia. Maternal plasma samples were prepared from 17 cases with early onset preeclampsia (34 weeks gestation) with 10 matched normotensive controls. Levels of circulatory nucleosomes were quantified by commercial ELISA (enzyme-linked immunosorbant assay). The level of circulatory nucleosomes was significantly elevated in both study preeclampsia groups, compared to the matched normotensive control group (p = 0.000 and p = 0.001, respectively). Our data suggests that preeclampsia is associated with the elevated presence of circulatory nucleosomes, and that this phenomenon occurs in both early- and late-onset forms of the disorder. Copyright 2005 John Wiley & Sons, Ltd.

  15. TNFRSF14 aberrations in follicular lymphoma increase clinically significant allogeneic T-cell responses.

    Science.gov (United States)

    Kotsiou, Eleni; Okosun, Jessica; Besley, Caroline; Iqbal, Sameena; Matthews, Janet; Fitzgibbon, Jude; Gribben, John G; Davies, Jeffrey K

    2016-07-07

    Donor T-cell immune responses can eradicate lymphomas after allogeneic hematopoietic stem cell transplantation (AHSCT), but can also damage healthy tissues resulting in harmful graft-versus-host disease (GVHD). Next-generation sequencing has recently identified many new genetic lesions in follicular lymphoma (FL). One such gene, tumor necrosis factor receptor superfamily 14 (TNFRSF14), abnormal in 40% of FL patients, encodes the herpes virus entry mediator (HVEM) which limits T-cell activation via ligation of the B- and T-lymphocyte attenuator. As lymphoma B cells can act as antigen-presenting cells, we hypothesized that TNFRSF14 aberrations that reduce HVEM expression could alter the capacity of FL B cells to stimulate allogeneic T-cell responses and impact the outcome of AHSCT. In an in vitro model of alloreactivity, human lymphoma B cells with TNFRSF14 aberrations had reduced HVEM expression and greater alloantigen-presenting capacity than wild-type lymphoma B cells. The increased immune-stimulatory capacity of lymphoma B cells with TNFRSF14 aberrations had clinical relevance, associating with higher incidence of acute GVHD in patients undergoing AHSCT. FL patients with TNFRSF14 aberrations may benefit from more aggressive immunosuppression to reduce harmful GVHD after transplantation. Importantly, this study is the first to demonstrate the impact of an acquired genetic lesion on the capacity of tumor cells to stimulate allogeneic T-cell immune responses which may have wider consequences for adoptive immunotherapy strategies. © 2016 by The American Society of Hematology.

  16. Exposure to Tumescent Solution Significantly Increases Phosphorylation of Perilipin in Adipocytes.

    Science.gov (United States)

    Keskin, Ilknur; Sutcu, Mustafa; Eren, Hilal; Keskin, Mustafa

    2017-02-01

    Lidocaine and epinephrine could potentially decrease adipocyte viability, but these effects have not been substantiated. The phosphorylation status of perilipin in adipocytes may be predictive of cell viability. Perilipin coats lipid droplets and restricts access of lipases; phospho-perilipin lacks this protective function. The authors investigated the effects of tumescent solution containing lidocaine and epinephrine on the phosphorylation status of perilipin in adipocytes. In this in vitro study, lipoaspirates were collected before and after tumescence from 15 women who underwent abdominoplasty. Fat samples were fixed, sectioned, and stained for histologic and immunohistochemical analyses. Relative phosphorylation of perilipin was inferred from pixel intensities of immunostained adipocytes observed with confocal microscopy. For adipocytes collected before tumescent infiltration, 10.08% of total perilipin was phosphorylated. In contrast, 30.62% of total perilipin was phosphorylated for adipocytes collected from tumescent tissue (P < .01). The tumescent technique increases the relative phosphorylation of perilipin in adipocytes, making these cells more vulnerable to lipolysis. Tumescent solution applied for analgesia or hemostasis of the donor site should contain the lowest possible concentrations of lidocaine and epinephrine. LEVEL OF EVIDENCE 5. © 2016 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com.

  17. Significance of Increasing n-3 PUFA Content in Pork on Human Health.

    Science.gov (United States)

    Ma, Xianyong; Jiang, Zongyong; Lai, Chaoqiang

    2016-01-01

    Evidence for the health-promoting effects of food rich in n-3 polyunsaturated fatty acids (n-3 PUFA) is reviewed. Pork is an important meat source for humans. According to a report by the US Department of Agriculture ( http://www.ers.usda.gov/topics ), the pork consumption worldwide in 2011 was about 79.3 million tons, much higher than that of beef (48.2 million tons). Pork also contains high levels of unsaturated fatty acids relative to ruminant meats (Enser, M., Hallett, K., Hewett, B., Fursey, G. A. J. and Wood, J. D. (1996) . Fatty acid content and composition of English beef, lamb, and pork at retail. Meat Sci. 44:443-458). The available literature indicates that the levels of eicosatetraenoic and docosahexaenoic in pork may be increased by fish-derived or linseed products, the extent of which being dependent on the nature of the supplementation. Transgenic pigs and plants show promise with high content of n-3 PUFA and low ratio of n-6/n-3 fatty acids in their tissues. The approaches mentioned for decreasing n-6/n-3 ratios have both advantages and disadvantages. Selected articles are critically reviewed and summarized.

  18. Continues administration of Nano-PSO significantly increased survival of genetic CJD mice.

    Science.gov (United States)

    Binyamin, Orli; Keller, Guy; Frid, Kati; Larush, Liraz; Magdassi, Shlomo; Gabizon, Ruth

    2017-12-01

    We have shown previously that Nano-PSO, a nanodroplet formulation of pomegranate seed oil, delayed progression of neurodegeneration signs when administered for a designated period of time to TgMHu2ME199K mice, modeling for genetic prion disease. In the present work, we treated these mice with a self-emulsion formulation of Nano-PSO or a parallel Soybean oil formulation from their day of birth until a terminal disease stage. We found that long term Nano-PSO administration resulted in increased survival of TgMHu2ME199K lines by several months. Interestingly, initiation of treatment at day 1 had no clinical advantage over initiation at day 70, however cessation of treatment at 9months of age resulted in the rapid loss of the beneficial clinical effect. Pathological studies revealed that treatment with Nano-PSO resulted in the reduction of GAG accumulation and lipid oxidation, indicating a strong neuroprotective effect. Contrarily, the clinical effect of Nano-PSO did not correlate with reduction in the levels of disease related PrP, the main prion marker. We conclude that long term administration of Nano-PSO is safe and may be effective in the prevention/delay of onset of neurodegenerative conditions such as genetic CJD. Copyright © 2017. Published by Elsevier Inc.

  19. Elicitor Mixtures Significantly Increase Bioactive Compounds, Antioxidant Activity, and Quality Parameters in Sweet Bell Pepper

    Directory of Open Access Journals (Sweden)

    Lina Garcia-Mier

    2015-01-01

    Full Text Available Sweet bell peppers are greatly appreciated for their taste, color, pungency, and aroma. Additionally, they are good sources of bioactive compounds with antioxidant activity, which can be improved by the use of elicitors. Elicitors act as metabolite-inducing factors (MIF by mimic stress conditions. Since plants rarely experience a single stress condition one by one but are more likely to be exposed to simultaneous stresses, it is important to evaluate the effect of elicitors on plant secondary metabolism as mixtures. Jasmonic acid (JA, hydrogen peroxide (HP, and chitosan (CH were applied to fruits and plants of bell pepper as mixtures. Bioactive compounds, antioxidant activity, and quality parameters were evaluated. The assessed elicitor cocktail leads to an increase in the variables evaluated (P ≤ 0.05 when applied to mature fruits after harvest, whereas the lowest values were observed in the treatment applied to immature fruits. Therefore, the application of the elicitor cocktail to harvested mature fruits is recommended in order to improve bioactive compounds and the antioxidant activity of sweet bell peppers.

  20. Regulation of glutamate transporter 1 (GLT-1) gene expression by cocaine self-administration and withdrawal.

    Science.gov (United States)

    Kim, Ronald; Sepulveda-Orengo, Marian T; Healey, Kati L; Williams, Emily A; Reissner, Kathryn J

    2018-01-01

    Downregulation of the astroglial glutamate transporter GLT-1 is observed in the nucleus accumbens (NAc) following administration of multiple drugs of abuse. The decrease in GLT-1 protein expression following cocaine self-administration is dependent on both the amount of cocaine self-administered and the length of withdrawal, with longer access to cocaine and longer withdrawal periods leading to greater decreases in GLT-1 protein. However, the mechanism(s) by which cocaine downregulates GLT-1 protein remains unknown. We used qRT-PCR to examine gene expression of GLT-1 splice isoforms (GLT-1A, GLT-1B) in the NAc, prelimbic cortex (PL) and basolateral amygdala (BLA) of rats, following two widely used models of cocaine self-administration: short-access (ShA) self-administration, and the long-access (LgA) self-administration/incubation model. While downregulation of GLT-1 protein is observed following ShA cocaine self-administration and extinction, this model did not lead to a change in GLT-1A or GLT-1B gene expression in any brain region examined. Forced abstinence following ShA cocaine self-administration also was without effect. In contrast, LgA cocaine self-administration and prolonged abstinence significantly decreased GLT-1A gene expression in the NAc and BLA, and significantly decreased GLT-1B gene expression in the PL. No change was observed in NAc GLT-1A gene expression one day after LgA cocaine self-administration, indicating withdrawal-induced decreases in GLT-1A mRNA. In addition, LgA cocaine self-administration and withdrawal induced hypermethylation of the GLT-1 gene in the NAc. These results indicate that a decrease in NAc GLT-1 mRNA is only observed after extended access to cocaine combined with protracted abstinence, and that epigenetic mechanisms likely contribute to this effect. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. dcc Haploinsufficiency results in blunted sensitivity to cocaine enhancement of reward seeking.

    Science.gov (United States)

    Reynolds, Lauren M; Gifuni, Anthony J; McCrea, E Tess; Shizgal, Peter; Flores, Cecilia

    2016-02-01

    Mesocortical dopamine connectivity continues to mature during adolescence. This protracted development confers increased vulnerability for environmental and genetic factors to disrupt mesocortical wiring and subsequently influence responses to drugs of abuse in adulthood. The netrin-1 receptor, DCC, orchestrates medial prefrontal cortex dopamine input during adolescence and dictates the functional organization of local circuitry. Haploinsufficiency of dcc results in increased dopamine innervation to the medial prefrontal cortex, which in turn leads to resilience against the behavioral activating effects of stimulant drugs. However, whether sensitivity to the rewarding effects of drugs of abuse is also altered in dcc haploinsufficiency remains to be resolved. Here, we used the curve-shift method to measure cocaine-induced facilitation of intracranial self-stimulation (ICSS) in adult dcc haploinsufficient mice and wild-type littermates. We found that dcc haploinsufficient mice acquire ICSS behavior at comparable stimulation parameters to wild-type controls. However, cocaine-induced potentiation of ICSS is significantly blunted in dcc haploinsufficient mice. These results are consistent with decreased sensitivity to the rewarding effects of cocaine and/or decreased proclivity to invest effort in the pursuit of reward in dcc haploinsufficient mice. Moreover, these findings suggest that DCC signaling determines adult susceptibility to drug abuse most likely by controlling prefrontal cortex development in adolescence. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Cocaine-seeking behavior in a genetic model of attention-deficit/hyperactivity disorder following adolescent methylphenidate or atomoxetine treatments*

    Science.gov (United States)

    Jordan, Chloe J.; Harvey, Roxann C.; Baskin, Britahny B.; Dwoskin, Linda P.; Kantak, Kathleen M.

    2014-01-01

    Background Attention-deficit/hyperactivity disorder (ADHD) is often comorbid with cocaine abuse. Controversy exists regarding long-term consequences of ADHD medications on cocaine abuse liability. Whereas childhood methylphenidate treatment may be preventative, methylphenidate in teens appears to further increase later cocaine abuse risk. In rodents, adolescent methylphenidate treatment further increases adult cocaine self-administration in the Spontaneously Hypertensive Rat (SHR) model of ADHD, whereas adolescent atomoxetine treatment does not. Effects of ADHD medications on cocaine cue reactivity, a critical component of addiction, are unknown. Methods To investigate this, SHR, Wistar-Kyoto (inbred control) and Wistar (outbred control) rats received therapeutically relevant doses of methylphenidate (1.5 mg/kg, oral) and atomoxetine (0.3 mg/kg, intraperitoneal), or respective vehicles from post-natal day 28–55. Cocaine seeking, reflecting cue reactivity, was measured in adulthood during self-administration maintenance and cue-induced reinstatement tests conducted under a second-order schedule. Results Compared to control strains, SHR earned more cocaine infusions, emitted more cocaine-seeking responses during maintenance and reinstatement testing, and required more sessions to reach the extinction criterion. Compared to vehicle, adolescent methylphenidate, but not atomoxetine, further increased cocaine intake during maintenance testing in SHR. Adolescent atomoxetine, but not methylphenidate, decreased cocaine seeking during reinstatement testing in SHR. Neither medication had effects on cocaine intake or cue reactivity in control strains. Conclusions The SHR successfully model ADHD and cocaine abuse comorbidity and show differential effects of adolescent ADHD medications on cocaine intake and cue reactivity during adulthood. Thus, SHR have heuristic value for assessing neurobiology underlying the ADHD phenotype and for evaluating pharmacotherapeutics for ADHD

  3. Transcranial magnetic stimulation of dorsolateral prefrontal cortex reduces cocaine use: A pilot study.

    Science.gov (United States)

    Terraneo, Alberto; Leggio, Lorenzo; Saladini, Marina; Ermani, Mario; Bonci, Antonello; Gallimberti, Luigi

    2016-01-01

    Recent animal studies demonstrate that compulsive cocaine seeking strongly reduces prelimbic frontal cortex activity, while optogenetic stimulation of this brain area significantly inhibits compulsive cocaine seeking, providing a strong rationale for applying brain stimulation to reduce cocaine consumption. Thus, we employed repetitive transcranial magnetic stimulation (rTMS), to test if dorsolateral prefrontal cortex (DLPFC) stimulation might prevent cocaine use in humans. Thirty-two cocaine-addicted patients were randomly assigned to either the experimental group (rTMS) on the left DLPFC, or to a control group (pharmacological agents) during a 29-day study (Stage 1). This was followed by a 63-day follow-up (Stage 2), during which all participants were offered rTMS treatment. Amongst the patients who completed Stage 1, 16 were in the rTMS group (100%) and 13 in the control group (81%). No significant adverse events were noted. During Stage 1, there were a significantly higher number of cocaine-free urine drug tests in the rTMS group compared to control (p=0.004). Craving for cocaine was also significantly lower in the rTMS group compared to the controls (p=0.038). Out of 13 patients who completed Stage 1 in the control group, 10 patients received rTMS treatment during Stage 2 and showed significant improvement with favorable outcomes becoming comparable to those of the rTMS group. The present preliminary findings support the safety of rTMS in cocaine-addicted patients, and suggest its potential therapeutic role for rTMS-driven PFC stimulation in reducing cocaine use, providing a strong rationale for developing larger placebo-controlled studies. Trial name: Repetitive transcranial magnetic stimulation (rTMS) in cocaine abusers, URL:〈http://www.isrctn.com/ISRCTN15823943?q=&filters=&sort=&offset=8&totalResults=13530&page=1&pageSize=10&searchType=basic-search〉, ISRCTN15823943. Published by Elsevier B.V.

  4. Alterations in offspring behavior induced by chronic prenatal cocaine dosing.

    Science.gov (United States)

    Smith, R F; Mattran, K M; Kurkjian, M F; Kurtz, S L

    1989-01-01

    Sperm-positive female Long-Evans hooded rats were dosed subcutaneously with 10 mg/kg/day cocaine or an equal volume of vehicle (0.9% sterile saline) from gestation day 4 (GD4) through GD18. Offspring were assessed for development of negative geotaxis, righting reflex, spontaneous alternation, and open field activity, and for adult behaviors including DRL-20 acquisition, water maze, visual discrimination, barbiturate sleep time, shuttlebox avoidance, footshock sensitivity, and tail flick latency. Cocaine dosing produced no significant effects on dam weight gain, any measure of litter size and weight, or early postnatal behavioral tests, but there were significant drug effects on development of spontaneous alternation, development of open field activity, DRL-20 acquisition, water maze performance, tail flick, and footshock sensitivity. These data suggest that chronic administration of a modest dose of cocaine during gestation in the rat alters a number of behaviors in the offspring.

  5. A laboratory approach to the control of cocaine in Bolivia.

    Science.gov (United States)

    Morales-Vaca, M

    1984-01-01

    Of the 4,196 samples of drugs seized and analysed at the Toxicology Laboratory of the National Bureau for the Control of Dangerous Substances during the period 1975-1982, 3,768 samples (89.8 per cent) contained coca paste, cocaine hydrochloride or related substances. Most of the samples analysed contained coca paste and came from La Paz, Santa Cruz and Cochabamba. With a slight exception in 1980, the number of samples increased steadily over an eight-year period. The increase in the number of seizures of cocaine-related substances was a result of the growth in the illicit production of these substances, which began to assume larger dimensions in 1976. In many areas, coca-paste and cocaine-related problems are growing out of all proportion. The smoking of cigarettes that contain a mixture of tobacco and coca paste, popularly known as pitillos, is the most common form of drug abuse.

  6. Extinction of Contextual Cocaine Memories Requires Cav1.2 within D1R-Expressing Cells and Recruits Hippocampal Cav1.2-Dependent Signaling Mechanisms.

    Science.gov (United States)

    Burgdorf, Caitlin E; Schierberl, Kathryn C; Lee, Anni S; Fischer, Delaney K; Van Kempen, Tracey A; Mudragel, Vladimir; Huganir, Richard L; Milner, Teresa A; Glass, Michael J; Rajadhyaksha, Anjali M

    2017-12-06

    Exposure to cocaine-associated contextual cues contributes significantly to relapse. Extinction of these contextual associations, which involves a new form of learning, reduces cocaine-seeking behavior; however, the molecular mechanisms underlying this process remain largely unknown. We report that extinction, but not acquisition, of cocaine conditioned place preference (CPP) in male mice increased Ca v 1.2 L-type Ca 2+ channel mRNA and protein in postsynaptic density (PSD) fractions of the hippocampus, a brain region involved in drug-context associations. Moreover, viral-mediated deletion of Ca v 1.2 in the dorsal hippocampus attenuated extinction of cocaine CPP. Molecular studies examining downstream Ca v 1.2 targets revealed that extinction recruited calcium/calmodulin (Ca 2+ /CaMK)-dependent protein kinase II (CaMKII) to the hippocampal PSD. This occurred in parallel with an increase in phosphorylation of the AMPA GluA1 receptor subunit at serine 831 (S831), a CaMKII site, along with an increase in total PSD GluA1. The necessity of S831 GluA1 was further demonstrated by the lack of extinction in S831A GluA1 phosphomutant mice. Of note hippocampal GluA1 levels remained unaltered at the PSD, but were reduced near the PSD and at perisynaptic sites of dendritic spines in extinction-resistant S831A mutant mice. Finally, conditional knock-out of Ca v 1.2 in dopamine D1 receptor (D1R)-expressing cells resulted in attenuation of cocaine CPP extinction and lack of extinction-dependent changes in hippocampal PSD CaMKII expression and S831 GluA1 phosphorylation. In summary, we demonstrate an essential role for the hippocampal Ca v 1.2/CaMKII/S831 GluA1 pathway in cocaine CPP extinction, with data supporting contribution of hippocampal D1R-expressing cells in this process. These findings demonstrate a novel role for Ca v 1.2 channels in extinction of contextual cocaine-associated memories. SIGNIFICANCE STATEMENT Continued drug-seeking behavior, a defining characteristic of

  7. 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...

  8. Cocaine-induced encephalocele: case report and literature review.

    Science.gov (United States)

    Albert, Ladislau; DeMattia, Joseph A

    2011-01-01

    The abuse of cocaine can lead to significant destruction of midline craniofacial structures. This process occurs secondary to myriad mechanisms, including ischemic necrosis, irritation by chemical adulterants, and direct trauma during its administration. Coupled with a prolonged chronic infection of intranasal and anterior skull base regions, an encephalocele can be formed. We report a case of an encephalocele secondary to cocaine use and its associated complications. A 56-year-old man presented with altered mental status and cerebritis secondary to the presence of an intranasal encephalocele. On computed tomography, extensive destruction of the anterior cranial fossa was observed. The patient had a 30-year history of intranasal cocaine abuse, and his urine tested positive for the presence of cocaine on admission. The patient was treated with intravenous antibiotics and underwent a repair of his cranial defect and resection of the encephalocele. The patient made a good recovery after treatment. Alternative causes of an encephalocele, including trauma, surgery, and congenital malformation, were ruled out in this patient. Histopathological analysis of the necrotic tissue and the absence of renal or pulmonary disease also indicated that the patient did not suffer from Wegener granulomatosis, a known cause of spontaneous intranasal lesions. To the best of our knowledge, this is the first report of an encephalocele likely induced solely by cocaine abuse.

  9. 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.

  10. The Role of Accumbal Hypoactivity in Cocaine Addiction.

    Directory of Open Access Journals (Sweden)

    L. L. Peoples

    2007-01-01

    Full Text Available Cocaine-induced hypoactivity of the nucleus accumbens (NAC is hypothesized to contribute to cocaine addiction. There are two important questions related to this hypothesis. First, cocaine addiction is characterized by an increase in drug-directed behavior and a simultaneous weakening of other motivated behaviors. However, the NAC contributes to both drug- and nondrug-directed behavior. Moreover, the nature of the contributions is similar and associated predominantly with excitatory phasic firing patterns. Given these observations it is not clear how hypoactivity of NAC neurons might contribute to the behaviors that characterize cocaine addiction. Second, various types of investigations have documented neurochemical and molecular adaptations that could underlie NAC hypoactivity. However, there is also evidence of other adaptations in the NAC, and in NAC afferents, which are expected to have an excitatory influence on NAC neural activity. In the present review we will briefly overview these issues. We will also describe a hypothesis, and related empirical evidence, that may contribute to answering these questions. Further investigation of the issues and the hypothesis may contribute to a better understanding of the neuroadaptations that contribute to cocaine addiction.

  11. 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. ...

  12. Prenatal Cocaine Exposure and Infant Cortisol Reactivity

    Science.gov (United States)

    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,…

  13. 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

  14. Cocaine and Caffeine Effects on the Conditioned Place Preference Test: Concomitant Changes on Early Genes within the Mouse Prefrontal Cortex and Nucleus Accumbens

    Directory of Open Access Journals (Sweden)

    Javier A. Muñiz

    2017-10-01

    Full Text Available Caffeine is the world's most popular psychostimulant and is frequently used as an active adulterant in many illicit drugs including cocaine. Previous studies have shown that caffeine can potentiate the stimulant effects of cocaine and cocaine-induced drug seeking behavior. However, little is known about the effects of this drug combination on reward-related learning, a key process in the maintenance of addiction and vulnerability to relapse. The goal of the present study was thus to determine caffeine and cocaine combined effects on the Conditioned Place Preference (CPP test and to determine potential differential mRNA expression in the Nucleus Accumbens (NAc and medial prefrontal cortex (mPFC of immediate-early genes (IEGs as well as dopamine and adenosine receptor subunits. Mice were treated with caffeine (5 mg/kg, CAF, cocaine (10 mg/kg, COC, or their combination (caffeine 5 mg/kg + cocaine 10 mg/kg, CAF-COC and trained in the CPP test or treated with repeated injections inside the home cage. NAc and mPFC tissues were dissected immediately after the CPP test, after a single conditioning session or following psychostimulant injection in the home cage for mRNA expression analysis. CAF-COC induced a marked change of preference to the drug conditioned side of the CPP and a significant increase in locomotion compared to COC. Gene expression analysis after CPP test revealed specific up-regulation in the CAF-COC group of Drd1a, cFos, and FosB in the NAc, and cFos, Egr1, and Npas4 in the mPFC. Importantly, none of these changes were observed when animals received same treatments in their home cage. With a single conditioning session, we found similar effects in both CAF and CAF-COC groups: increased Drd1a and decreased cFos in the NAc, and increased expression of Drd1a and Drd2, in the mPFC. Interestingly, we found that cFos and Npas4 gene expression were increased only in the mPFC of the CAF-COC. Our study provides evidence that caffeine acting as

  15. Obesity-resistant S5B rats showed great cocaine conditioned place preference than the obesity-prone OM rats

    Energy Technology Data Exchange (ETDEWEB)

    Thanos, P.K.; Wang, G.; Thanos, P.K..; Kim, R.; Cho, J.; Michaelides, M.; Anderson, B.J.; Primeaux, S.D.; Bray, G.A.; Wang, G.-J.; Robinson, J.K.; Volkow, N.D.

    2010-12-01

    Dopamine (DA) and the DA D2 receptor (D2R) are involved in the rewarding and conditioned responses to food and drug rewards. Osborne-Mendel (OM) rats are genetically prone and S5B/P rats are genetically resistant to obesity when fed a high-fat diet. We hypothesized that the differential sensitivity of these two rat strains to natural rewards may also be reflected in sensitivity to drugs of abuse. Therefore, we tested whether OM and S5B/P rats showed a differential preference to cocaine using conditioned place preference (CPP). To also evaluate whether there is specific involvement of the D2R in this differential conditioning sensitivity, we then tested whether the D2R agonist bromocriptine (BC) would differentially affect the effects of cocaine in the two strains. OM and S5B/P rats were conditioned with cocaine (5 or 10 mg/kg) in one chamber and saline in another for 8 days. Rats were then tested for cocaine preference. The effects of BC (0.5, 1, 5, 10, 20 mg/kg) on cocaine preference were then assessed in subsequent test sessions. OM rats did not show a significant preference for the cocaine-paired chamber on test day. Only the S5B/P rats showed cocaine CPP. Later treatment with only the highest dose of BC resulted in reduced cocaine CPP in S5B/P rats when treated with 5 mg/kg cocaine and in OM rats treated with 10 mg/kg cocaine. Our results indicated that obesity-resistant S5B rats showed greater cocaine CPP than the obesity-prone OM rats. These findings do not support a theory of common vulnerability for reinforcer preferences (food and cocaine). However, they show that BC reduced cocaine conditioning effects supporting at least a partial regulatory role of D2R in conditioned responses to drugs.

  16. Cocaine users manifest impaired prosodic and cross-modal emotion processing

    Directory of Open Access Journals (Sweden)

    Lea M Hulka

    2013-09-01

    Full Text Available Background: A small number of previous studies have provided evidence that cocaine users exhibit impairments in complex social cognition tasks, while the more basic facial emotion recognition is widely unaffected. However, prosody and cross-modal emotion processing has not been systematically investigated in cocaine users so far. Therefore, the aim of the present study was to assess complex multisensory emotion processing in cocaine users in comparison to controls and to examine a potential association with drug use patterns.Method: The abbreviated version of the Comprehensive Affect Testing System (CATS-A was used to measure emotion perception across the three channels of facial affect, prosody, and semantic content in 58 cocaine users and 48 healthy control subjects who were matched for age, sex, verbal intelligence, and years of education.Results: Cocaine users had significantly lower scores than controls in the quotient scales of Emotion Recognition and Prosody Recognition and the subtests Conflicting Prosody/Meaning – Attend to Prosody and Match Emotional Prosody to Emotional Face either requiring to attend to prosody or to integrate cross-modal information. In contrast, no group difference emerged for the Affect Recognition Quotient. Cumulative cocaine doses and duration of cocaine use correlated negatively with emotion processing.Conclusion: Cocaine users show impaired cross-modal integration of different emotion processing channels particularly with regard to prosody, whereas more basic aspects of emotion processing such as facial affect perception are comparable to the performance of healthy controls.

  17. 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.

  18. 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.

  19. 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.

  20. Norepinephrine signaling through β-adrenergic receptors is critical for expression of cocaine-induced anxiety

    Science.gov (United States)

    Schank, Jesse R.; Liles, L. Cameron; Weinshenker, David

    2008-01-01

    Background Cocaine is a widely abused psychostimulant that has both rewarding and aversive properties. While the mechanisms underlying cocaine’s rewarding effects have been studied extensively, less attention has been paid to the unpleasant behavioral states induced by cocaine, such as anxiety. Methods In this study we evaluated the performance of dopamine β-hydroxylase knockout (Dbh −/−) mice, which lack norepinephrine (NE), in the elevated plus maze (EPM) to examine the contribution of noradrenergic signaling to cocaine-induced anxiety. Results We found that cocaine dose-dependently increased anxiety-like behavior in control (Dbh +/−) mice, as measured by a decrease in open arm exploration. Dbh −/− mice had normal baseline performance in the EPM, but were completely resistant to the anxiogenic effects of cocaine. Cocaine-induced anxiety was also attenuated in Dbh +/− mice following administration of disulfiram, a DBH inhibitor. In experiments using specific adrenergic antagonists, we found that pretreatment with the β-adrenergic receptor antagonist propranolol blocked cocaine-induced anxiety-like behavior in Dbh +/− and wild-type C57BL6/J mice, while the α1 antagonist prazosin and the α2 antagonist yohimbine had no effect. Conclusions These results indicate that noradrenergic signaling via β-adrenergic receptors is required for cocaine-induced anxiety in mice. PMID:18083142

  1. Social and physical environment alter cocaine conditioned place preference and dopaminergic markers in adolescent male rats.

    Science.gov (United States)

    Zakharova, E; Miller, J; Unterwald, E; Wade, D; Izenwasser, S

    2009-10-20

    This study was done to determine whether social and environmental factors alter cocaine reward and proteins implicated in mediating drug reward in rats during early adolescence. On postnatal day (PND) 23, rats were housed under conditions where both social (number of rats per cage) and environmental (availability of toys) factors were manipulated. Socially isolated rats were housed alone impoverished with no toys (II) or enriched with toys (IE). Social rats were housed two rats/cage with no toys (SI2) or with toys (SE2), or three/cage with (SE3) or without (SI3) toys. On PND 43, cocaine conditioned place preference (CPP) sessions began with the post-test done on PND 47. Cocaine CPP was established in response to 5 or 10 mg/kg cocaine in II rats, and CPP was decreased with the addition of cage mates or toys. No CPP was seen to any dose in SI3 or SE3 rats. Enriched housing (SE3) increased dopamine transporter (DAT) protein in the nucleus accumbens compared to II. There also were differential effects of cocaine on tyrosine hydroxylase and DAT depending on housing, with both increased by cocaine in II but not SE3 rats. DARPP-32 was unchanged by housing or cocaine, while phospho-Thr(34)-DARPP-32 was increased by cocaine treatment across conditions. Thus, both social and environmental enrichment decrease cocaine CPP during adolescence and different housing alters proteins that regulate dopaminergic neurotransmission in a manner that may account for the observed differences in cocaine-induced reward.

  2. 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.

  3. 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

  4. 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.

  5. The effects of the macro-environment on treatment retention for problem cocaine users.

    Science.gov (United States)

    Lorenzoni, Valentina; Curzio, Olivia; Karakachoff, Matilde; Saponaro, Alessio; Sanza, Michele; Mariani, Fabio; Molinaro, Sabrina

    2013-01-01

    Client dropout is commonly used as an indicator of quality and effectiveness of drug treatment. Following increasing cocaine use in recent years, research has attempted to identify predictors of retention in treatment for cocaine users but there is no consensus about how individual characteristics and system variables (referral source, treatment setting), what we term here as the "macro-environment" - effect risk of dropout. This study sought to identify macro-environmental factors and examine the way these impact upon treatment retention. A retrospective longitudinal study of an admission cohort among drug services in Vasta Romagna in Emilia Romagna Region, Italy (up to 8 years of treatment or until discharge) was conducted to determine the effect of macro-environmental variables on retention among first time admitted cocaine-dependent clients in different treatment settings. The sample consisted of 1178 clients meeting DSM-IV-R criteria for cocaine dependence. The joint effect of individual and system factors had a significant impact on dropout rates. In particular, lower rates of dropout were observed for those treated in prison and those who had a stable home, HR: 0.09 (0.02-0.48), or lived in rehabilitation units, HR: 0.36 (0.15-0.88), and among clients referred by the local authority and those living with parents, HR: 0.60 (0.38-0.95). The combined effect of individual and system factors on retention in treatment sets a critical background necessary to assess any impact of organizational dynamics and delineate the trajectory for future interventions. Copyright © 2012 Elsevier B.V. All rights reserved.

  6. Comorbidity effects on cocaine dependence treatment and examination of reciprocal relationships between abstinence and depression.

    Science.gov (United States)

    Milby, Jesse B; Conti, Kimberly; Wallace, Dennis; Mennemeyer, Stephen; Mrug, Sylvie; Schumacher, Joseph E

    2015-02-01

    We examined comorbid disorders' prevalence, their impact on abstinence, and the impact of depressive symptoms on abstinence and of abstinence on depressive symptoms. A randomized controlled trial's data on outcomes from treating cocaine dependence were used. It compared abstinence-contingent housing and work to contingency management plus behavioral day treatment. Regardless of original trial arm assignment, groups of participants with no additional Axis I disorders (n = 87) and 1 or more additional Axis I disorders (n = 113) were compared for abstinence. Changes in depression symptoms, measured by the Beck Depression Inventory, were analyzed as a function of 4 cohorts of increased consecutive weeks abstinent. An autoregressive cross-lagged path model examined reciprocal relationships between depression and abstinence. Most prevalent additional disorders were depressive disorders, followed by anxiety disorders. Additional disorders did not significantly affect abstinence. Cohorts with more abstinence were linearly related to lower depression symptoms. The cross-lagged model showed that longer abstinence predicted decreases in depressive symptoms at 6 months. However, depressive symptoms did not predict changes in abstinence. Our study adds to others that have found an effective treatment targeted at specific problems such as substance abuse, social anxiety disorder, and posttraumatic stress disorder that may have the side benefit of reducing depression. Additionally, we find that depression does not interfere with effective substance abuse treatment for cocaine dependency. This may be the 1st formal analysis comparing the ability of cocaine abstinence to predict future depressive symptoms versus depressive symptoms to predict future cocaine abstinence. (PsycINFO Database Record (c) 2015 APA, all rights reserved).

  7. Purpura and leukopenia in a cocaine user.

    Science.gov (United States)

    Dezman, Zachary; Rimi, Barbara; McClain, Joshua

    2016-08-01

    A previously healthy 42-year-old woman presented to the emergency department (ED) for arthralgias and painful lesions on her ears, feet, and knee (Figures 1 and 2) that had developed over the last month. She had no significant past medical history and was not taking any prescribed medications. The rash was purpuric with violaceous borders and hemorrhagic bullae. While she had mild pain with movement, her joint examination was otherwise normal and without signs of infection. ED laboratory testing revealed leukopenia (2500/mm(3)) and cocaine metabolites in her urine.

  8. Cocaine Dysregulates Opioid Gating of GABA Neurotransmission in the Ventral Pallidum

    Science.gov (United States)

    Scofield, Michael D.; Rice, Kenner C.; Cheng, Kejun; Roques, Bernard P.

    2014-01-01

    The ventral pallidum (VP) is a target of dense nucleus accumbens projections. Many of these projections coexpress GABA and the neuropeptide enkephalin, a δ and μ opioid receptor (MOR) ligand. Of these two, the MOR in the VP is known to be involved in reward-related behaviors, such as hedonic responses to palatable food, alcohol intake, and reinstatement of cocaine seeking. Stimulating MORs in the VP decreases extracellular GABA, indicating that the effects of MORs in the VP on cocaine seeking are via modulating GABA neurotransmission. Here, we use whole-cell patch-clamp on a rat model of withdrawal from cocaine self-administration to test the hypothesis that MORs presynaptically regulate GABA transmission in the VP and that cocaine withdrawal changes the interaction between MORs and GABA. We found that in cocaine-extinguished rats pharmacological activation of MORs no longer presynaptically inhibited GABA release, whereas blocking the MORs disinhibited GABA release. Moreover, MOR-dependent long-term depression of GABA neurotransmission in the VP was lost in cocaine-extinguished rats. Last, GABA neurotransmission was found to be tonically suppressed in cocaine-extinguished rats. These substantial synaptic changes indicated that cocaine was increasing tone on MOR receptors. Accordingly, increasing endogenous tone by blocking the enzymatic degradation of enkephalin inhibited GABA neurotransmission in yoked saline rats but not in cocaine-extinguished rats. In conclusion, our results indicate that following withdrawal from cocaine self-administration enkephalin levels in the VP are elevated and the opioid modulation of GABA neurotransmission is impaired. This may contribute to the difficulties withdrawn addicts experience when trying to resist relapse. PMID:24431463

  9. 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.

  10. 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.

  11. Dysfunctional amygdala activation and connectivity with the prefrontal cortex in current cocaine users

    NARCIS (Netherlands)

    Crunelle, C.L.; Kaag, A.M.; van den Munkhof, H.E.; Reneman, L.; Homberg, J.R.; Sabbe, B.; van den Brink, W.; van Wingen, G.

    2015-01-01

    OBJECTIVES: Stimulant use is associated with increased anxiety and a single administration of dexamphetamine increases amygdala activation to biologically salient stimuli in healthy individuals. Here, we investigate how current cocaine use affects amygdala activity and amygdala connectivity with the

  12. Dysfunctional amygdala activation and connectivity with the prefrontal cortex in current cocaine users

    NARCIS (Netherlands)

    Crunelle, Cleo L.; Kaag, Anne Marije; van den Munkhof, Hanna E.; Reneman, Liesbeth; Homberg, Judith R.; Sabbe, Bernard; van den Brink, Wim; van Wingen, Guido

    2015-01-01

    Stimulant use is associated with increased anxiety and a single administration of dexamphetamine increases amygdala activation to biologically salient stimuli in healthy individuals. Here, we investigate how current cocaine use affects amygdala activity and amygdala connectivity with the prefrontal

  13. 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.

  14. 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

  15. 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.

  16. Snow Control - An RCT protocol for a web-based self-help therapy to reduce cocaine consumption in problematic cocaine users

    Directory of Open Access Journals (Sweden)

    Sullivan Robin

    2011-09-01

    Full Text Available Abstract Background Cocaine use has increased in most European countries, including Switzerland, and many states worldwide. The international literature has described treatment models that target the general population. In addition to supplying informative measures at the level of primary and secondary prevention, the literature also offers web-based self-help tools for problematic substance users, which is in line with tertiary prevention. Such programs, however, have been primarily tested on individuals with problematic alcohol and cannabis consumption, but not on cocaine-dependent individuals. Methods/Design This paper presents the protocol of a randomised clinical trial to test the effectiveness of a web-based self-help therapy to reduce cocaine use in problematic cocaine users. The primary outcome is severity of cocaine dependence. Secondary outcome measures include cocaine craving, consumption of cocaine and other substances of abuse in the past month, and changes in depression characteristics. The therapy group will receive a 6-week self-help therapy to reduce cocaine consumption based on methods of Cognitive Behavioural Therapy, principles of Motivational Interviewing and self-control practices. The control group will be presented weekly psycho-educative information with a quiz. The predictive validity of participant characteristics on treatment retention and outcome will be explored. Discussion To the best of our knowledge, this will be the first randomised clinical trial to test the effectiveness of online self-help therapy to reduce or abstain from cocaine use. It will also investigate predictors of outcome and retention. This trial is registered at Current Controlled Trials and is traceable as NTR-ISRCTN93702927.

  17. Cocaine craving during protracted withdrawal requires PKCε priming within vmPFC.

    Science.gov (United States)

    Miller, Bailey W; Wroten, Melissa G; Sacramento, Arianne D; Silva, Hannah E; Shin, Christina B; Vieira, Philip A; Ben-Shahar, Osnat; Kippin, Tod E; Szumlinski, Karen K

    2017-05-01

    In individuals with a history of drug taking, the capacity of drug-associated cues to elicit indices of drug craving intensifies or incubates with the passage of time during drug abstinence. This incubation of cocaine craving, as well as difficulties with learning to suppress drug-seeking behavior during protracted withdrawal, are associated with a time-dependent deregulation of ventromedial prefrontal cortex (vmPFC) function. As the molecular bases for cocaine-related vmPFC deregulation remain elusive, the present study assayed the consequences of extended access to intravenous cocaine (6 hours/day; 0.25 mg/infusion for 10 day) on the activational state of protein kinase C epsilon (PKCε), an enzyme highly implicated in drug-induced neuroplasticity. The opportunity to engage in cocaine seeking during cocaine abstinence time-dependently altered PKCε phosphorylation within vmPFC, with reduced and increased p-PKCε expression observed in early (3 days) and protracted (30 days) withdrawal, respectively. This effect was more robust within the ventromedial versus dorsomedial PFC, was not observed in comparable cocaine-experienced rats not tested for drug-seeking behavior and was distinct from the rise in phosphorylated extracellular signal-regulated kinase observed in cocaine-seeking rats. Further, the impact of inhibiting PKCε translocation within the vmPFC using TAT infusion proteins upon cue-elicited responding was determined and inhibition coinciding with the period of testing attenuated cocaine-seeking behavior, with an effect also apparent the next day. In contrast, inhibitor pretreatment prior to testing during early withdrawal was without effect. Thus, a history of excessive cocaine taking influences the cue reactivity of important intracellular signaling molecules within the vmPFC, with PKCε playing a critical role in the manifestation of cue-elicited cocaine seeking during protracted drug withdrawal. © 2016 Society for the Study of Addiction.

  18. 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.

  19. A generalized matching law analysis of cocaine vs. food choice in rhesus monkeys: effects of candidate 'agonist-based' medications on sensitivity to reinforcement.

    Science.gov (United States)

    Hutsell, Blake A; Negus, S Stevens; Banks, Matthew L

    2015-01-01

    We have previously demonstrated reductions in cocaine choice produced by either continuous 14-day phendimetrazine and d-amphetamine treatment or removing cocaine availability under a cocaine vs. food choice procedure in rhesus monkeys. The aim of the present investigation was to apply the concatenated generalized matching law (GML) to cocaine vs. food choice dose-effect functions incorporating sensitivity to both the relative magnitude and price of each reinforcer. Our goal was to determine potential behavioral mechanisms underlying pharmacological treatment efficacy to decrease cocaine choice. A multi-model comparison approach was used to characterize dose- and time-course effects of both pharmacological and environmental manipulations on sensitivity to reinforcement. GML models provided an excellent fit of the cocaine choice dose-effect functions in individual monkeys. Reductions in cocaine choice by both pharmacological and environmental manipulations were principally produced by systematic decreases in sensitivity to reinforcer price and non-systematic changes in sensitivity to reinforcer magnitude. The modeling approach used provides a theoretical link between the experimental analysis of choice and pharmacological treatments being evaluated as candidate 'agonist-based' medications for cocaine addiction. The analysis suggests that monoamine releaser treatment efficacy to decrease cocaine choice was mediated by selectively increasing the relative price of cocaine. Overall, the net behavioral effect of these pharmacological treatments was to increase substitutability of food pellets, a nondrug reinforcer, for cocaine. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  20. Use of NMR in profiling of cocaine seizures

    DEFF Research Database (Denmark)

    Pagano, Bruno; Lauri, Ilaria; De Tito, Stefano

    2013-01-01

    Cocaine is the most widely used illicit drug, and its origin is always the focus of intense investigation aimed at identifying the trafficking routes. Since NMR represents a unique methodology for performing chemical identification and quantification, here it is proposed a strategy based on (1)H...... adding significant information in the process toward identification of the trafficking routes for this drug....

  1. 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.

  2. Desipramine in opioid-dependent cocaine abusers maintained on buprenorphine vs methadone.

    Science.gov (United States)

    Oliveto, A H; Feingold, A; Schottenfeld, R; Jatlow, P; Kosten, T R

    1999-09-01

    Cocaine abuse occurs in 40% to 60% of patients entering opioid maintenance treatment, and effective pharmacotherapies are needed for this combined dependence. This 13-week, randomized, double-blind, placebo-controlled trial evaluated the efficacy of desipramine hydrochloride (0 or 150 mg/d) plus buprenorphine hydrochloride (12 mg/d) or methadone hydrochloride (65 mg/d) in 180 opioid-dependent cocaine abusers (124 men, 56 women). Supervised urine samples were obtained thrice weekly, and self-reported cocaine and heroin use was reported once weekly. Desipramine plasma levels were determined at weeks 4 and 10. In men, opioid abstinence was increased more rapidly over time when treated with methadone than with buprenorphine, whereas cocaine abstinence was increased more with buprenorphine than with methadone. In women, opioid abstinence was increased the least rapidly when treated with buprenorphine plus placebo, while cocaine abstinence was increased more rapidly over time when treated with methadone than with buprenorphine. Regardless of sex or opioid medication, desipramine increased opioid and cocaine abstinence more rapidly over time than placebo. Self-reported opioid use confirmed these findings. Desipramine plasma levels were higher in women than in men, particularly those on buprenorphine maintenance. Higher desipramine plasma levels were associated with greater opioid, but not cocaine, abstinence. Desipramine may be a useful adjunctive medication in facilitating opioid and cocaine abstinence in opioid-maintained patients. The efficacy of opioid medications to treat opioid or cocaine dependence may differ by sex. These findings highlight the importance of including sex as a factor when examining treatment outcome in these types of trials.

  3. 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…

  4. Longitudinal Modeling of Depressive Trajectories Among HIV-Infected Men Using Cocaine.

    Science.gov (United States)

    Mukerji, Shibani; Haghighat, Roxanna; Misra, Vikas; Lorenz, David R; Holman, Alex; Dutta, Anupriya; Gabuzda, Dana

    2017-07-01

    Cocaine use is prevalent among HIV-infected individuals. While cross-sectional studies suggest that cocaine users may be at increased risk for depression, long-term effects of cocaine on depressive symptoms remain unclear. This is a longitudinal study of 341 HIV-infected and uninfected men (135 cocaine users and 206 controls) ages 30-60 enrolled in the Multicenter AIDS Cohort Study during 1996-2009. The median baseline age was 41; 73% were African-American. In mixed-effects models over a median of 4.8 years of observation, cocaine use was associated with higher depressive symptoms independent of age, education level, and smoking (n = 288; p = 0.02); HIV infection modified this association (p = 0.03). Latent class mixed models were used to empirically identify distinct depressive trajectories (n = 160). In adjusted models, cocaine use was associated with threefold increased odds of membership in the class with persistent high depressive symptoms (95% confidence interval (CI) 1.38-6.69) and eightfold increased odds (95% CI (2.73-25.83) when tested among HIV-infected subjects only. Cocaine use is a risk factor for chronic depressive symptoms, particularly among HIV-infected men, highlighting the importance of integrating mental health and substance use treatments to address barriers to well-being and successful HIV-care.

  5. Cocaine modulates HIV-1 integration in primary CD4+ T cells: implications in HIV-1 pathogenesis in drug-abusing patients

    Science.gov (United States)

    Addai, Amma B.; Pandhare, Jui; Paromov, Victor; Mantri, Chinmay K.; Pratap, Siddharth; Dash, Chandravanu

    2015-01-01

    Epidemiologic studies suggest that cocaine abuse worsens HIV-1 disease progression. Increased viral load has been suggested to play a key role for the accelerated HIV disease among cocaine-abusing patients. The goal of this study was to investigate whether cocaine enhances proviral DNA integration as a mechanism to increase viral load. We infected CD4+ T cells that are the primary targets of HIV-1 in vivo and treated the cells with physiologically relevant concentrations of cocaine (1 µM–100 µM). Proviral DNA integration in the host genome was measured by nested qPCR. Our results illustrated that cocaine from 1 µM through 50 µM increased HIV-1 integration in CD4+ T cells in a dose-dependent manner. As integration can be modulated by several early postentry steps of HIV-1 infection, we examined the direct effects of cocaine on viral integration by in vitro integration assays by use of HIV-1 PICs. Our data illustrated that cocaine directly increases viral DNA integration. Furthermore, our MS analysis showed that cocaine is able to enter CD4+ T cells and localize to the nucleus-. In summary, our data provide strong evidence that cocaine can increase HIV-1 integration in CD4+ T cells. Therefore, we hypothesize that increased HIV-1 integration is a novel mechanism by which cocaine enhances viral load and worsens disease progression in drug-abusing HIV-1 patients. PMID:25691383

  6. 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.

  7. New sorbent materials for selective extraction of cocaine and benzoylecgonine from human urine samples.

    Science.gov (United States)

    Bujak, Renata; Gadzała-Kopciuch, Renata; Nowaczyk, Alicja; Raczak-Gutknecht, Joanna; Kordalewska, Marta; Struck-Lewicka, Wiktoria; Waszczuk-Jankowska, Małgorzata; Tomczak, Ewa; Kaliszan, Michał; Buszewski, Bogusław; Markuszewski, Michał J

    2016-02-20

    An increase in cocaine consumption has been observed in Europe during the last decade. Benzoylecgonine, as a main urinary metabolite of cocaine in human, is so far the most reliable marker of cocaine consumption. Determination of cocaine and its metabolite in complex biological samples as urine or blood, requires efficient and selective sample pretreatment. In this preliminary study, the newly synthesized sorbent materials were proposed for selective extraction of cocaine and benzoylecgonine from urine samples. Application of these sorbent media allowed to determine cocaine and benzoylecgonine in urine samples at the concentration level of 100ng/ml with good recovery values as 81.7%±6.6 and 73.8%±4.2, respectively. The newly synthesized materials provided efficient, inexpensive and selective extraction of both cocaine and benzoylecgonine from urine samples, which can consequently lead to an increase of the sensitivity of the current available screening diagnostic tests. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Influence of the dopaminergic system, CREB, and transcription factor-κB on cocaine neurotoxicity

    International Nuclear Information System (INIS)

    Planeta, C.S.; Lepsch, L.B.; Alves, R.; Scavone, C.

    2013-01-01

    Cocaine is a widely used drug and its abuse is associated with physical, psychiatric and social problems. Abnormalities in newborns have been demonstrated to be due to the toxic effects of cocaine during fetal development. The mechanism by which cocaine causes neurological damage is complex and involves interactions of the drug with several neurotransmitter systems, such as the increase of extracellular levels of dopamine and free radicals, and modulation of transcription factors. The aim of this review was to evaluate the importance of the dopaminergic system and the participation of inflammatory signaling in cocaine neurotoxicity. Our study showed that cocaine activates the transcription factors NF-κB and CREB, which regulate genes involved in cellular death. GBR 12909 (an inhibitor of dopamine reuptake), lidocaine (a local anesthetic), and dopamine did not activate NF-κB in the same way as cocaine. However, the attenuation of NF-κB activity after the pretreatment of the cells with SCH 23390, a D1 receptor antagonist, suggests that the activation of NF-κB by cocaine is, at least partially, due to activation of D1 receptors. NF-κB seems to have a protective role in these cells because its inhibition increased cellular death caused by cocaine. The increase in BDNF (brain-derived neurotrophic factor) mRNA can also be related to the protective role of both CREB and NF-κB transcription factors. An understanding of the mechanisms by which cocaine induces cell death in the brain will contribute to the development of new therapies for drug abusers, which can help to slow down the progress of degenerative processes

  9. Oxytocin Reduces Cocaine Cued Fos Activation in a Regionally Specific Manner

    Science.gov (United States)

    Leong, Kah-Chung; Freeman, Linnea R; Berini, Carole R; Ghee, Shannon M; See, Ronald E

    2017-01-01

    Abstract Background Oxytocin may be a possible treatment for multiple neuropsychiatric disorders, including cocaine addiction. Little is known about the site-specific effects of oxytocin on various drug addiction-related brain regions. Furthermore, sexually dimorphic effects of oxytocin on neural function in the addiction circuit have not been established. Here, we studied Fos expression following cocaine-cued reinstatement in both male and female rats. Methods Male and female rats underwent self-administration, extinction, and reinstatement tests. On test days, rats were given oxytocin or vehicle, and lever pressing was measured in response to conditioned cocaine cues. Rats were perfused and Fos staining measured in the central amygdala, medial prefrontal cortex, nucleus accumbens core, and subthalamic nucleus. Fos/oxytocin double labeling occurred in the paraventricular nucleus of the hypothalamus. Results Rats reinstated to cocaine cues relative to extinction responding and oxytocin reduced cocaine seeking. Oxytocin combined with contingent cue presentations increased Fos+ oxytocin cell bodies within the paraventricular nucleus of the hypothalamus relative to vehicle. Fos expression robustly increased in the central amygdala following oxytocin administration. Oxytocin reversed cue-induced Fos expression in the medial prefrontal cortex, nucleus accumbens core, and subthalamic nucleus. Central oxytocin infusion also attenuated reinstated cocaine seeking. Conclusions Oxytocin decreased reinstated cocaine seeking, increased Fos activation in the paraventricular nucleus of the hypothalamus and central amygdala, but normalized cue-induced Fos activation in the medial prefrontal cortex, nucleus accumbens core, and subthalamic nucleus, thereby demonstrating regionally specific activation patterns. No sex differences were seen for the effects of oxytocin on cocaine seeking and Fos activation, indicating that oxytocin acts on similar central neural circuits critical to

  10. Influence of the dopaminergic system, CREB, and transcription factor-κB on cocaine neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Planeta, C.S. [Laboratório de Neuropsicofarmacologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP (Brazil); Lepsch, L.B.; Alves, R.; Scavone, C. [Departamento de Farmacologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP (Brazil)

    2013-10-15

    Cocaine is a widely used drug and its abuse is associated with physical, psychiatric and social problems. Abnormalities in newborns have been demonstrated to be due to the toxic effects of cocaine during fetal development. The mechanism by which cocaine causes neurological damage is complex and involves interactions of the drug with several neurotransmitter systems, such as the increase of extracellular levels of dopamine and free radicals, and modulation of transcription factors. The aim of this review was to evaluate the importance of the dopaminergic system and the participation of inflammatory signaling in cocaine neurotoxicity. Our study showed that cocaine activates the transcription factors NF-κB and CREB, which regulate genes involved in cellular death. GBR 12909 (an inhibitor of dopamine reuptake), lidocaine (a local anesthetic), and dopamine did not activate NF-κB in the same way as cocaine. However, the attenuation of NF-κB activity after the pretreatment of the cells with SCH 23390, a D1 receptor antagonist, suggests that the activation of NF-κB by cocaine is, at least partially, due to activation of D1 receptors. NF-κB seems to have a protective role in these cells because its inhibition increased cellular death caused by cocaine. The increase in BDNF (brain-derived neurotrophic factor) mRNA can also be related to the protective role of both CREB and NF-κB transcription factors. An understanding of the mechanisms by which cocaine induces cell death in the brain will contribute to the development of new therapies for drug abusers, which can help to slow down the progress of degenerative processes.

  11. Self-reported cocaine use is not associated with elevations in high-sensitivity troponin I.

    Science.gov (United States)

    Jordan, Candice D; Korley, Frederick K; Stolbach, Andrew I

    2017-06-01

    High-sensitivity troponin (hsTn) assays detect 10 times lower concentrations of cardiac troponin than conventional assays. We examined the effects of self-reported cocaine use to determine whether those with acute cocaine use being evaluated for ACS are more likely to have elevated hsTnI than those nonusers being evaluated for ACS. We conducted a sub-analysis of a prospective cohort of ED patients evaluated for acute coronary syndrome. Recent cocaine use was determined by structured patient interviews. High-sensitivity troponin (Abbott) and conventional troponin I (Abbott, cTnI) were measured on samples drawn at presentation. Urine toxicology screen for cocaine metabolite was obtained at the discretion of treating clinicians. Of 1862 patients enrolled, 444 reported prior cocaine use and 99 reported cocaine use within the preceding month. Median hsTn in patients with last cocaine use within 24 h, 2-7 days, 1 week-1 month, >1 month, and no prior cocaine use were: 9 (IQR: 3-17) ng/L, 6 (IQR: 3-24.3) ng/L, 6 (IQR: 3-89.5) ng/L, 3 (IQR: 3-18.5) ng/L and 3 (IQR: 3-17) ng/L, respectively. Urine toxicology assays (UTox) for cocaine were performed in 640 (34.4%) patients. The median hsTn for those who were UTox+, UTox - and those without a UTox were: 9 ng/L (IQR: 3-48.5), 9 ng/L (IQR: 3-40) and 3 ng/L (IQR: 3-12), respectively. There were no differences in the prevalence of new troponin elevations (hsTn >99th percentile but cTnI cocaine use compared to those without recent cocaine use. In this first investigation of hsTn in patients with self-reported recent cocaine use, we have determined that hsTn does not lead to an increase in the prevalence of troponin elevation in cocaine users.

  12. Effects of 14-day treatment with the schedule III anorectic phendimetrazine on choice between cocaine and food in rhesus monkeys.

    Science.gov (United States)

    Banks, Matthew L; Blough, Bruce E; Negus, S Stevens

    2013-08-01

    The clinical utility of monoamine releasers such as phenmetrazine or d-amphetamine as candidate agonist medications for cocaine dependence is hindered by their high abuse liability. Phendimetrazine is a clinically available schedule III anorectic that functions as a prodrug for phenmetrazine and thus may have lower abuse liability. This study determined the effects of continuous 14-day treatment with phendimetrazine on cocaine vs. food choice in rhesus monkeys (N=4). Responding was maintained under a concurrent schedule of food delivery (1-g pellets, fixed-ratio 100 schedule) and cocaine injections (0-0.1mg/kg/injection, fixed-ratio 10 schedule). Cocaine choice dose-effect curves were determined daily before and during 14-day periods of continuous intravenous treatment with saline or (+)-phendimetrazine (0.32-1.0mg/kg/h). Effects of 14-day treatment with (+)-phenmetrazine (0.1-0.32 mg/kg/h; N=5) and d-amphetamine (0.032-0.1mg/kg/h; N=6) were also examined for comparison. During saline treatment, food was primarily chosen during availability of low cocaine doses (0, 0.0032, and 0.01 mg/kg/injection), and cocaine was primarily chosen during availability of higher cocaine doses (0.032 and 0.1mg/kg/injection). Phendimetrazine initially decreased overall responding without significantly altering cocaine choice. Over the course of 14 days, tolerance developed to rate decreasing effects, and phendimetrazine dose-dependently decreased cocaine choice (significant at 0.032 mg/kg/injection cocaine). Phenmetrazine and d-amphetamine produced qualitatively similar effects. These results demonstrate that phendimetrazine can produce significant, though modest, reductions in cocaine choice in rhesus monkeys. Phendimetrazine may be especially suitable as a candidate medication for human studies because of its schedule III clinical availability. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  13. Atomoxetine effects on attentional bias to drug-related cues in cocaine dependent individuals.

    Science.gov (United States)

    Passamonti, Luca; Luijten, M; Ziauddeen, H; Coyle-Gilchrist, I T S; Rittman, T; Brain, S A E; Regenthal, R; Franken, I H A; Sahakian, B J; Bullmore, E T; Robbins, T W; Ersche, K D

    2017-08-01

    Biased attention towards drug-related cues and reduced inhibitory control over the regulation of drug-intake characterize drug addiction. The noradrenaline system has been critically implicated in both attentional and response inhibitory processes and is directly affected by drugs such as cocaine. We examined the potentially beneficial effects of the noradrenaline reuptake inhibitor atomoxetine in improving cognitive control during two tasks that used cocaine- and non-cocaine-related stimuli. A double-blind, placebo-controlled, and cross-over psycho-pharmacological design was employed. A single oral dose of atomoxetine (40 mg) was administered to 28 cocaine-dependent individuals (CDIs) and 28 healthy controls. All participants performed a pictorial attentional bias task involving both cocaine- and non-cocaine-related pictures as well as a verbal go/no-go task composed of cocaine- and food-related words. As expected, CDIs showed attentional bias to cocaine-related cues whilst controls did not. More importantly, however, atomoxetine, relative to placebo, significantly attenuated attentional bias in CDIs (F 26  = 6.73, P = 0.01). During the go/no-go task, there was a treatment × trial × group interaction, although this finding only showed a trend towards statistical significance (F 26  = 3.38, P = 0.07). Our findings suggest that atomoxetine reduces attentional bias to drug-related cues in CDIs. This may result from atomoxetine's modulation of the balance between tonic/phasic activity in the locus coeruleus and the possibly parallel enhancement of noradrenergic neurotransmission within the prefrontal cortex. Studying how cognitive enhancers such as atomoxetine influence key neurocognitive indices in cocaine addiction may help to develop reliable biomarkers for patient stratification in future clinical trials.

  14. Triglyceride content in remnant lipoproteins is significantly increased after food intake and is associated with plasma lipoprotein lipase.

    Science.gov (United States)

    Nakajima, Katsuyuki; Tokita, Yoshiharu; Sakamaki, Koji; Shimomura, Younosuke; Kobayashi, Junji; Kamachi, Keiko; Tanaka, Akira; Stanhope, Kimber L; Havel, Peter J; Wang, Tao; Machida, Tetsuo; Murakami, Masami

    2017-02-01

    Previous large population studies reported that non-fasting plasma triglyceride (TG) reflect a higher risk for cardiovascular disease than TG in the fasting plasma. This is suggestive of the presence of higher concentration of remnant lipoproteins (RLP) in postprandial plasma. TG and RLP-TG together with other lipids, lipoproteins and lipoprotein lipase (LPL) in both fasting and postprandial plasma were determined in generally healthy volunteers and in patients with coronary artery disease (CAD) after consuming a fat load or a more typical moderate meal. RLP-TG/TG ratio (concentration) and RLP-TG/RLP-C ratio (particle size) were significantly increased in the postprandial plasma of both healthy controls and CAD patients compared with those in fasting plasma. LPL/RLP-TG ratio demonstrated the interaction correlation between RLP concentration and LPL activity The increased RLP-TG after fat consumption contributed to approximately 90% of the increased plasma TG, while approximately 60% after a typical meal. Plasma LPL in postprandial plasma was not significantly altered after either type of meal. Concentrations of RLP-TG found in the TG along with its particle size are significantly increased in postprandial plasma compared with fasting plasma. Therefore, non-fasting TG determination better reflects the presence of higher RLP concentrations in plasma. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  15. Attenuation of cocaine's reinforcing and discriminative stimulus effects via muscarinic M1 acetylcholine receptor stimulation

    DEFF Research Database (Denmark)

    Thomsen, Morgane; Conn, P Jeffrey; Lindsley, Craig

    2010-01-01

    substituted for cocaine and enhanced its discriminative stimulus. Conversely, muscarinic agonists blunted cocaine discrimination and abolished cocaine self-administration with varying effects on food-maintained behavior. Specifically, increasing selectivity for the M(1) subtype (oxotremorine ...'s abuse-related effects, whereas non-M(1)/M(4) receptors probably contribute to undesirable effects of muscarinic stimulation. These data provide the first demonstration of anticocaine effects of systemically applied, M(1) receptor agonists and suggest the possibility of a new approach to pharmacotherapy...

  16. St. John's wort significantly increased the systemic exposure and toxicity of methotrexate in rats

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Shih-Ying [Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan (China); Juang, Shin-Hun [Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan (China); Department of Medical Research, China Medical University Hospital, Taichung, Taiwan (China); Tsai, Shang-Yuan; Chao, Pei-Dawn Lee [School of Pharmacy, China Medical University, Taichung, Taiwan (China); Hou, Yu-Chi, E-mail: hou5133@gmail.com [School of Pharmacy, China Medical University, Taichung, Taiwan (China); Department of Medical Research, China Medical University Hospital, Taichung, Taiwan (China)

    2012-08-15

    St. John's wort (SJW, Hypericum perforatum) is one of the popular nutraceuticals for treating depression. Methotrexate (MTX) is an immunosuppressant with narrow therapeutic window. This study investigated the effect of SJW on MTX pharmacokinetics in rats. Rats were orally given MTX alone and coadministered with 300 and 150 mg/kg of SJW, and 25 mg/kg of diclofenac, respectively. Blood was withdrawn at specific time points and serum MTX concentrations were assayed by a specific monoclonal fluorescence polarization immunoassay method. The results showed that 300 mg/kg of SJW significantly increased the AUC{sub 0−t} and C{sub max} of MTX by 163% and 60%, respectively, and 150 mg/kg of SJW significantly increased the AUC{sub 0−t} of MTX by 55%. In addition, diclofenac enhanced the C{sub max} of MTX by 110%. The mortality of rats treated with SJW was higher than that of controls. In conclusion, coadministration of SJW significantly increased the systemic exposure and toxicity of MTX. The combined use of MTX with SJW would need to be with caution. -- Highlights: ► St. John's wort significantly increased the AUC{sub 0−t} and C{sub max} of methotrexate. ► Coadministration of St. John's wort increased the exposure and toxicity of methotrexate. ► The combined use of methotrexate with St. John's wort will need to be with caution.

  17. Acute renal failure, thrombocytopenia, and elevated liver enzymes after concurrent abuse of alcohol and cocaine

    Directory of Open Access Journals (Sweden)

    Alireza Hosseinnezhad

    2011-05-01

    Full Text Available Cocaine has been associated with known adverse effects on cardiac, cerebrovascular and pulmonary systems. However, the effect of cocaine on other organs has not been extensively reported. A middle age man presented with abdominal pain and nausea after inhalation of crack cocaine. On admission, he was found to be hypertensive and tachycardic. Physical examination revealed mild abdominal tenderness without rebound. Laboratory investigations were significant for acute kidney failure with elevated serum creatinine (3.72 mg/dL, thrombocytopenia (platelet count 74,000/UL, elevated alanine and aspartate transaminases (ALT 331 U/L; AST 462 U/L and elevated creatine phosphokinase (CPK 5885 U/L. Urine toxicology screening solely revealed cocaine. A clinical diagnosis of cocaine toxicity was made and patient was admitted to the intensive care unit because of multi organ failure. Despite downward trending of liver enzymes during the hospital course, he continued to have residual renal insufficiency and a low platelet count at the time of discharge. In a patient with history of recent cocaine use presenting with these manifestations, cocaine itself should be considered as a likely cause.

  18. Shallow discounting of delayed cocaine by male rhesus monkeys when immediate food is the choice alternative.

    Science.gov (United States)

    Huskinson, Sally L; Myerson, Joel; Green, Leonard; Rowlett, James K; Woolverton, William L; Freeman, Kevin B

    2016-12-01

    Huskinson et al. (2015) recently examined delay discounting in monkeys choosing between an immediate drug (cocaine) reinforcer and a delayed nondrug (food) reinforcer. The present experiment examined the reverse situation: choice between immediate nondrug (food) and delayed drug (cocaine) reinforcers. Whereas the former choice situation exemplifies drug abuse from a delay-discounting perspective, our interest in the latter choice situation is derived from the observation that drug abusers, who characteristically are associated with impulsive choice, typically must devote considerable time to procuring drugs, often at the expense of immediate nondrug alternatives. Accordingly, we analyzed 3 male rhesus monkeys' choices between immediate food and delayed cocaine (0.1 and 0.2 mg/kg/injection) using a hyperbolic model that allowed us to compare discounting rates between qualitatively different reinforcers. Choice of immediate food increased with food amount, and choice functions generally shifted leftward as delay to cocaine increased, indicating a decrease in the subjective value of cocaine. Compared with our previous delay-discounting experiment with immediate cocaine versus delayed food, both doses of delayed cocaine were discounted at a shallow rate. The present results demonstrate that rhesus monkeys will tolerate relatively long delays in an immediate-food versus delayed-drug situation, suggesting that in intertemporal choices between cocaine and food, the subjective value of cocaine is less affected by the delay until reinforcement than is the subjective value of delayed food. More generally, the present findings suggest that although drug abusers may choose impulsively when immediate drug reinforcement is available, they exercise self-control in the acquisition of a highly preferred, delayed drug reinforcer. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  19. Electrical stimulation of the lateral habenula produces enduring inhibitory effect on cocaine seeking behavior.

    Science.gov (United States)

    Friedman, Alexander; Lax, Elad; Dikshtein, Yahav; Abraham, Lital; Flaumenhaft, Yakov; Sudai, Einav; Ben-Tzion, Moshe; Ami-Ad, Lavi; Yaka, Rami; Yadid, Gal

    2010-11-01

    The lateral habenula (LHb) is critical for modulation of negative reinforcement, punishment and aversive responses. In light of the success of deep-brain-stimulation (DBS) in the treatment of neurological disorders, we explored the use of LHb DBS as a method of intervention in cocaine self-administration, extinction, and reinstatement in rats. An electrode was implanted into the LHb and rats were trained to self-administer cocaine (21 days; 0.25-1 mg/kg) until they achieved at least three days of stable performance (as measured by daily recordings of active lever presses in self-administration cages). Thereafter, rats received DBS in the presence or absence of cocaine. DBS reduced cocaine seeking behavior during both self-administration and extinction training. DBS also attenuated the rats' lever presses following cocaine reinstatement (5-20 mg/kg) in comparison to sham-operated rats. These results were also controlled by the assessment of physical performance as measured by water self-administration and an open field test, and by evaluation of depressive-like manifestations as measured by the swim and two-bottles-choice tests. In contrast, LHb lesioned rats demonstrated increased cocaine seeking behavior as demonstrated by a delayed extinction response. In the ventral tegmental area, cocaine self-administration elevated glutamatergic receptor subunits NR1 and GluR1 and scaffolding protein PSD95, but not GABA(A)β, protein levels. Following DBS treatment, levels of these subunits returned to control values. We postulate that the effect of both LHb modulation and LHb DBS on cocaine reinforcement may be via attenuation of the cocaine-induced increase in glutaminergic input to the VTA. Copyright © 2010 Elsevier Ltd. All rights reserved.

  20. 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

  1. Effects of 7-day continuous D-amphetamine, methylphenidate, and cocaine treatment on choice between methamphetamine and food in male rhesus monkeys.

    Science.gov (United States)

    Schwienteck, Kathryn L; Banks, Matthew L

    2015-10-01

    Methamphetamine addiction is a significant public health problem for which no Food and Drug Administration-approved pharmacotherapies exist. Preclinical drug vs. food choice procedures have been predictive of clinical medication efficacy in the treatment of opioid and cocaine addiction. Whether preclinical choice procedures are predictive of candidate medication effects for other abused drugs, such as methamphetamine, remains unclear. The present study aim was to determine continuous 7-day treatment effects with the monoamine releaser d-amphetamine and the monoamine uptake inhibitor methylphenidate on methamphetamine vs. food choice. In addition, 7-day cocaine treatment effects were also examined. Behavior was maintained under a concurrent schedule of food delivery (1-g pellets, fixed-ratio 100 schedule) and methamphetamine injections (0-0.32mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n=4). Methamphetamine choice dose-effect functions were determined daily before and during 7-day periods of continuous intravenous treatment with d-amphetamine (0.01-0.1mg/kg/h), methylphenidate (0.032-0.32mg/kg/h), or cocaine (0.1-0.32mg/kg/h). During saline treatment, increasing methamphetamine doses resulted in a corresponding increase in methamphetamine vs. food choice. Continuous 7-day treatments with d-amphetamine, methylphenidate or cocaine did not significantly attenuate methamphetamine vs. food choice up to doses that decreased rates of operant responding. However, 0.1mg/kg/h d-amphetamine did eliminate methamphetamine choice in two monkeys. The present subchronic treatment results support the utility of preclinical methamphetamine choice to evaluate candidate medications for methamphetamine addiction. Furthermore, these results confirm and extend previous results demonstrating differential pharmacological mechanisms between cocaine choice and methamphetamine choice. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  2. Significant social events and increasing use of life-sustaining treatment: trend analysis using extracorporeal membrane oxygenation as an example.

    Science.gov (United States)

    Chen, Yen-Yuan; Chen, Likwang; Huang, Tien-Shang; Ko, Wen-Je; Chu, Tzong-Shinn; Ni, Yen-Hsuan; Chang, Shan-Chwen

    2014-03-04

    Most studies have examined the outcomes of patients supported by extracorporeal membrane oxygenation as a life-sustaining treatment. It is unclear whether significant social events are associated with the use of life-sustaining treatment. This study aimed to compare the trend of extracorporeal membrane oxygenation use in Taiwan with that in the world, and to examine the influence of significant social events on the trend of extracorporeal membrane oxygenation use in Taiwan. Taiwan's extracorporeal membrane oxygenation uses from 2000 to 2009 were collected from National Health Insurance Research Dataset. The number of the worldwide extracorporeal membrane oxygenation cases was mainly estimated using Extracorporeal Life Support Registry Report International Summary July 2012. The trend of Taiwan's crude annual incidence rate of extracorporeal membrane oxygenation use was compared with that of the rest of the world. Each trend of extracorporeal membrane oxygenation use was examined using joinpoint regression. The measurement was the crude annual incidence rate of extracorporeal membrane oxygenation use. Each of the Taiwan's crude annual incidence rates was much higher than the worldwide one in the same year. Both the trends of Taiwan's and worldwide crude annual incidence rates have significantly increased since 2000. Joinpoint regression selected the model of the Taiwan's trend with one joinpoint in 2006 as the best-fitted model, implying that the significant social events in 2006 were significantly associated with the trend change of extracorporeal membrane oxygenation use following 2006. In addition, significantly social events highlighted by the media are more likely to be associated with the increase of extracorporeal membrane oxygenation use than being fully covered by National Health Insurance. Significant social events, such as a well-known person's successful extracorporeal membrane oxygenation use highlighted by the mass media, are associated with the use of

  3. Employment-based abstinence reinforcement following inpatient detoxification in HIV-positive opioid and/or cocaine-dependent patients.

    Science.gov (United States)

    Dunn, Kelly E; Fingerhood, Michael; Wong, Conrad J; Svikis, Dace S; Nuzzo, Paul; Silverman, Kenneth

    2014-02-01

    Employment-based reinforcement interventions have been used to promote abstinence from drugs among chronically unemployed injection drug users. The current study used an employment-based reinforcement intervention to promote opioid and cocaine abstinence among opioid and/or cocaine-dependent, HIV-positive participants who had recently completed a brief inpatient detoxification. Participants (n = 46) were randomly assigned to an abstinence and work group that was required to provide negative urine samples in order to enter the workplace and to earn incentives for work (n = 16), a work-only group that was permitted to enter the workplace and to earn incentives independent of drug use (n = 15), and a no-voucher control group that did not receive any incentives for working (n = 15) over a 26-week period. The primary outcome was urinalysis-confirmed opioid, cocaine, and combined opioid/cocaine abstinence. Participants were 78% male and 89% African American. Results showed no significant between-groups differences in urinalysis-verified drug abstinence or HIV risk behaviors during the 6-month intervention. The work-only group had significantly greater workplace attendance, and worked more minutes per day when compared to the no-voucher group. Several features of the study design, including the lack of an induction period, setting the threshold for entering the workplace too high by requiring immediate abstinence from several drugs, and increasing the risk of relapse by providing a brief detoxification that was not supported by any continued pharmacological intervention, likely prevented the workplace from becoming established as a reinforcer that could be used to promote drug abstinence. However, increases in workplace attendance have important implications for adult training programs.

  4. 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

  5. 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.

  6. 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...

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

    Science.gov (United States)

    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.

  8. Effects of haloperidol and cocaine pretreatments on brain distribution and kinetics of [{sup 11}C]methamphetamine in methamphetamine sensitized dog: Application of PET to drug pharmacokinetic study

    Energy Technology Data Exchange (ETDEWEB)

    Nakamura, Hitoshi; Hishinuma, Takanori; Tomioka, Yoshihisa; Ishiwata, Shunji; Ido, Tatsuo; Iwata, Ren; Funaki, Yoshihito; Itoh, Masatoshi; Fujiwara, Takehiko; Yanai, Kazuhiko; Sato, Mitsumoto; Numachi, Yohtaro; Yoshida, Sumiko; Mizugaki, Michinao

    1997-02-01

    Repeated administration of methamphetamine (MAP) causes behavioral sensitization in animals. We previously reported that the maximum accumulation level of [{sup 11}C]MAP in the MAP-sensitized dog brain was 1.4 times higher than that in the control. In behavioral studies, haloperidol (a dopamine D{sub 2} receptor antagonist) prevents MAP-induced behavioral sensitization, and cocaine (a dopamine reuptake blocker) has the cross-behavioral sensitization with MAP. In the present study, to elucidate the relation between the MAP-induced behavioral sensitization and the pharmacokinetics of MAP, we investigated the effects of haloperidol and cocaine pretreatments on brain regional distribution and kinetics of [{sup 11}C]MAP using positron emission tomography (PET). A significant increase of [{sup 11}C]MAP uptake into the sensitized dog brain was prevented by haloperidol and cocaine pretreatments. These pharmacokinetic changes were not due to the changes in the rate of MAP metabolism. These results suggest haloperidol and cocaine can change the cerebral pharmacokinetic profile of MAP in the behavioral-sensitized dog. The variations of MAP-accumulation may affect the development or expression of MAP-induced behavioral sensitization.

  9. Effects of haloperidol and cocaine pretreatments on brain distribution and kinetics of [11C]methamphetamine in methamphetamine sensitized dog: Application of PET to drug pharmacokinetic study

    International Nuclear Information System (INIS)

    Nakamura, Hitoshi; Hishinuma, Takanori; Tomioka, Yoshihisa; Ishiwata, Shunji; Ido, Tatsuo; Iwata, Ren; Funaki, Yoshihito; Itoh, Masatoshi; Fujiwara, Takehiko; Yanai, Kazuhiko; Sato, Mitsumoto; Numachi, Yohtaro; Yoshida, Sumiko; Mizugaki, Michinao

    1997-01-01

    Repeated administration of methamphetamine (MAP) causes behavioral sensitization in animals. We previously reported that the maximum accumulation level of [ 11 C]MAP in the MAP-sensitized dog brain was 1.4 times higher than that in the control. In behavioral studies, haloperidol (a dopamine D 2 receptor antagonist) prevents MAP-induced behavioral sensitization, and cocaine (a dopamine reuptake blocker) has the cross-behavioral sensitization with MAP. In the present study, to elucidate the relation between the MAP-induced behavioral sensitization and the pharmacokinetics of MAP, we investigated the effects of haloperidol and cocaine pretreatments on brain regional distribution and kinetics of [ 11 C]MAP using positron emission tomography (PET). A significant increase of [ 11 C]MAP uptake into the sensitized dog brain was prevented by haloperidol and cocaine pretreatments. These pharmacokinetic changes were not due to the changes in the rate of MAP metabolism. These results suggest haloperidol and cocaine can change the cerebral pharmacokinetic profile of MAP in the behavioral-sensitized dog. The variations of MAP-accumulation may affect the development or expression of MAP-induced behavioral sensitization

  10. Benzodiazepines and antipsychotic medications for treatment of acute cocaine toxicity in animal models--a systematic review and meta-analysis.

    Science.gov (United States)

    Heard, Kennon; Cleveland, Nathan R; Krier, Shay

    2011-11-01

    There are no controlled human studies to determine the efficacy of benzodiazepines or antipsychotic medications for prevention or treatment of acute cocaine toxicity. The only available controlled data are from animal models and these studies have reported inconsistent benefits. The objective of this study was to quantify the reported efficacy of benzodiazepines and antipsychotic medication for the prevention of mortality due to cocaine poisoning. We conducted a systematic review to identify English language articles describing experiments that compared a benzodiazepine or antipsychotic medication to placebo for the prevention of acute cocaine toxicity in an animal model. We then used these articles in a meta-analysis with a random-effects model to quantify the absolute risk reduction observed in these experiments. We found 10 articles evaluating antipsychotic medications and 15 articles evaluating benzodiazepines. Antipsychotic medications reduced the risk of death by 27% (95% CI, 15.2%-38.7%) compared to placebo and benzodiazepines reduced the risk of death by 52% (42.8%-60.7%) compared to placebo. Both treatments showed evidence of a dose-response effect, and no experiment found a statistically significant increase in risk of death. We conclude that both benzodiazepines and antipsychotic medications are effective for the prevention of lethality from cocaine toxicity in animal models.

  11. Characterization of a cocaine binding protein in human placenta

    International Nuclear Information System (INIS)

    Ahmed, M.S.; Zhou, D.H.; Maulik, D.; Eldefrawi, M.E.

    1990-01-01

    [ 3 H]-Cocaine binding sites are identified in human placental villus tissue plasma membranes. These binding sites are associated with a protein and show saturable and specific binding of [ 3 H]-cocaine with a high affinity site of 170 fmole/mg protein. The binding is lost with pretreatment with trypsin or heat. The membrane bound protein is solubilized with the detergent 3-(3-cholamidopropyl)dimethyl-ammonio-1-propane sulphonate (CHAPS) with retention of its saturable and specific binding of [ 3 H]-cocaine. The detergent-protein complex migrates on a sepharose CL-6B gel chromatography column as a protein with an apparent molecular weight of 75,900. The protein has an S 20,w value of 5.1. The binding of this protein to norcocaine, pseudococaine, nomifensine, imipramine, desipramine, amphetamine and dopamine indicates that it shares some, but not all, the properties of the brain cocaine receptor. The physiologic significance of this protein in human placenta is currently unclear

  12. 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.

  13. Social marketing campaign significantly associated with increases in syphilis testing among gay and bisexual men in San Francisco.

    Science.gov (United States)

    Montoya, Jorge A; Kent, Charlotte K; Rotblatt, Harlan; McCright, Jacque; Kerndt, Peter R; Klausner, Jeffrey D

    2005-07-01

    Between 1999 and 2002, San Francisco experienced a sharp increase in early syphilis among gay and bisexual men. In response, the San Francisco Department of Public Health launched a social marketing campaign to increase testing for syphilis, and awareness and knowledge about syphilis among gay and bisexual men. A convenience sample of 244 gay and bisexual men (18-60 years of age) were surveyed to evaluate the effectiveness of the campaign. Respondents were interviewed to elicit unaided and aided awareness about the campaign, knowledge about syphilis, recent sexual behaviors, and syphilis testing behavior. After controlling for other potential confounders, unaided campaign awareness was a significant correlate of having a syphilis test in the last 6 months (odds ratio, 3.21; 95% confidence interval, 1.30-7.97) compared with no awareness of the campaign. A comparison of respondents aware of the campaign with those not aware also revealed significant increases in awareness and knowledge about syphilis. The Healthy Penis 2002 campaign achieved its primary objective of increasing syphilis testing, and awareness and knowledge about syphilis among gay and bisexual men in San Francisco.

  14. 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)

  15. 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.

  16. 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.

  17. Cocaine Disrupts Histamine H3 Receptor Modulation of Dopamine D1 Receptor Signaling: σ1-D1-H3 Receptor Complexes as Key Targets for Reducing Cocaine's Effects

    Science.gov (United States)

    Moreno, Estefanía; Moreno-Delgado, David; Navarro, Gemma; Hoffmann, Hanne M.; Fuentes, Silvia; Rosell-Vilar, Santi; Gasperini, Paola; Rodríguez-Ruiz, Mar; Medrano, Mireia; Mallol, Josefa; Cortés, Antoni; Casadó, Vicent; Lluís, Carme; Ferré, Sergi; Ortiz, Jordi; Canela, Enric

    2014-01-01

    The general effects of cocaine are not well understood at the molecular level. What is known is that the dopamine D1 receptor plays an important role. Here we show that a key mechanism may be cocaine's blockade of the histamine H3 receptor-mediated inhibition of D1 receptor function. This blockade requires the σ1 receptor and occurs upon cocaine binding to σ1-D1-H3 receptor complexes. The cocaine-mediated disruption leaves an uninhibited D1 receptor that activates Gs, freely recruits β-arrestin, increases p-ERK 1/2 levels, and induces cell death when over activated. Using in vitro assays with transfected cells and in ex vivo experiments using both rats acutely treated or self-administered with cocaine along with mice depleted of σ1 receptor, we show that blockade of σ1 receptor by an antagonist restores the protective H3 receptor-mediated brake on D1 receptor signaling and prevents the cell death from elevated D1 receptor signaling. These findings suggest that a combination therapy of σ1R antagonists with H3 receptor agonists could serve to reduce some effects of cocaine. PMID:24599455

  18. Dynorphin/KOP and nociceptin/NOP gene expression and epigenetic changes by cocaine in rat striatum and nucleus accumbens.

    Science.gov (United States)

    Caputi, Francesca Felicia; Di Benedetto, Manuela; Carretta, Donatella; Bastias del Carmen Candia, Sussy; D'Addario, Claudio; Cavina, Chiara; Candeletti, Sanzio; Romualdi, Patrizia

    2014-03-03

    Cocaine induces neurochemical changes of endogenous prodynorphin-kappa opioid receptor (pDYN-KOP) and pronociceptin/orphaninFQ-nociceptin receptor (pN/OFQ-NOP) systems. Both systems play an important role in rewarding mechanisms and addictive stimulus processing by modulating drug-induced dopaminergic activation in the mesocortico-limbic brain areas. They are also involved in regulating stress mechanisms related to addiction. The aim of this study was to investigate possible changes of gene expression of the dynorphinergic and nociceptinergic system components in the nucleus accumbens (NA) and in medial and lateral caudate putamen (mCPu and lCPu, respectively) of rats, following chronic subcutaneous infusion of cocaine. In addition, the epigenetic histone modifications H3K4me3 and H3K27me3 (an activating and a repressive marker, respectively) at the promoter level of the pDYN, KOP, pN/OFQ and NOP genes were investigated. Results showed that cocaine induced pDYN gene expression up-regulation in the NA and lCPu, and its down-regulation in the mCPu, whereas KOP mRNA levels were unchanged. Moreover, cocaine exposure decreased pN/OFQ gene expression in the NA and lCPu, while NOP mRNA levels appeared significantly increased in the NA and decreased in the lCPu. Specific changes of the H3K4me3 and H3K27me3 levels were found at pDYN, pN/OFQ, and NOP gene promoter, consistent with the observed gene expression alterations. The present findings contribute to better define the role of endogenous pDYN-KOP and pN/OFQ-NOP systems in neuroplasticity mechanisms following chronic cocaine treatment. The epigenetic histone modifications underlying the gene expression changes likely mediate the effects of cocaine on transcriptional regulation of specific gene promoters that result in long-lasting drug-induced plasticity. © 2013.

  19. Response of the Ubiquitin-Proteasome System to Memory Retrieval After Extended-Access Cocaine or Saline Self-Administration.

    Science.gov (United States)

    Werner, Craig T; Milovanovic, Mike; Christian, Daniel T; Loweth, Jessica A; Wolf, Marina E

    2015-12-01

    The ubiquitin-proteasome system (UPS) has been implicated in the retrieval-induced destabilization of cocaine- and fear-related memories in Pavlovian paradigms. However, nothing is known about its role in memory retrieval after self-administration of cocaine, an operant paradigm, or how the length of withdrawal from cocaine may influence retrieval mechanisms. Here, we examined UPS activity after an extended-access cocaine self-administration regimen that leads to withdrawal-dependent incubation of cue-induced cocaine craving. Controls self-administered saline. In initial experiments, memory retrieval was elicited via a cue-induced seeking/retrieval test on withdrawal day (WD) 50-60, when craving has incubated. We found that retrieval of cocaine- and saline-associated memories produced similar increases in polyubiquitinated proteins in the nucleus accumbens (NAc), compared with rats that did not undergo a seeking/retrieval test. Measures of proteasome catalytic activity confirmed similar activation of the UPS after retrieval of saline and cocaine memories. However, in a subsequent experiment in which testing was conducted on WD1, proteasome activity in the NAc was greater after retrieval of cocaine memory than saline memory. Analysis of other brain regions confirmed that effects of cocaine memory retrieval on proteasome activity, relative to saline memory retrieval, depend on withdrawal time. These results, combined with prior studies, suggest that the relationship between UPS activity and memory retrieval depends on training paradigm, brain region, and time elapsed between training and retrieval. The observation that mechanisms underlying cocaine memory retrieval change depending on the age of the memory has implications for development of memory destabilization therapies for cue-induced relapse in cocaine addicts.

  20. Comparison of 4% and 6% topical cocaine solutions for reduction of epistaxis induced by nasotracheal intubation.

    Science.gov (United States)

    Lu, I-Cheng; Hsieh, Yu-Hui; Hsu, Hung-Te; Chen, Chung-Ho; Hsu, Ching-Wei; Tseng, Kuang-Yi; Cheng, Kuang-I

    2014-03-01

    Nasotracheal intubation (NTI) provides a good field for surgeons in patients undergoing oromaxillofacial surgery; however, NTI is often complicated by epistaxis. The aim of this study was to compare the efficacy of 4% and 6% topical cocaine solutions in reducing epistaxis during NTI. A total of 79 patients (16-65 years old) undergoing oromaxillofacial surgery were randomly assigned to two groups treated with either 4% cocaine (n = 39) or 6% cocaine (n = 40). Topical cocaine (1 mL) was sprayed onto the selected nasal cavity prior to NTI. All intubations were performed by an expert anesthesiologist using a GlideScope. The incidence and severity of epistaxis was examined along the nasal cavity up to the nasopharynx using a fiber optic bronchoscope. The hemodynamic responses to stimuli during the peri-NTI period were also recorded. The incidence of epistaxis was 43.59% (17/39) in the 4% cocaine group and 50% (20/40) in the 6% cocaine group (p = 0.57). The severity of epistaxis did not differ between the two groups (p = 0.46). High resistance during NTI and epistaxis were closely correlated and the major bleeding sites were located at the nasopharynx. Compared with the 4% cocaine group, treatment with 6% cocaine resulted in a higher heart rate and mean arterial pressure (both p epistaxis. However, 6% cocaine may increase the hemodynamic responses while being sprayed. Therefore spraying with 4% topical cocaine had advantages with respect to 6% cocaine and is recommended for use prior to NTI. Copyright © 2014. Published by Elsevier B.V.

  1. Cocaine- and amphetamine-regulated transcript (CART signaling within the paraventricular thalamus modulates cocaine-seeking behaviour.

    Directory of Open Access Journals (Sweden)

    Morgan H James

    Full Text Available BACKGROUND: Cocaine- and amphetamine-regulated transcript (CART has been demonstrated to play a role in regulating the rewarding and reinforcing effects of various drugs of abuse. A recent study demonstrated that i.c.v. administration of CART negatively modulates reinstatement of alcohol seeking, however, the site(s of action remains unclear. We investigated the paraventricular thalamus (PVT as a potential site of relapse-relevant CART signaling, as this region is known to receive dense innervation from CART-containing hypothalamic cells and to project to a number of regions known to be involved in mediating reinstatement, including the nucleus accumbens (NAC, medial prefrontal cortex (mPFC and basolateral amygdala (BLA. METHODOLOGY/PRINCIPAL FINDINGS: Male rats were trained to self-administer cocaine before being extinguished to a set criterion. One day following extinction, animals received intra-PVT infusions of saline, tetrodotoxin (TTX; 2.5 ng, CART (0.625 µg or 2.5 µg or no injection, followed by a cocaine prime (10 mg/kg, i.p.. Animals were then tested under extinction conditions for one hour. Treatment with either TTX or CART resulted in a significant attenuation of drug-seeking behaviour following cocaine-prime, with the 2.5 µg dose of CART having the greatest effect. This effect was specific to the PVT region, as misplaced injections of both TTX and CART resulted in responding that was identical to controls. CONCLUSIONS/SIGNIFICANCE: We show for the first time that CART signaling within the PVT acts to inhibit drug-primed reinstatement of cocaine seeking behaviour, presumably by negatively modulating PVT efferents that are important for drug seeking, including the NAC, mPFC and BLA. In this way, we identify a possible target for future pharmacological interventions designed to suppress drug seeking.

  2. Metabotropic glutamate receptor I (mGluR1) antagonism impairs cocaine-induced conditioned place preference via inhibition of protein synthesis.

    Science.gov (United States)

    Yu, Fei; Zhong, Peng; Liu, Xiaojie; Sun, Dalong; Gao, Hai-Qing; Liu, Qing-Song

    2013-06-01

    Antagonism of group I metabotropic glutamate receptors (mGluR1 and mGluR5) reduces behavioral effects of drugs of abuse, including cocaine. However, the underlying mechanisms remain poorly understood. Activation of mGluR5 increases protein synthesis at synapses. Although mGluR5-induced excessive protein synthesis has been implicated in the pathology of fragile X syndrome, it remains unknown whether group I mGluR-mediated protein synthesis is involved in any behavioral effects of drugs of abuse. We report that group I mGluR agonist DHPG induced more pronounced initial depression of inhibitory postsynaptic currents (IPSCs) followed by modest long-term depression (I-LTD) in dopamine neurons of rat ventral tegmental area (VTA) through the activation of mGluR1. The early component of DHPG-induced depression of IPSCs was mediated by the cannabinoid CB1 receptors, while DHPG-induced I-LTD was dependent on protein synthesis. Western blotting analysis indicates that mGluR1 was coupled to extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR) signaling pathways to increase translation. We also show that cocaine conditioning activated translation machinery in the VTA via an mGluR1-dependent mechanism. Furthermore, intra-VTA microinjections of mGluR1 antagonist JNJ16259685 and protein synthesis inhibitor cycloheximide significantly attenuated or blocked the acquisition of cocaine-induced conditioned place preference (CPP) and activation of translation elongation factors. Taken together, these results suggest that mGluR1 antagonism inhibits de novo protein synthesis; this effect may block the formation of cocaine-cue associations and thus provide a mechanism for the reduction in CPP to cocaine.

  3. A competitive enzyme immunoassay for the quantitative detection of cocaine from banknotes and latent fingermarks.

    Science.gov (United States)

    van der Heide, Susan; Garcia Calavia, Paula; Hardwick, Sheila; Hudson, Simon; Wolff, Kim; Russell, David A

    2015-05-01

    -effective alternative to the current mass spectrometry based techniques for the quantitation of cocaine at forensically significant concentrations. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  4. Cocaine induces a mixed lysosomal lipidosis in cultured fibroblasts, by inactivation of acid sphingomyelinase and inhibition of phospholipase A1

    International Nuclear Information System (INIS)

    Nassogne, Marie-Cecile; Lizarraga, Chantal; N'Kuli, Francisca; Van Bambeke, Francoise; Van Binst, Roger; Wallemacq, Pierre; Tulkens, Paul M.; Mingeot-Leclercq, Marie-Paule; Levade, Thierry; Courtoy, Pierre J.

    2004-01-01

    This paper reports that cocaine may induce a lysosomal storage disorder. Indeed, culture of Rat-1 fibroblasts with 250-500 μM cocaine induced after 2-3 days a major accumulation in lysosomes of electron-dense lamellar structures. By subcellular fractionation, this was reflected by a selective decrease of the buoyant density of several lysosomal enzymes, indicating lysosomal lipid overload. Biochemical analysis confirmed an increased cellular content of major phospholipids and sphingomyelin, but not of cholesterol. Cocaine, a membrane-permeant weak base, is concentrated by acidotropic sequestration, because its accumulation was abrogated by the proton ionophore, monensin and the vacuolar ATPase inhibitor, bafilomycin A 1 . At its estimated lysosomal concentration, cocaine almost completely inhibited phospholipase A 1 activity on liposomes. Cell incubation with cocaine, but not with its inactive metabolite, benzoylecgonine, rapidly inactivated acid sphingomyelinase, as reflected by a 10-fold decrease in V max with identical K m . Acid sphingomyelinase inactivation was fully prevented by the thiol proteinases inhibitors, leupeptin and E64, indicating that cocaine induces selective sphingomyelinase proteolysis. Upon cocaine removal, acid sphingomyelinase activity was rapidly restored, pointing to its fast turnover. In contrast, the cellular content of several other lysosomal hydrolases was increased up to 2-fold. Together, these data show that acidotropic accumulation of cocaine in lysosomes rapidly inhibits acid phospholipase A 1 and inactivates acid sphingomyelinase, which can explain induction of a mixed lysosomal lipidosis

  5. Effects of muscarinic receptor antagonists on cocaine discrimination in wild-type mice and in muscarinic receptor M1, M2, and M4 receptor knockout mice.

    Science.gov (United States)

    Joseph, Lauren; Thomsen, Morgane

    2017-06-30

    Muscarinic M 1 /M 4 receptor stimulation can reduce abuse-related effects of cocaine and may represent avenues for treating cocaine addiction. Muscarinic antagonists can mimic and enhance effects of cocaine, including discriminative stimulus (S D ) effects, but the receptor subtypes mediating those effects are not known. A better understanding of the complex cocaine/muscarinic interactions is needed to evaluate and develop potential muscarinic-based medications. Here, knockout mice lacking M 1 , M 2 , or M 4 receptors (M 1 -/- , M 2 -/- , M 4 -/- ), as well as control wild-type mice and outbred Swiss-Webster mice, were trained to discriminate 10mg/kg cocaine from saline. Muscarinic receptor antagonists with no subtype selectivity (scopolamine), or preferential affinity at the M 1 , M 2 , or M 4 subtype (telenzepine, trihexyphenidyl; methoctramine, AQ-RA 741; tropicamide) were tested alone and in combination with cocaine. In intact animals, antagonists with high affinity at M 1 /M 4 receptors partially substituted for cocaine and increased the S D effect of cocaine, while M 2 -preferring antagonists did not substitute, and reduced the S D effect of cocaine. The cocaine-like effects of scopolamine were absent in M 1 -/- mice. The cocaine S D attenuating effects of methoctramine were absent in M 2 -/- mice and almost absent in M 1 -/- mice. The findings indicate that the cocaine-like S D effects of muscarinic antagonists are primarily mediated through M 1 receptors, with a minor contribution of M 4 receptors. The data also support our previous findings that stimulation of M 1 receptors and M 4 receptors can each attenuate the S D effect of cocaine, and show that this can also be achieved by blocking M 2 autoreceptors, likely via increased acetylcholine release. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Ethical issues in using a cocaine vaccine to treat and prevent cocaine abuse and dependence.

    Science.gov (United States)

    Hall, W; Carter, L

    2004-08-01

    A "cocaine vaccine" is a promising immunotherapeutic approach to treating cocaine dependence which induces the immune system to form antibodies that prevent cocaine from crossing the blood brain barrier to act on receptor sites in the brain. Studies in rats show that cocaine antibodies block cocaine from reaching the brain and prevent the reinstatement of cocaine self administration. A successful phase 1 trial of a human cocaine vaccine has been reported. The most promising application of a cocaine vaccine is to prevent relapse to dependence in abstinent users who voluntarily enter treatment. Any use of a vaccine to treat cocaine addicts under legal coercion raises major ethical issues. If this is done at all, it should be carefully trialled first, and only after considerable clinical experience has been obtained in using the vaccine to treat voluntary patients. There will need to be an informed community debate about what role, if any, a cocaine vaccine may have as a way of preventing cocaine addiction in children and adolescents.

  7. 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 ...

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

    Science.gov (United States)

    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.

  9. A Randomized Trial of Employment-Based Reinforcement of Cocaine Abstinence in Injection Drug Users

    OpenAIRE

    Silverman, Kenneth; Wong, Conrad J; Needham, Mick; Diemer, Karly N; Knealing, Todd; Crone-Todd, Darlene; Fingerhood, Michael; Nuzzo, Paul; Kolodner, Kenneth

    2007-01-01

    High-magnitude and long-duration abstinence reinforcement can promote drug abstinence but can be difficult to finance. Employment may be a vehicle for arranging high-magnitude and long-duration abstinence reinforcement. This study determined if employment-based abstinence reinforcement could increase cocaine abstinence in adults who inject drugs and use cocaine during methadone treatment. Participants could work 4 hr every weekday in a workplace where they could earn about $10.00 per hour in ...

  10. Accelerating cocaine metabolism as an approach to the treatment of cocaine abuse and toxicity

    Science.gov (United States)

    Schindler, Charles W; Goldberg, Steven R

    2012-01-01

    One pharmacokinetic approach to the treatment of cocaine abuse and toxicity involves the development of compounds that can be safely administered to humans and that accelerate the metabolism of cocaine to inactive components. Catalytic antibodies have been developed and shown to accelerate cocaine metabolism, but their catalytic efficiency for cocaine is relatively low. Mutations of human butyrylcholinesterase and a bacterial cocaine esterase found in the soil of coca plants have also been developed. These compounds accelerate cocaine metabolism and antagonize the behavioral and toxic effects of cocaine in animal models. Of these two approaches, the human butyrylcholinesterase mutants show the most immediate promise as they would not be expected to evoke an immune response in humans. PMID:22300096

  11. Prefrontal Neuronal Excitability Maintains Cocaine-Associated Memory During Retrieval

    Directory of Open Access Journals (Sweden)

    James M. Otis

    2018-06-01

    Full Text Available Presentation of drug-associated cues provokes craving and drug seeking, and elimination of these associative memories would facilitate recovery from addiction. Emotionally salient memories are maintained during retrieval, as particular pharmacologic or optogenetic perturbations of memory circuits during retrieval, but not after, can induce long-lasting memory impairments. For example, in rats, inhibition of noradrenergic beta-receptors, which control intrinsic neuronal excitability, in the prelimbic medial prefrontal cortex (PL-mPFC can cause long-term memory impairments that prevent subsequent cocaine-induced reinstatement. The physiologic mechanisms that allow noradrenergic signaling to maintain drug-associated memories during retrieval, however, are unclear. Here we combine patch-clamp electrophysiology ex vivo and behavioral neuropharmacology in vivo to evaluate the mechanisms that maintain drug-associated memory during retrieval in rats. Consistent with previous studies, we find that cocaine experience increases the intrinsic excitability of pyramidal neurons in PL-mPFC. In addition, we now find that this intrinsic plasticity positively predicts the retrieval of a cocaine-induced conditioned place preference (CPP memory, suggesting that such plasticity may contribute to drug-associated memory retrieval. In further support of this, we find that pharmacological blockade of a cAMP-dependent signaling cascade, which allows noradrenergic signaling to elevate neuronal excitability, is required for memory maintenance during retrieval. Thus, inhibition of PL-mPFC neuronal excitability during memory retrieval not only leads to long-term deficits in the memory, but this memory deficit provides protection against subsequent cocaine-induced reinstatement. These data reveal that PL-mPFC intrinsic neuronal excitability maintains a cocaine-associated memory during retrieval and suggest a unique mechanism whereby drug-associated memories could be targeted

  12. Significance and prognostic value of increased serum direct bilirubin level for lymph node metastasis in Chinese rectal cancer patients.

    Science.gov (United States)

    Gao, Chun; Fang, Long; Li, Jing-Tao; Zhao, Hong-Chuan

    2016-02-28

    To determine the significance of increased serum direct bilirubin level for lymph node metastasis (LNM) in Chinese rectal cancer patients, after those with known hepatobiliary and pancreatic diseases were excluded. A cohort of 469 patients, who were treated at the China-Japan Friendship Hospital, Ministry of Health (Beijing, China), in the period from January 2003 to June 2011, and with a pathological diagnosis of rectal adenocarcinoma, were recruited. They included 231 patients with LNM (49.3%) and 238 patients without LNM. Follow-up for these patients was taken through to December 31, 2012. The baseline serum direct bilirubin concentration was (median/inter-quartile range) 2.30/1.60-3.42 μmol/L. Univariate analysis showed that compared with patients without LNM, the patients with LNM had an increased level of direct bilirubin (2.50/1.70-3.42 vs 2.10/1.40-3.42, P = 0.025). Multivariate analysis showed that direct bilirubin was independently associated with LNM (OR = 1.602; 95%CI: 1.098-2.338, P = 0.015). Moreover, we found that: (1) serum direct bilirubin differs between male and female patients; a higher concentration was associated with poor tumor classification; (2) as the baseline serum direct bilirubin concentration increased, the percentage of patients with LNM increased; and (3) serum direct bilirubin was associated with the prognosis of rectal cancer patients and higher values indicated poor prognosis. Higher serum direct bilirubin concentration was associated with the increased risk of LNM and poor prognosis in our rectal cancers.

  13. Expression of a bacterial catalase in a strictly anaerobic methanogen significantly increases tolerance to hydrogen peroxide but not oxygen

    Science.gov (United States)

    Jennings, Matthew E.; Schaff, Cody W.; Horne, Alexandra J.; Lessner, Faith H.

    2014-01-01

    Haem-dependent catalase is an antioxidant enzyme that degrades H2O2, producing H2O and O2, and is common in aerobes. Catalase is present in some strictly anaerobic methane-producing archaea (methanogens), but the importance of catalase to the antioxidant system of methanogens is poorly understood. We report here that a survey of the sequenced genomes of methanogens revealed that the majority of species lack genes encoding catalase. Moreover, Methanosarcina acetivorans is a methanogen capable of synthesizing haem and encodes haem-dependent catalase in its genome; yet, Methanosarcina acetivorans cells lack detectable catalase activity. However, inducible expression of the haem-dependent catalase from Escherichia coli (EcKatG) in the chromosome of Methanosarcina acetivorans resulted in a 100-fold increase in the endogenous catalase activity compared with uninduced cells. The increased catalase activity conferred a 10-fold increase in the resistance of EcKatG-induced cells to H2O2 compared with uninduced cells. The EcKatG-induced cells were also able to grow when exposed to levels of H2O2 that inhibited or killed uninduced cells. However, despite the significant increase in catalase activity, growth studies revealed that EcKatG-induced cells did not exhibit increased tolerance to O2 compared with uninduced cells. These results support the lack of catalase in the majority of methanogens, since methanogens are more likely to encounter O2 rather than high concentrations of H2O2 in the natural environment. Catalase appears to be a minor component of the antioxidant system in methanogens, even those that are aerotolerant, including Methanosarcina acetivorans. Importantly, the experimental approach used here demonstrated the feasibility of engineering beneficial traits, such as H2O2 tolerance, in methanogens. PMID:24222618

  14. The adipokine leptin increases skeletal muscle mass and significantly alters skeletal muscle miRNA expression profile in aged mice

    International Nuclear Information System (INIS)

    Hamrick, Mark W.; Herberg, Samuel; Arounleut, Phonepasong; He, Hong-Zhi; Shiver, Austin; Qi, Rui-Qun; Zhou, Li; Isales, Carlos M.

    2010-01-01

    Research highlights: → Aging is associated with muscle atrophy and loss of muscle mass, known as the sarcopenia of aging. → We demonstrate that age-related muscle atrophy is associated with marked changes in miRNA expression in muscle. → Treating aged mice with the adipokine leptin significantly increased muscle mass and the expression of miRNAs involved in muscle repair. → Recombinant leptin therapy may therefore be a novel approach for treating age-related muscle atrophy. -- Abstract: Age-associated loss of muscle mass, or sarcopenia, contributes directly to frailty and an increased risk of falls and fractures among the elderly. Aged mice and elderly adults both show decreased muscle mass as well as relatively low levels of the fat-derived hormone leptin. Here we demonstrate that loss of muscle mass and myofiber size with aging in mice is associated with significant changes in the expression of specific miRNAs. Aging altered the expression of 57 miRNAs in mouse skeletal muscle, and many of these miRNAs are now reported to be associated specifically with age-related muscle atrophy. These include miR-221, previously identified in studies of myogenesis and muscle development as playing a role in the proliferation and terminal differentiation of myogenic precursors. We also treated aged mice with recombinant leptin, to determine whether leptin therapy could improve muscle mass and alter the miRNA expression profile of aging skeletal muscle. Leptin treatment significantly increased hindlimb muscle mass and extensor digitorum longus fiber size in aged mice. Furthermore, the expression of 37 miRNAs was altered in muscles of leptin-treated mice. In particular, leptin treatment increased the expression of miR-31 and miR-223, miRNAs known to be elevated during muscle regeneration and repair. These findings suggest that aging in skeletal muscle is associated with marked changes in the expression of specific miRNAs, and that nutrient-related hormones such as leptin

  15. The adipokine leptin increases skeletal muscle mass and significantly alters skeletal muscle miRNA expression profile in aged mice

    Energy Technology Data Exchange (ETDEWEB)

    Hamrick, Mark W., E-mail: mhamrick@mail.mcg.edu [Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Herberg, Samuel; Arounleut, Phonepasong [Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); He, Hong-Zhi [Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI (United States); Department of Dermatology, Henry Ford Health System, Detroit, MI (United States); Shiver, Austin [Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Qi, Rui-Qun [Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI (United States); Department of Dermatology, Henry Ford Health System, Detroit, MI (United States); Zhou, Li [Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI (United States); Department of Dermatology, Henry Ford Health System, Detroit, MI (United States); Department of Internal Medicine, Henry Ford Health System, Detroit, MI (United States); Isales, Carlos M. [Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); others, and

    2010-09-24

    Research highlights: {yields} Aging is associated with muscle atrophy and loss of muscle mass, known as the sarcopenia of aging. {yields} We demonstrate that age-related muscle atrophy is associated with marked changes in miRNA expression in muscle. {yields} Treating aged mice with the adipokine leptin significantly increased muscle mass and the expression of miRNAs involved in muscle repair. {yields} Recombinant leptin therapy may therefore be a novel approach for treating age-related muscle atrophy. -- Abstract: Age-associated loss of muscle mass, or sarcopenia, contributes directly to frailty and an increased risk of falls and fractures among the elderly. Aged mice and elderly adults both show decreased muscle mass as well as relatively low levels of the fat-derived hormone leptin. Here we demonstrate that loss of muscle mass and myofiber size with aging in mice is associated with significant changes in the expression of specific miRNAs. Aging altered the expression of 57 miRNAs in mouse skeletal muscle, and many of these miRNAs are now reported to be associated specifically with age-related muscle atrophy. These include miR-221, previously identified in studies of myogenesis and muscle development as playing a role in the proliferation and terminal differentiation of myogenic precursors. We also treated aged mice with recombinant leptin, to determine whether leptin therapy could improve muscle mass and alter the miRNA expression profile of aging skeletal muscle. Leptin treatment significantly increased hindlimb muscle mass and extensor digitorum longus fiber size in aged mice. Furthermore, the expression of 37 miRNAs was altered in muscles of leptin-treated mice. In particular, leptin treatment increased the expression of miR-31 and miR-223, miRNAs known to be elevated during muscle regeneration and repair. These findings suggest that aging in skeletal muscle is associated with marked changes in the expression of specific miRNAs, and that nutrient

  16. Blockade of NMDA receptors blocks the acquisition of cocaine conditioned approach in rats.

    Science.gov (United States)

    Galaj, Ewa; Seepersad, Neal; Dakmak, Zena; Ranaldi, Robert

    2018-01-05

    Conditioned stimuli (CSs) exert motivational effects on both adaptive and pathological reward-related behaviors, including drug taking and seeking. We developed a paradigm that allows us to investigate the neuropharmacology by which previously neutral stimuli acquire the capacity to function as CSs and elicit (intravenous) cocaine conditioned approach and used this paradigm to test the role of NMDA receptor stimulation in the acquisition of cocaine conditioned approach. Rats were injected systemically with the NMDA receptor antagonist, MK-801, before the start of 4 consecutive conditioning sessions, each of which consisted of 20 randomly presented light/tone (CS) presentations paired with cocaine infusion contingent upon nose pokes. Rats later were subjected to a CS-only test. To test the role of NMDA receptor stimulation in the already established conditioned approach, rats were injected with MK-801 prior to the CS-only test that occurred after 18 CS-cocaine conditioning sessions. Blockade of NMDA receptors significantly impaired the acquisition of cocaine-conditioned approach as indicated by the emission of significantly fewer nose pokes and significantly longer latencies to nose poke during CS presentations. When MK-801 treatment was applied after the acquisition of conditioned approach responding it had no effect on these measures. These results suggest that NMDA receptor stimulation plays an important role in the acquisition of reward-related conditioned responses driven by intravenous cocaine-associated CSs. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Prognostic significance of increased bone marrow microcirculation in newly diagnosed multiple myeloma: results of a prospective DCE-MRI study

    Energy Technology Data Exchange (ETDEWEB)

    Merz, Maximilian; Hillengass, Jens [Department of Radiology, German Cancer Research Center, Heidelberg (Germany); University of Heidelberg, Department of Hematology, Oncology and Rheumatology, Heidelberg (Germany); Moehler, Thomas M.; Ritsch, Judith; Delorme, Stefan [Department of Radiology, German Cancer Research Center, Heidelberg (Germany); Baeuerle, Tobias [University of Erlangen-Nuremberg, Department of Radiology, Erlangen (Germany); Zechmann, Christian M. [Rinecker Proton Therapy, Muenchen (Germany); Wagner, Barbara; Hose, Dirk [University of Heidelberg, Department of Hematology, Oncology and Rheumatology, Heidelberg (Germany); Jauch, Anna [University of Heidelberg, Institute of Human Genetics, Heidelberg (Germany); Kunz, Christina; Hielscher, Thomas [German Cancer Research Center, Department of Biostatistics, Heidelberg (Germany); Laue, Hendrik [Fraunhofer MEVIS, Bremen (Germany); Goldschmidt, Hartmut [University of Heidelberg, Department of Hematology, Oncology and Rheumatology, Heidelberg (Germany); National Center for Tumor Diseases, Heidelberg (Germany)

    2016-05-15

    Aim of this prospective study was to investigate prognostic significance of increased bone marrow microcirculation as detected by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for survival and local complications in patients with multiple myeloma (MM). We performed DCE-MRI of the lumbar spine in 131 patients with newly diagnosed MM and analysed data according to the Brix model to acquire amplitude A and exchange rate constant k{sub ep}. In 61 patients a second MRI performed after therapy was evaluated t