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Sample records for chronic cocaine administration

  1. Chronic administration of the methylxanthine propentofylline impairs reinstatement to cocaine by a GLT-1-dependent mechanism.

    Science.gov (United States)

    Reissner, Kathryn J; Brown, Robyn M; Spencer, Sade; Tran, Phuong K; Thomas, Charles A; Kalivas, Peter W

    2014-01-01

    In recent years, interactions between neurons and glia have been evaluated as mediators of neuropsychiatric diseases, including drug addiction. In particular, compounds that increase expression of the astroglial glutamate transporter GLT-1 (N-acetylcysteine and ceftriaxone) can decrease measures of drug seeking. However, it is unknown whether the compounds that influence broad measures of glial physiology can influence behavioral measures of drug relapse, nor is it clear whether the upregulated GLT-1 is functionally important for suppressing of drug seeking. To address these questions, we sought to determine whether the glial modulator and neuroprotective agent propentofylline (PPF) modifies drug seeking in rats using a reinstatement model of cocaine relapse. We found that 7 days of chronic (but not acute) administration of PPF significantly decreased both cue- and cocaine-induced reinstatement of cocaine seeking. We next determined whether the effect of systemic PPF on reinstatement depended upon its ability to restore expression of GLT-1 in the nucleus accumbens. PPF restored the cocaine-induced decrease in GLT-1 in the accumbens core; then, using an antisense strategy against glutamate transporter GLT-1, we found that restored transporter expression was necessary for PPF to inhibit cue-primed cocaine seeking. These findings indicate that modulating glial physiology with atypical xanthine derivatives like PPF is a potential avenue for developing new medications for cocaine abuse, and support the hypothesis that neuron-glial interactions contribute to mechanisms of psychostimulant addiction, particularly via expression and function of astroglial glutamate transporters.

  2. Bidirectional Synaptic Structural Plasticity after Chronic Cocaine Administration Occurs through Rap1 Small GTPase Signaling.

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    Cahill, Michael E; Bagot, Rosemary C; Gancarz, Amy M; Walker, Deena M; Sun, HaoSheng; Wang, Zi-Jun; Heller, Elizabeth A; Feng, Jian; Kennedy, Pamela J; Koo, Ja Wook; Cates, Hannah M; Neve, Rachael L; Shen, Li; Dietz, David M; Nestler, Eric J

    2016-02-03

    Dendritic spines are the sites of most excitatory synapses in the CNS, and opposing alterations in the synaptic structure of medium spiny neurons (MSNs) of the nucleus accumbens (NAc), a primary brain reward region, are seen at early versus late time points after cocaine administration. Here we investigate the time-dependent molecular and biochemical processes that regulate this bidirectional synaptic structural plasticity of NAc MSNs and associated changes in cocaine reward in response to chronic cocaine exposure. Our findings reveal key roles for the bidirectional synaptic expression of the Rap1b small GTPase and an associated local synaptic protein translation network in this process. The transcriptional mechanisms and pathway-specific inputs to NAc that regulate Rap1b expression are also characterized. Collectively, these findings provide a precise mechanism by which nuclear to synaptic interactions induce "metaplasticity" in NAc MSNs, and we reveal the specific effects of this plasticity on reward behavior in a brain circuit-specific manner.

  3. Effects of acute and chronic aripiprazole treatment on choice between cocaine self-administration and food under a concurrent schedule of reinforcement in rats

    DEFF Research Database (Denmark)

    Thomsen, Morgane; Fink-Jensen, Anders; Woldbye, David

    2008-01-01

    the hypothesis that aripiprazole, both as acute and as chronic treatment, would preferentially decrease cocaine self-administration while sparing behavior maintained by a natural reinforcer, resulting in a shift in the allocation of behavior from cocaine-taking towards the alternative reinforcer. MATERIALS...... AND METHODS: Rats were trained to self-administer intravenous cocaine in a concurrent choice procedure, with a palatable food as the competing reinforcer, under a fixed ratio (FR) 1 FR 5 chain schedule. Aripiprazole was then administered as continuous infusion by osmotic minipumps for 5 days, during which...... performance in the choice procedure was assessed daily. RESULTS: An intermediate dose of aripiprazole decreased cocaine self-administration and shifted the cocaine choice curve to the right as an acute treatment. However, as a chronic treatment, aripiprazole failed to decrease cocaine self...

  4. Chronic cocaine administration causes extensive white matter damage in brain: diffusion tensor imaging and immunohistochemistry studies.

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    Narayana, Ponnada A; Herrera, Juan J; Bockhorst, Kurt H; Esparza-Coss, Emilio; Xia, Ying; Steinberg, Joel L; Moeller, F Gerard

    2014-03-30

    The effect of chronic cocaine exposure on multiple white matter structures in rodent brain was examined using diffusion tensor imaging (DTI), locomotor behavior, and end point histology. The animals received either cocaine at a dose of 100mg/kg (N=19), or saline (N=17) for 28 days through an implanted osmotic minipump. The animals underwent serial DTI scans, locomotor assessment, and end point histology for determining the expressions of myelin basic protein (MBP), neurofilament-heavy protein (NF-H), proteolipid protein (PLP), Nogo-A, aquaporin-4 (AQP-4), and growth associated protein-43 (GAP-43). Differences in the DTI measures were observed in the splenium (scc) and genu (gcc) of the corpus callosum (cc), fimbria (fi), and the internal capsule (ic). A significant increase in the activity in the fine motor movements and a significant decrease in the number of rearing events were observed in the cocaine-treated animals. Reduced MBP and Nogo-A and increased GAP-43 expressions were most consistently observed in these structures. A decrease in the NF-H expression was observed in fi and ic. The reduced expression of Nogo-A and the increased expression of GAP-43 may suggest destabilization of axonal connectivity and increased neurite growth with aberrant connections. Increased GAP-43 suggests drug-induced plasticity or a possible repair mechanism response. The findings indicated that multiple white matter tracts are affected following chronic cocaine exposure.

  5. Cocaine challenge enhances release of neuroprotective amino acid taurine in the striatum of chronic cocaine treated rats: a microdialysis study

    OpenAIRE

    Yablonsky-Alter, Elena; Agovic, Mervan S.; Gashi, Eleonora; Lidsky, Theodore I.; Friedman, Eitan; Banerjee, Shailesh P.

    2009-01-01

    Drug addiction is a serious public health problem. There is increasing evidence on the involvement of augmented glutamatergic transmission in cocaine-induced addiction and neurotoxicity. We investigated effects of acute or chronic cocaine administration and cocaine challenge following chronic cocaine exposure on the release of excitotoxic glutamate and neuroprotective taurine in the rat striatum by microdialysis. Cocaine challenge, following withdrawal after repeated cocaine exposure markedly...

  6. Effects of chronic methylphenidate on cocaine self-administration under a progressive-ratio schedule of reinforcement in rhesus monkeys.

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    Czoty, Paul W; Martelle, Susan E; Gould, Robert W; Nader, Michael A

    2013-06-01

    It has been hypothesized that drugs that serve as substrates for dopamine (DA) and norepinephrine (NE) transporters may be more suitable medications for cocaine dependence than drugs that inhibit DA and NE uptake by binding to transporters. Previous studies have shown that the DA/NE releaser d-amphetamine can decrease cocaine self-administration in preclinical and clinical studies. The present study examined the effects of methylphenidate (MPD), a DA uptake inhibitor, for its ability to decrease cocaine self-administration under conditions designed to reflect clinically relevant regimens of cocaine exposure and pharmacotherapy. Each morning, rhesus monkeys pressed a lever to receive food pellets under a fixed-ratio 50 schedule of reinforcement; cocaine was self-administered under a progressive-ratio schedule of reinforcement in the evening. After cocaine (0.003-0.56 mg/kg per injection, i.v.) dose-response curves were determined, self-administration sessions were suspended and MPD (0.003-0.0056 mg/kg per hour, i.v.; or 1.0-9.0 mg/kg p.o., b.i.d.) was administered for several weeks. A cocaine self-administration session was conducted every 7 days. When a MPD dose was reached that either persistently decreased cocaine self-administration or produced disruptive effects, the cocaine dose-effect curve was re-determined. In most cases, MPD treatment either produced behaviorally disruptive effects or increased cocaine self-administration; it took several weeks for these effects to dissipate. These data are consistent with the largely negative results of clinical trials with MPD. In contrast to the positive effects with the monoamine releaser d-amphetamine under identical conditions, these results do not support use of monoamine uptake inhibitors like MPD as a medication for cocaine dependence.

  7. The inhibition of cocaine-induced locomotor activity by CART 55-102 is lost after repeated cocaine administration.

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    Job, Martin O; Shen, Li L; Kuhar, Michael J

    2013-08-29

    CART peptide is known for having an inhibitory effect on cocaine- and dopamine-mediated actions after acute administration of cocaine and dopamine. In this regard, it is postulated to be a homeostatic, regulatory factor on dopaminergic activity in the nucleus accumbens (NAc). However, there is no data on the effect of CART peptide after chronic administration of cocaine, and this study addresses this. It was found that CART peptide blunted cocaine-induced locomotion (LMA) after acute administration of cocaine, as expected, but it did not affect cocaine-mediated LMA after chronic administration of cocaine. The loss of CART peptide's inhibitory effect did not return for up to 9 weeks after stopping the repeated cocaine administration. It may not be surprising that homeostatic regulatory mechanisms in the NAc are lost after repeated cocaine administration, and that this may be a mechanism in the development of addiction.

  8. Decrease of D2 receptor binding but increase in D2-stimulated G-protein activation, dopamine transporter binding and behavioural sensitization in brains of mice treated with a chronic escalating dose 'binge' cocaine administration paradigm.

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    Bailey, A; Metaxas, A; Yoo, J H; McGee, T; Kitchen, I

    2008-08-01

    Understanding the neurobiology of the transition from initial drug use to excessive drug use has been a challenge in drug addiction. We examined the effect of chronic 'binge' escalating dose cocaine administration, which mimics human compulsive drug use, on behavioural responses and the dopaminergic system of mice and compared it with a chronic steady dose (3 x 15 mg/kg/day) 'binge' cocaine administration paradigm. Male C57BL/6J mice were injected with saline or cocaine in an escalating dose paradigm for 14 days. Locomotor and stereotypy activity were measured and quantitative autoradiographic mapping of D(1) and D(2) receptors, dopamine transporters and D(2)-stimulated [(35)S]GTPgammaS binding was performed in the brains of mice treated with this escalating and steady dose paradigm. An initial sensitization to the locomotor effects of cocaine followed by a dose-dependent increase in the duration of the locomotor effect of cocaine was observed in the escalating but not the steady dose paradigm. Sensitization to the stereotypy effect of cocaine and an increase in cocaine-induced stereotypy score was observed from 3 x 20 to 3 x 25 mg/kg/day cocaine. There was a significant decrease in D(2) receptor density, but an increase in D(2)-stimulated G-protein activity and dopamine transporter density in the striatum of cocaine-treated mice, which was not observed in our steady dose paradigm. Our results document that chronic 'binge' escalating dose cocaine treatment triggers profound behavioural and neurochemical changes in the dopaminergic system, which might underlie the transition from drug use to compulsive drug use associated with addiction, which is a process of escalation.

  9. 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...... for the first time the involvement of M4 receptors in the reinforcing effects of cocaine using chronic intravenous cocaine self-administration in extensively backcrossed M4 receptor knockout (M4 -/-) mice. Methods We evaluated acquisition of cocaine self-administration in experimentally naïve mice. Both cocaine...... self-administration and food-maintained operant behavior were evaluated under fixed ratio 1 (FR 1) and progressive ratio (PR) schedules of reinforcement. In addition, cocaine-induced dopamine release and cocaine-induced hyperactivity were evaluated. Results M4 -/- mice earned significantly more cocaine...

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

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    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.

  11. The glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 reduces cocaine self-administration in mice

    DEFF Research Database (Denmark)

    Sorensen, Gunnar; Reddy, India A.; Weikop, Pia

    2015-01-01

    reward, we decided to investigate the effect of the GLP-1 analogue exendin-4 on cocaine- and dopamine D1-receptor agonist-induced hyperlocomotion, on acute and chronic cocaine self-administration, on cocaine-induced striatal dopamine release in mice and on cocaine-induced c-fos activation. Here, we...... report that GLP-1 receptor stimulation reduces acute and chronic cocaine self-administration and attenuates cocaine-induced hyperlocomotion. In addition, we show that peripheral administration of exendin-4 reduces cocaine-induced elevation of striatal dopamine levels and striatal c-fos expression...... implicating central GLP-1 receptors in these responses. The present results demonstrate that the GLP-1 system modulates cocaine's effects on behavior and dopamine homeostasis, indicating that the GLP-1 receptor may be a novel target for the pharmacological treatment of drug addiction....

  12. Stimulus control of cocaine self-administration.

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    Weiss, Stanley J.; Kearns, David N.; Cohn, Scott I.; Schindler, Charles W.; Panlilio, Leigh V.

    2003-01-01

    Environmental stimuli that set the occasion wherein drugs are acquired can "trigger" drug-related behavior. Investigating the stimulus control of drug self-administration in laboratory animals should help us better understand this aspect of human drug abuse. Stimulus control of cocaine self-administration was generated here for the first time using multiple and chained schedules with short, frequently-alternating components--like those typically used to study food-maintained responding. The p...

  13. Transforming growth factor beta receptor 1 is increased following abstinence from cocaine self-administration, but not cocaine sensitization.

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    Amy M Gancarz-Kausch

    Full Text Available The addicted phenotype is characterized as a long-lasting, chronically relapsing disorder that persists following long periods of abstinence, suggesting that the underlying molecular changes are stable and endure for long periods even in the absence of drug. Here, we investigated Transforming Growth Factor-Beta Type I receptor (TGF-β R1 expression in the nucleus accumbens (NAc following periods of withdrawal from cocaine self-administration (SA and a sensitizing regimen of non-contingent cocaine. Rats were exposed to either (i repeated systemic injections (cocaine or saline, or (ii self-administration (cocaine or saline and underwent a period of forced abstinence (either 1 or 7 days of drug cessation. Withdrawal from cocaine self-administration resulted in an increase in TGF-β R1 protein expression in the NAc compared to saline controls. This increase was specific for volitional cocaine intake as no change in expression was observed following a sensitizing regimen of experimenter-administered cocaine. These findings implicate TGF-β signaling as a novel potential therapeutic target for treating drug addiction.

  14. Neural Changes Developed during the Extinction of Cocaine Self-Administration Behavior

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    Nuria del Olmo

    2011-10-01

    Full Text Available The high rate of recidivism in cocaine addiction after prolonged periods of abstinence poses a significant problem for the effective treatment of this condition. Moreover, the neurobiological basis of this relapse phenomenon remains poorly understood. In this review, we will discuss the evidence currently available regarding the neurobiological changes during the extinction of cocaine self-administration. Specifically, we will focus on alterations in the dopaminergic, opioidergic, glutamatergic, cholinergic, serotoninergic and CRF systems described in self-administration experiments and extinction studies after chronic cocaine administration. We will also discuss the differences related to contingent versus non-contingent cocaine administration, which highlights the importance of environmental cues on drug effects and extinction. The findings discussed in this review may aid the development of more effective therapeutic approaches to treat cocaine relapse.

  15. Neural Changes Developed during the Extinction of Cocaine Self-Administration Behavior

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    Higuera-Matas, Alejandro; Miguens, Miguel; del Olmo, Nuria; García-Lecumberri, Carmen; Ambrosio, Emilio

    2011-01-01

    The high rate of recidivism in cocaine addiction after prolonged periods of abstinence poses a significant problem for the effective treatment of this condition. Moreover, the neurobiological basis of this relapse phenomenon remains poorly understood. In this review, we will discuss the evidence currently available regarding the neurobiological changes during the extinction of cocaine self-administration. Specifically, we will focus on alterations in the dopaminergic, opioidergic, glutamatergic, cholinergic, serotoninergic and CRF systems described in self-administration experiments and extinction studies after chronic cocaine administration. We will also discuss the differences related to contingent versus non-contingent cocaine administration, which highlights the importance of environmental cues on drug effects and extinction. The findings discussed in this review may aid the development of more effective therapeutic approaches to treat cocaine relapse. PMID:26791639

  16. Diazepam alters cocaine self-administration, but not cocaine-stimulated locomotion or nucleus accumbens dopamine

    OpenAIRE

    2008-01-01

    Cocaine is known to enhance nucleus accumbens dopamine (NAcc DA), serve as a positive reinforcer and produce negative effects, such as anxiety. The influence of diazepam on cocaine intake, cocaine-stimulated behavioral activity and NAcc DA was investigated using self-administration and experimenter-administered intravenous (i.v.) cocaine. In Experiment 1, rats were pretreated with diazepam (0.25 mg/kg) or saline (0.1 ml) 30 minutes prior to 20 daily 1-hr cocaine (0.75 mg/kg/inj) self-administ...

  17. Stimulus control of cocaine self-administration.

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    Weiss, Stanley J; Kearns, David N; Cohn, Scott I; Schindler, Charles W; Panlilio, Leigh V

    2003-01-01

    Environmental stimuli that set the occasion wherein drugs are acquired can "trigger" drug-related behavior. Investigating the stimulus control of drug self-administration in laboratory animals should help us better understand this aspect of human drug abuse. Stimulus control of cocaine self-administration was generated here for the first time using multiple and chained schedules with short, frequently-alternating components--like those typically used to study food-maintained responding. The procedures and results are presented along with case histories to illustrate the strategies used to produce this stimulus control. All these multicomponent schedules contained variable-interval (VI) components as well as differential-reinforcement-of-other-behavior (DRO) or extinction components. Schedule parameters and unit dose were adjusted for each rat to produce stable, moderate rates in VI components, with minimal postreinforcement (infusion) pausing, and response cessation in extinction and DRO components. Whole-body drug levels on terminal baselines calculated retrospectively revealed that all rats maintained fairly stable drug levels (mean, 2.3 to 3.4 mg/kg) and molar rates of intake (approximately 6.0 mg/kg/hr). Within this range, no relation between local VI response rates and drug level was found. The stimulus control revealed in cumulative records was indistinguishable from that achieved with food under these schedules, suggesting that common mechanisms may underlie the control of cocaine- and food-maintained behavior.

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

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    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.

    2017-01-01

    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 20mg/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, asexpected. However, compared to control ratson 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. PMID:25712697

  19. Quality of life and sleep impairment in chronic cocaine dependents

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    Lima,Adriana; ROSSINI, Sueli; Reimão,Rubens

    2008-01-01

    OBJECTIVE: To evaluate quality of life (QL) and sleep quality impairment of cocaine chronic dependents in use of cocaine. METHOD: 40 patients, chronic cocaine dependents were evaluated (37 M; 3 F), with mean age of 28.92 years, along with 40 controls paired for gender and age. The following instruments were used: a) the semi-structured clinical interview; b) the Brazil Economic Classification; c) the Pittsburgh Sleep Quality Index; d) World Heath Organization Quality of Life-BREF (WHOQOL-BREF...

  20. Varenicline effects on cocaine self administration and reinstatement behavior.

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    Guillem, Karine; Peoples, Laura L

    2010-03-01

    This study tested the effects of the nicotine addiction treatment varenicline on cocaine self administration (SA) and reinstatement. In one SA experiment, rats were trained to self-administer cocaine (0.75 mg/kg/infusion). Thereafter, daily SA sessions continued as before except that every fourth session was preceded by a presession injection of varenicline (0.0, 0.3, 1.0 and 2.0 mg/kg, SC, 50-min presession). In three reinstatement experiments, animals were exposed sequentially to SA training, extinction training, and several reinstatement test sessions. In two of the reinstatement experiments, cocaine-seeking was reinstated by presentation of cocaine-predictive cues at the onset of the test session (cue reinstatement). In a third reinstatement experiment, cocaine-seeking was reinstated by a presession injection of cocaine (drug reinstatement). Each reinstatement session was preceded by an injection of either vehicle or varenicline (dose range of 0.1-2.0 mg/kg). The SA and reinstatement experiments showed that low-dose varenicline decreases reinstatement behavior, without significantly affecting cocaine SA. In contrast, high-dose varenicline increases reinstatement of cocaine-directed behavior and decreases cocaine SA. A control study showed that sucrose-directed behavior is unaltered by varenicline. On the basis of these findings, low-varenicline doses might decrease relapse in cocaine-addicted individuals, but high doses of varenicline might have the opposite effect.

  1. Effects of the NADPH oxidase inhibitor apocynin on the left ventricular dysfunction induced by cocaine administration

    Institute of Scientific and Technical Information of China (English)

    MarcISABELLE; ChristelleMONTEIL; ChristianTHUILLEZ

    2004-01-01

    AIM: In a previous study, we have shown the role of alphaladrenoceptor in the left ventricular (LV) dysfunction after chronic cocaine administration via the induction of NADPH oxidase. In this study we used the NADPH oxidase inhibitor apocynin, to further investigate the real involvement of this prooxidant system in this LV dysfunction. METHODS: Wistar rats were treated

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

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    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

  3. The glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 reduces cocaine self-administration in mice.

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    Sørensen, Gunnar; Reddy, India A; Weikop, Pia; Graham, Devon L; Stanwood, Gregg D; Wortwein, Gitta; Galli, Aurelio; Fink-Jensen, Anders

    2015-10-01

    Glucagon-like peptide 1 (GLP-1) analogues are used for the treatment of type 2 diabetes. The ability of the GLP-1 system to decrease food intake in rodents has been well described and parallels results from clinical trials. GLP-1 receptors are expressed in the brain, including within the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Dopaminergic neurons in the VTA project to the NAc, and these neurons play a pivotal role in the rewarding effects of drugs of abuse. Based on the anatomical distribution of GLP-1 receptors in the brain and the well-established effects of GLP-1 on food reward, we decided to investigate the effect of the GLP-1 analogue exendin-4 on cocaine- and dopamine D1-receptor agonist-induced hyperlocomotion, on acute and chronic cocaine self-administration, on cocaine-induced striatal dopamine release in mice and on cocaine-induced c-fos activation. Here, we report that GLP-1 receptor stimulation reduces acute and chronic cocaine self-administration and attenuates cocaine-induced hyperlocomotion. In addition, we show that peripheral administration of exendin-4 reduces cocaine-induced elevation of striatal dopamine levels and striatal c-fos expression implicating central GLP-1 receptors in these responses. The present results demonstrate that the GLP-1 system modulates cocaine's effects on behavior and dopamine homeostasis, indicating that the GLP-1 receptor may be a novel target for the pharmacological treatment of drug addiction.

  4. Optogenetically evoked gamma oscillations are disturbed by cocaine administration

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    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.

  5. A touch screen based Stop Signal Response Task in rhesus monkeys for studying impulsivity associated with chronic cocaine self-administration.

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    Liu, Shijing; Heitz, Richard P; Bradberry, Charles W

    2009-02-15

    Among a range of cognitive deficits, human cocaine addicts display increased impulsivity and decreased performance monitoring. In order to establish an animal model that can be used to study the underlying neurobiology of these deficits associated with addiction, we have developed a touch screen based Stop Signal Response Task for rhesus monkeys. This task is essentially identical to the clinically used Stop Signal Task employed for diagnostic and research purposes. In this task, impulsivity is reflected in the amount of time needed to inhibit a response after it has been initiated, the Stop Signal Response Time (SSRT). Performance monitoring is reflected by the slowing of response times following Stop trials (Post-Stop Slowing, PSS). Herein we report on the task structure, the staged methods for training animals to perform the task, and a comparison of performance values for control and cocaine experienced animals. Relative to controls, monkeys that had self-administered cocaine, followed by 18 months abstinence, displayed increased impulsivity (increased SSRT values), and decreased performance monitoring (decreased PSS values). Our results are consistent with human data, and thereby establish an ideal animal model for studying the etiology and underlying neurobiology of cocaine-induced impulse control and performance monitoring deficits.

  6. Cocaine residue in plasma, cardiac and tracheal tissues of chronic cocaine-treated guinea-pigs

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    Malinee Wongnawa

    2010-03-01

    Full Text Available Supersensitivity of adrenoceptors to catecholamines is one of the mechanisms of cocaine-related cardiac complication. The precise mechanism of cocaine enhancing supersensitivity of adrenoceptors is unconcluded. The aim of this study was todetermine the levels of cocaine in plasma, cardiac and tracheal tissues in order to correlate with the supersensitivity ofadrenoceptors to catecholamines. In this study, two groups of ten guinea-pigs each were injected with 2.5 mg/kg cocaine or normal saline solution intraperitoneally twice daily for 14 days. After 24 hours of cocaine cessation, the cocaine levels in plasma, cardiac and tracheal tissues were determined using high performance liquid chromatography. The results showed that the cocaine levels in plasma and tracheal smooth muscle were 5.08±0.63 ng/ml and 2.8±0.41 ng/mg, respectively, while those in atria and ventricle were lower than 17.5 ng/g and 3.8 ng/g, respectively. These levels were less than the level that had been reported to block norepinephrine uptake (more than 30.34 ng/ml. Moreover, it had been demonstrated that cocainetreatment in the same condition as the present study produced supersensitivity to norepinephrine and epinephrine in isolatedguinea-pig atria as well as in trachea which is almost entirely not innervated by the adrenergic nerves. In addition, supersensitivityto oxymetazoline, isoproterenol and salbutamol which are not the substrates of neuronal reuptake were also demonstrated. All these data support the postsynaptic mechanism of cocaine enhancing supersensitivity which might be correlated with cardiac complication in chronic cocaine use.

  7. Influence of chronic cocaine treatment and sleep deprivation on sexual behavior and neurogenesis of the male rat.

    Science.gov (United States)

    Andersen, Monica L; Perry, Juliana C; Bignotto, Magda; Perez-Mendes, Patricia; Cinini, Simone M; Mello, Luiz E A; Tufik, Sergio

    2007-08-15

    The present study investigated the influence of chronic cocaine treatment on genital reflexes associated with paradoxical sleep deprivation (PSD), and possible alterations in hippocampus neurogenesis of the male rat. At 21 days of age, the rats were distributed into two groups and injected with saline or cocaine (7 mg/kg, three times a week for 12 weeks). At age 90 days, they were submitted to a four-day period of PSD (PSD groups) or maintained in home-cages (control groups), challenged with saline or cocaine administration, and placed in observation cages to assess genital reflexes. Two additional groups were used to quantify neurogenesis. PSD rats treated chronically with cocaine and challenged with saline did not differ from their respective control groups. The association of PSD with cocaine potentiated penile erection (PE) when compared to PSD-saline (saline challenged) rats, and these effects were similar to those observed in long-term cocaine treated rats. The bromodeoxyuridine (BrdU) assay indicated a reduction in BrdU-positive cells in the adult hippocampus after chronic cocaine treatment. These findings show that long-term cocaine treatment from brain development through adulthood had a marked effect on sexual responses and neuronal proliferation.

  8. 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...

  9. Cardiovascular complications following chronic treatment with cocaine and testosterone in adolescent rats.

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    Sheila A Engi

    Full Text Available Concomitant use of anabolic androgenic steroids and cocaine has increased in the last years. However, the effects of chronic exposure to these substances during adolescence on cardiovascular function are unknown. Here, we investigated the effects of treatment for 10 consecutive days with testosterone and cocaine alone or in combination on basal cardiovascular parameters, baroreflex activity, hemodynamic responses to vasoactive agents, and cardiac morphology in adolescent rats. Administration of testosterone alone increased arterial pressure, reduced heart rate (HR, and exacerbated the tachycardiac baroreflex response. Cocaine-treated animals showed resting bradycardia without changes in arterial pressure and baroreflex activity. Combined treatment with testosterone and cocaine did not affect baseline arterial pressure and HR, but reduced baroreflex-mediated tachycardia. None of the treatments affected arterial pressure response to either vasoconstrictor or vasodilator agents. Also, heart to body ratio and left and right ventricular wall thickness were not modified by drug treatments. However, histological analysis of left ventricular sections of animals subjected to treatment with testosterone and cocaine alone and combined showed a greater spacing between cardiac muscle fibers, dilated blood vessels, and fibrosis. These data show important cardiovascular changes following treatment with testosterone in adolescent rats. However, the results suggest that exposure to cocaine alone or combined with testosterone during adolescence minimally affect cardiovascular function.

  10. Route of cocaine administration: patterns of use and problems among a Brazilian sample.

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    Ferri, C P; Gossop, M

    1999-01-01

    Route of administration has important implications for the understanding of drug addiction and related-problems. This cross-sectional study investigates patterns of consumption and cocaine-related problems among snorting and crack cocaine users in São Paulo and outlines changes in route of cocaine administration in Brazil between 1980-1997. Crack cocaine users had more social and health problems and higher involvement in crime than intranasal users. These problems, compounded by the larger doses being used and their greater involvement in prostitution, place crack cocaine users at higher risk from HIV infection and other sexually transmitted diseases as well as other physical risks.

  11. 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 ...

  12. 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.

  13. The Infralimbic Cortex Regulates the Consolidation of Extinction after Cocaine Self-Administration

    Science.gov (United States)

    LaLumiere, Ryan T.; Niehoff, Kate E.; Kalivas, Peter W.

    2010-01-01

    The infralimbic cortex (IL) regulates the consolidation of extinction learning for fear conditioning. Whether the IL influences the consolidation of extinction learning for cocaine self-administration is unknown. To address this issue, male Sprague-Dawley rats underwent 2 wk of cocaine self-administration followed by extinction training. On the…

  14. Recurrent febrile neutropenia and thrombocytopenia in a chronic cocaine user: a case of levamisole induced complications.

    Science.gov (United States)

    Martinez, Eduardo; Alvi, Raza; Venkatram, Sindhaghatta; Diaz-Fuentes, Gilda

    2015-01-01

    Cocaine is used by approximately 1.5 million Americans each month and up to 69% of the cocaine seized contains levamisole. The real incidence of cocaine-levamisole induced neutropenia is unclear but probably underestimated. Associated complications include fever, thrombocytopenia, skin-vasculitis disorders, and rarely kidney injury. We present a young male, with chronic active cocaine use presenting with recurrent episodes of febrile neutropenia and thrombocytopenia. He underwent extensive work-up and was treated with many antibiotics and we suspect that his neutropenia and thrombocytopenia were caused by recurrent cocaine-levamisole use.

  15. Recurrent Febrile Neutropenia and Thrombocytopenia in a Chronic Cocaine User: A Case of Levamisole Induced Complications

    Directory of Open Access Journals (Sweden)

    Eduardo Martinez

    2015-01-01

    Full Text Available Cocaine is used by approximately 1.5 million Americans each month and up to 69% of the cocaine seized contains levamisole. The real incidence of cocaine-levamisole induced neutropenia is unclear but probably underestimated. Associated complications include fever, thrombocytopenia, skin-vasculitis disorders, and rarely kidney injury. We present a young male, with chronic active cocaine use presenting with recurrent episodes of febrile neutropenia and thrombocytopenia. He underwent extensive work-up and was treated with many antibiotics and we suspect that his neutropenia and thrombocytopenia were caused by recurrent cocaine-levamisole use.

  16. Cocaine self-administration punished by intravenous histamine in adolescent and adult rats.

    Science.gov (United States)

    Holtz, Nathan A; Carroll, Marilyn E

    2015-06-01

    Adolescence is a transitional phase marked by a heightened vulnerability to substances of abuse. It has been hypothesized that both increased sensitivity to reward and decreased sensitivity to aversive events may drive drug-use liability during this phase. To investigate possible age-related differences in sensitivity to the aversive consequences of drug use, adolescent and adult rats were compared on self-administration of cocaine before, during, and after a 10-day period in which an aversive agent, histamine, was added to the cocaine solution. Adult and adolescent female rats were trained to self-administer intravenous cocaine (0.4 mg/kg/infusion) over 10 sessions (2 h/session; 2 sessions/day). Histamine (4 mg/kg/infusion) was then added directly into the cocaine solution for the next 10 sessions. Finally, the cocaine/histamine solution was replaced with a cocaine-only solution, and rats continued to self-administer cocaine (0.4 mg/kg) for 20 sessions. Compared with adolescent rats, adult rats showed a greater decrease in cocaine self-administration when it was punished with intravenous histamine compared with their baseline cocaine self-administration rates. These results suggest that differences in the sensitivity to negative consequences of drug use may partially explain developmental differences in drug use vulnerability.

  17. Glutamatergic Mechanisms of Comorbidity Between Acute Stress and Cocaine Self-administration

    Science.gov (United States)

    Garcia-Keller, Constanza; Kupchik, Yonatan; Gipson, Cassandra D; Brown, Robyn M; Spencer, Sade; Bollati, Flavia; Esparza, Maria A; Roberts-Wolfe, Doug; Heinsbroek, Jasper; Bobadilla, Ana-Clara; Cancela, Liliana M; Kalivas, Peter W

    2015-01-01

    There is substantial comorbidity between stress disorders and substance use disorders (SUDs), and acute stress augments the locomotor stimulant effect of cocaine in animal models. Here we endeavor to understand the neural underpinnings of comorbid stress disorders and drug use by determining if the glutamatergic neuroadaptations that characterize cocaine self-administration are induced by acute stress. Rats were exposed to acute (2 h) immobilization stress and 3 weeks later the nucleus accumbens core was examined for changes in glutamate transport, glutamate mediated synaptic currents, and dendritic spine morphology. We also determined if acute stress potentiated the acquisition of cocaine self-administration. Acute stress produced an enduring reduction in glutamate transport, and potentiated excitatory synapses on medium spiny neurons. Acute stress also augmented the acquisition of cocaine self-administration. Importantly, by restoring glutamate transport in the accumbens core with ceftriaxone the capacity of acute stress to augment the acquisition of cocaine self-administration was abolished. Similarly, ceftriaxone treatment prevented stress-induced potentiation of cocaine-induced locomotor activity. However, ceftriaxone did not reverse stress-induced synaptic potentiation, indicating that this effect of stress exposure did not underpin the increased acquisition of cocaine self-administration. Reversing acute stress-induced vulnerability to self-administer cocaine by normalizing glutamate transport poses a novel treatment possibility for reducing comorbid SUDs in stress disorders. PMID:26821978

  18. Runway self-administration of intracerebroventricular cocaine: evidence of mixed positive and negative drug actions.

    Science.gov (United States)

    Guzman, Daniel; Ettenberg, Aaron

    2007-02-01

    In previous work from our laboratory, animals running for intravenous cocaine developed a unique approach-avoidance 'retreat behavior' that was hypothesized to result from cocaine's well documented reinforcing (positive) and anxiogenic (negative) properties. To assess the role of central mechanisms in producing cocaine's positive and negative effects, we assessed whether or not animals running a straight alley for intracerebroventricular applications of cocaine would produce a similar behavioral profile to that previously observed with intravenous applications. Retreat frequency and location were measured in male Sprague-Dawley rats trained to run an alley for one of four doses of intracerebroventricular-administered cocaine (0, 25, 50 or 100 microg cocaine/infusion). Testing involved a single trial per day over 14 consecutive days with a single infusion of cocaine delivered upon goal box entry. The 100 and 50 microg intracerebroventricular cocaine groups exhibited significantly higher retreat frequencies than the 25 and 0 microg groups and the nature and magnitude of the behavior was comparable to that previously observed with intravenous cocaine. These results suggest that the intracerebroventricular self-administration of cocaine results in mixed positive and negative consequences and therefore likely stem from the drug's actions within the central nervous system.

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

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    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.

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

    Science.gov (United States)

    Rasakham, Khampaseuth; Schmidt, Heath D; Kay, Kevin; Huizenga, Megan N; Calcagno, Narghes; Pierce, R Christopher; Spires-Jones, Tara L; Sadri-Vakili, Ghazaleh

    2014-01-01

    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. 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.

  2. History of cocaine self-administration alters morphine reinforcement in the rat.

    Science.gov (United States)

    Mierzejewski, Pawel; Stefanski, Roman; Bienkowski, Przemyslaw; Kostowski, Wojciech

    2007-05-07

    It has been shown repeatedly that cocaine pre-exposure may sensitise neurochemical and behavioural responses to opioid drugs. The aim of the present study was to investigate effects of a prior history of cocaine self-administration on morphine reinforcement in the rat. Male Sprague-Dawley rats were allowed to acquire intravenous cocaine self-administration (0.3 mg/kg/infusion) for 20 days. When operant responding for cocaine had stabilised, morphine was introduced instead of cocaine in the next self-administration session. One group of cocaine-exposed rats was allowed to respond for 0.56 mg/kg/infusion of morphine (i.e. the dose which was willingly self-administered by drug-naive controls). The second group was allowed to respond for 0.056 mg/kg/infusion of morphine (i.e. the dose which did not maintain self-administration behaviour in the drug-naive rats). The subjects with the history of cocaine self-administration, in contrast to the drug-naive group, did not maintain operant responding for 0.56 mg/kg/infusion of morphine. These rats easily self-administered the ten times lower dose of the opioid (0.056 mg/kg/infusion). An opioid receptor antagonist, naltrexone (1 mg/kg i.p.) restored the positive reinforcing properties of the higher dose of morphine in the cocaine-exposed rats. Concluding, the present results suggest that prior history of cocaine self-administration sensitises rats to the positive reinforcing properties of morphine.

  3. Influence of cue-conditioning on acquisition, maintenance and relapse of cocaine intravenous self-administration.

    Science.gov (United States)

    Deroche-Gamonet, Véronique; Piat, Frédéric; Le Moal, Michel; Piazza, Pier Vincenzo

    2002-04-01

    Conditioning theories propose that, through a Pavlovian associative process, discrete stimuli acquire the ability to elicit neural states involved in the maintenance and relapse of a drug-taking behaviour. Experimental evidence indicates that drug-related cues play a role in relapse, however, their influence on the development and maintenance of drug self-administration has been poorly investigated. In this report, we analysed the effects of a drug-associated cue light on acquisition, maintenance and reinstatement of intravenous cocaine self-administration. The results show that a cocaine-associated cue light can act as an incentive in absence of the drug, but does not directly modify drug-reinforcing effects. Contingent and non-contingent presentations of a cocaine-associated cue light reinstated an extinguished self-administration behaviour. However, regardless of whether or not a cue light was associated with cocaine infusions, rats acquire cocaine intravenous self-administration reaching the same levels of intake. Furthermore, after self-administration has been acquired in presence of the cue light, the omission of the cue light or its non-contingent presentation did not modify rat behaviour. In conclusion, our work shows that cocaine-associated explicit cues do not directly interfere with the reinforcing effects of the drug.

  4. Cardiac Fas-dependent and mitochondria-dependent apoptosis after chronic cocaine abuse.

    Science.gov (United States)

    Liou, Cher-Ming; Tsai, Shiow-Chwen; Kuo, Chia-Hua; Ting, Hua; Lee, Shin-Da

    2014-04-09

    To evaluate whether chronic cocaine abuse will increase cardiac Fas-dependent and mitochondria-dependent apoptotic pathways, thirty-two male Wistar rats at 3-4 months of age were randomly divided into a vehicle-treated group (phosphate-buffered saline, PBS, 0.5 mL, SQ per day) and a cocaine-treated group (Cocaine, 10 mg/kg, SQ per day). After 3 months of treatment, the excised left ventricles were measured by H&E staining, Western blotting, DAPI staining and TUNEL assays. More cardiac TUNEL-positive apoptotic cells were observed in the Cocaine group than the PBS group. Protein levels of TNF-alpha, Fas ligand, Fas death receptor, FADD, activated caspase-8, and activated caspase-3 (Fas-dependent apoptosis) extracted from excised hearts in the Cocaine group were significantly increased, compared to the PBS group. Protein levels of cardiac Bax, cytosolic cytochrome c, t-Bid-to-Bid, Bak-to-Bcl-xL, Bax-to-Bcl-2 ratio, activated caspase-9, and activated caspase-3 (mitochondria-dependent apoptosis) were significantly increased in the Cocaine group, compared to the PBS group. Chronic cocaine exposure appeared to activate the cardiac Fas-dependent and mitochondria-dependent apoptosis, which may indicate a possible mechanism for the development of cardiac abnormalities in humans with chronic cocaine abuse.

  5. Cardiac Fas-Dependent and Mitochondria-Dependent Apoptosis after Chronic Cocaine Abuse

    Directory of Open Access Journals (Sweden)

    Cher-Ming Liou

    2014-04-01

    Full Text Available To evaluate whether chronic cocaine abuse will increase cardiac Fas-dependent and mitochondria-dependent apoptotic pathways, thirty-two male Wistar rats at 3–4 months of age were randomly divided into a vehicle-treated group (phosphate-buffered saline, PBS, 0.5 mL, SQ per day and a cocaine-treated group (Cocaine, 10 mg/kg, SQ per day. After 3 months of treatment, the excised left ventricles were measured by H&E staining, Western blotting, DAPI staining and TUNEL assays. More cardiac TUNEL-positive apoptotic cells were observed in the Cocaine group than the PBS group. Protein levels of TNF-alpha, Fas ligand, Fas death receptor, FADD, activated caspase-8, and activated caspase-3 (Fas-dependent apoptosis extracted from excised hearts in the Cocaine group were significantly increased, compared to the PBS group. Protein levels of cardiac Bax, cytosolic cytochrome c, t-Bid-to-Bid, Bak-to-Bcl-xL, Bax-to-Bcl-2 ratio, activated caspase-9, and activated caspase-3 (mitochondria-dependent apoptosis were significantly increased in the Cocaine group, compared to the PBS group. Chronic cocaine exposure appeared to activate the cardiac Fas-dependent and mitochondria-dependent apoptosis, which may indicate a possible mechanism for the development of cardiac abnormalities in humans with chronic cocaine abuse.

  6. Social Status in Monkeys: Effects of Social Confrontation on Brain Function and Cocaine Self-Administration.

    Science.gov (United States)

    Gould, Robert W; Czoty, Paul W; Porrino, Linda J; Nader, Michael A

    2017-04-01

    Individual differences in response to social stress and environmental enrichment may contribute to variability in response to behavioral and pharmacological treatments for drug addiction. In monkeys, social status influences the reinforcing effects of cocaine and the effects of some drugs on cocaine self-administration. In this study, we used male cynomolgus macaques (n=15) living in established social groups to examine the effects of social confrontation on the reinforcing effects of cocaine using a food-drug choice procedure. On the test day, a dominant or subordinate monkey was removed from his homecage and placed into another social pen; 30 min later he was studied in a cocaine-food choice paradigm. For the group, following social confrontation, sensitivity to cocaine reinforcement was significantly greater in subordinate monkeys compared with dominant animals. Examining individual-subject data revealed that for the majority of monkeys (9/15), serving as an intruder in another social group affected cocaine self-administration and these effects were dependent on the social rank of the monkey. For subordinate monkeys, sensitivity to the reinforcing effects of cocaine increased while sensitivity decreased in dominant monkeys. To investigate potential mechanisms mediating these effects, brain glucose metabolism was studied in a subset of monkeys (n=8) using [(18)F]fluorodeoxyglucose ([(18)F]FDG) with positron emission tomography. Dominant and subordinate monkeys displayed distinctly different patterns of brain glucose metabolism in their homecage, including areas associated with vigilance and stress/anxiety, respectively, and during social confrontation. These data demonstrate that, depending on an individual's social status, the same social experience can have divergent effects on brain function and cocaine self-administration. These phenotypic differences in response to social conditions support a personalized treatment approach to cocaine addiction.

  7. Withdrawal from continuous or intermittent cocaine administration: changes in D2 receptor function.

    Science.gov (United States)

    King, G R; Ellinwood, E H; Silvia, C; Joyner, C M; Xue, Z; Caron, M G; Lee, T H

    1994-05-01

    Intermittent cocaine administration produces sensitization, whereas the continuous administration of cocaine produces tolerance to the effects of subsequent cocaine administration during withdrawal. The present study examined whether the effects of these two dosing regimens are related to alterations in the functional status of dopamine (DA) D2 receptors. In all experiments, rats were withdrawn for 7 days from a 14-day pretreatment regimen involving either continuous or intermittent cocaine administration. Experiments examined changes in the behavioral response to an autoreceptor-selective dose of apomorphine, the effects of sulpiride on electrically stimulated DA release in striatal brain slices and striatal D2 receptor binding, and mRNA levels. The results indicate that the continuous administration of cocaine produces findings consistent with D2 autoreceptor supersensitivity; there was enhanced inhibition of behavior after the autoreceptor-selective dose of apomorphine, decreased electrically stimulated DA release in the absence of sulpiride, and enhanced electrically stimulated DA release in the presence of sulpiride. However, there were no changes in postsynaptic D2 receptor binding or mRNA levels. Intermittent cocaine administration did not produce evidence of D2 autoreceptor subsensitivity: there was no decrease in inhibition of behavior after the autoreceptor-selective dose of apomorphine, no changes in electrically stimulated DA release in the absence or presence of D2 receptor blockade, and no change in the levels of D2 receptor binding; however, D2 mRNA levels were decreased by 22%. Overall, the present results are consistent with the hypothesis that the expression of tolerance induced by continuous cocaine administration is associated with D2 autoreceptor supersensitivity.

  8. D-cycloserine deters reacquisition of cocaine self-administration by augmenting extinction learning.

    Science.gov (United States)

    Nic Dhonnchadha, Bríd A; Szalay, Jonathan J; Achat-Mendes, Cindy; Platt, Donna M; Otto, Michael W; Spealman, Roger D; Kantak, Kathleen M

    2010-01-01

    Augmentation of cue exposure (extinction) therapy with cognitive-enhancing pharmacotherapy may offer an effective strategy to combat cocaine relapse. To investigate this possibility at the preclinical level, rats and squirrel monkeys were trained to self-administer cocaine paired with a brief visual cue. Lever pressing was subsequently extinguished by withholding cocaine injections while maintaining response-contingent presentations of the cue. The glycine partial agonist D-cycloserine (DCS; 15 and 30 mg/kg in rats, 3 and 10 mg/kg in monkeys) was evaluated for its effects on the rate of extinction and subsequent reacquisition of cocaine self-administration. Compared with vehicle, pretreatment with 30 mg/kg DCS 0.5 h before extinction training reduced the number of responses and latency to reach the extinction criterion in rats, but neither dose of DCS altered these measures in monkeys. In both species, pretreatment with the higher dose of DCS before extinction training significantly attenuated reacquisition of cocaine self-administration compared with either extinction training in the absence of DCS or DCS in the absence of explicit extinction. Furthermore, treatment with 30 mg/kg DCS accompanied by brief handling (a stress induction) immediately after but not 6 h after extinction training attenuated reacquisition of cocaine self-administration in rats. No adverse effects of 10 mg/kg DCS were evident in quantitative observational studies in monkeys. The results suggest that DCS augmented consolidation of extinction learning to deter reacquisition of cocaine self-administration in rats and monkeys. The results suggest that DCS combined with exposure therapy may constitute a rational strategy for the clinical management of cocaine relapse.

  9. Effects of baclofen and raclopride on reinstatement of cocaine self-administration in the rat.

    Science.gov (United States)

    Froger-Colléaux, Christelle; Castagné, Vincent

    2016-04-15

    At present there is no satisfactory treatment against relapse of drug-seeking behavior. Relapse can be modeled in laboratory animals using reinstatement procedures, whereby previously extinguished self-administration for a drug is reinstated by different factors, such as exposure to cues or drug priming. It is thought that activation of gamma-aminobutyric acid (GABA) B receptor complexes could represent a promising approach to pharmacotherapy for diminishing relapse potential with drugs possessing reinforcing properties. The effects of baclofen (a prototypic GABAB receptor agonist) on cue-induced cocaine reinstatement were evaluated in the rat with or without a priming injection of cocaine. The effects of raclopride (an antagonist of dopamine D2 receptors) were also evaluated. Cue-induced reinstatement under vehicle resulted in a significant increase in the number of presses on the active lever, as compared with extinction lever responding. This effect was accentuated in rats receiving a priming injection of cocaine (cocaine-plus-cue-induced reinstatement). Baclofen, at doses without effects on food-motivated operant behavior (2.5 and 5mg/kg i.p.), dose-dependently decreased the number of active lever presses during cue-induced reinstatement. Baclofen had slightly weaker effects on cocaine-plus-cue-induced reinstatement. Raclopride (0.08 and 0.15 mg/kg s.c.) had similar effects against cue-induced reinstatement although it failed to inhibit cocaine-plus-cue-induced reinstatement at the lower dose. Baclofen dose-dependently and selectively decreased reinstatement of cocaine self-administration. The data obtained provide support for the potential anti-craving efficacy of baclofen in the treatment of cocaine drug-seeking.

  10. Effects of chronic exposure to crack cocaine on the respiratory tract of mice.

    Science.gov (United States)

    Herculiani, Percyleine P; Pires-Neto, Ruy C; Bueno, Heloisa M S; Zorzetto, Júlio C; Silva, Luiz C; Santos, Angela B G; Garcia, Raphael C T; Yonamine, Mauricio; Detregiachi, Cláudia R P; Saldiva, Paulo H N; Mauad, Thais

    2009-04-01

    Smoked cocaine (crack cocaine) causes several forms of injury to the respiratory tract, including asthma exacerbations, lung edema and hemorrhage, and nasal mucosal alterations. Few studies, however, have assessed respiratory tract pathology in habitual users of crack cocaine. Here, we describe the histological alterations in the respiratory tract of mice caused by chronic inhalation of crack cocaine. Twenty 2-month-old BALB/c mice were exposed to the smoke of 5 g crack cocaine in an inhalation chamber once a day for two months and compared to controls (n = 10). We then morphometrically analyzed nose and bronchiolar epithelial alterations, bronchiolar and alveolar macrophage cell density, alveolar hemosiderin content, and in addition determined the vasoconstriction index and the wall thickness of pulmonary arteries. The serum cocaine level was 212.5 ng/mL after a single inhalation. The mucus content of the nasal epithelium increased in crack-exposed animals, and the nasal and bronchial epithelium thickness decreased significantly. The alveolar hemosiderin content and the alveolar and bronchiolar macrophage cell density increased in animals exposed to crack. The vasoconstriction index increased in the pulmonary arteries of the exposed group. Chronic crack cocaine inhalation causes extensive histological changes along the entire respiratory tract.

  11. Inactivation of the central nucleus of the amygdala reduces the effect of punishment on cocaine self-administration in rats.

    Science.gov (United States)

    Xue, YueQiang; Steketee, Jeffery D; Sun, WenLin

    2012-03-01

    Continued cocaine use despite the negative consequences is a hallmark of cocaine addiction. One such consequence is punishment, which is often used by society to curb cocaine use. Unfortunately, we know little about the mechanism involved in regulation by punishment of cocaine use. The fact that cocaine addicts continue to use cocaine despite potentially severe punishment suggests that the mechanism may be impaired. Such impairment is expected to critically contribute to compulsive cocaine use. This study was aimed at testing the hypothesis that the central nucleus of the amygdala (CeN) plays a critical role in such regulation. To this end, rats were trained to press a lever to self-administer cocaine under a chained schedule: a response on one lever (cocaine-seeking lever) led to access to the other lever (cocaine-taking lever), on which a response was reinforced by cocaine and cues. Thereafter, responses on the seeking lever were punished by footshock with a probability of 0.5. Cocaine self-administration (SA) was significantly suppressed by punishment in an intensity-dependent manner. Interestingly, rats trained with daily 6-h (extended access) but not 2-h (limited access) sessions showed resistance to the lower intensity of punishment. Inactivation of the CeN induced a robust anti-punishment effect in both groups. These data provided evidence that the CeN is a critical neural substrate involved in regulation by punishment of cocaine SA. Rats with a history of extended cocaine SA appeared to be less sensitive to punishment. The decreased sensitivity could result from the neuroplastic changes induced by extended cocaine SA in the CeN.

  12. High anxiety is a predisposing endophenotype for loss of control over cocaine, but not heroin, self-administration in rats

    DEFF Research Database (Denmark)

    Dilleen, Ruth; Pelloux, Yann; Mar, Adam C

    2012-01-01

    RATIONALE: Although high anxiety is commonly associated with drug addiction, its causal role in this disorder is unclear. OBJECTIVES: In light of strong evidence for dissociable neural mechanisms underlying heroin and cocaine addiction, the present study investigated whether high anxiety predicts...... the propensity of rats to lose control over intravenous cocaine or heroin self-administration. METHODS: Sixty-four rats were assessed for anxiety in the elevated plus-maze, prior to extended access to intravenous cocaine or heroin self-administration. RESULTS: High-anxious rats, identified in the lower quartile...... of the population, showed a greater escalation of cocaine, but not heroin, self-administration compared with low-anxious rats selected in the upper quartile of the population. Anxiety scores were also positively correlated with the extent of escalation of cocaine self-administration. CONCLUSIONS: The present data...

  13. Effects of imipramine or GABA(B) receptor ligands on the immobility, swimming and climbing in the forced swim test in rats following discontinuation of cocaine self-administration.

    Science.gov (United States)

    Frankowska, Małgorzata; Gołda, Anna; Wydra, Karolina; Gruca, Piotr; Papp, Mariusz; Filip, Małgorzata

    2010-02-10

    We tested if discontinuation of cocaine self-administration can lead to the development of depressive-like symptoms in the forced swim test expressed as changes in immobility, swimming and climbing behaviors in rats. A "yoked" procedure in which rats were run simultaneously in groups of three, with two rats received the passive injection of cocaine or saline, was employed. Later, we examined whether acute treatment with the classical antidepressant imipramine or GABA(B) receptor ligands could alter the increases in immobility recorded after discontinuation of self-administered cocaine. We found a significant increase (44%) in the immobility time 3 days following discontinuation of cocaine (0.5mg/kg/infusion/2h daily) self-administration for 14 days; such enhancement resembled that observed in rats following the chronic mild stress. Acute administration with imipramine (15 or 30 mg/kg), the GABA(B) receptor agonists baclofen (0.125 mg/kg) and SKF 97541 (0.005 mg/kg), the positive allosteric modulator CGP 7930 (0.3mg/kg) or the antagonist SCH 50911 (0.3mg/kg) counteracted the cocaine discontinuation-induced enhancement in the immobility time. The enhanced immobility time in rats that self-administered cocaine (but not given cocaine passively) may reflect the motivated or cognitive processes of reinforced responding of cocaine and could be a potential driver of the addiction process per se. Moreover, either blockade or stimulation of GABA(B) receptors by their ligands in very low doses attenuated the enhanced immobility time in rats after discontinuation of cocaine self-administration and these findings extend preclinical studies demonstrating the potential involvement of GABA(B) receptor ligands to reduce cocaine craving.

  14. 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.

  15. Self-administration of ethanol, cocaine, or nicotine does not decrease the soma size of ventral tegmental area dopamine neurons.

    Directory of Open Access Journals (Sweden)

    Michelle S Mazei-Robison

    Full Text Available Our previous observations show that chronic opiate administration, including self-administration, decrease the soma size of dopamine (DA neurons in the ventral tegmental area (VTA of rodents and humans, a morphological change correlated with increased firing rate and reward tolerance. Given that a general hallmark of drugs of abuse is to increase activity of the mesolimbic DA circuit, we sought to determine whether additional drug classes produced a similar morphological change. Sections containing VTA were obtained from rats that self-administered cocaine or ethanol and from mice that consumed nicotine. In contrast to opiates, we found no change in VTA DA soma size induced by any of these other drugs. These data suggest that VTA morphological changes are induced in a drug-specific manner and reinforce recent findings that some changes in mesolimbic signaling and neuroplasticity are drug-class dependent.

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

    Directory of Open Access Journals (Sweden)

    Ma Xin-Ming

    2011-02-01

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

  17. Distinct effects of paradoxical sleep deprivation and cocaine administration on sexual behavior in male rats.

    Science.gov (United States)

    Andersen, Monica L; Tufik, Sergio

    2002-04-01

    As there are data showing enhanced sexual activity in paradoxical sleep deprived (PSD) rats, and cocaine (COC) is a drug of abuse known to also increase the sexual drive, the present study aimed to assess sexual behavior in animals submitted to PSD and/or COC administration. The data revealed that PSD followed by COC administration produced the largest percentage of animals having erection and ejaculation (100% and 60%) and differ statistically from the control groups. The PSD group that received saline produced 50% erections and 20% ejaculations whereas COC administration induced 10% erections and 10% ejaculations. Sexual activity was absent in control animals (saline injection). These findings are due probably to PSD causing supersensitivity of dopamine (DA) receptors exacerbating the cocaine actions on dopaminergic pathways inducing penile erection and ejaculation.

  18. Chronic cocaine-induced H3 acetylation and transcriptional activation of CaMKIIalpha in the nucleus accumbens is critical for motivation for drug reinforcement.

    Science.gov (United States)

    Wang, Lei; Lv, Zhigang; Hu, Zhaoyang; Sheng, Jian; Hui, Bin; Sun, Jie; Ma, Lan

    2010-03-01

    The regulation of gene expression in the brain reward regions is known to contribute to the pathogenesis and persistence of drug addiction. Increasing evidence suggests that the regulation of gene transcription is mediated by epigenetic mechanisms that alter the chromatin structure at specific gene promoters. To better understand the involvement of epigenetic regulation in drug reinforcement properties, rats were subjected to cocaine self-administration paradigm. Daily histone deacetylase (HDAC) inhibitor infusions in the shell of the nucleus accumbens (NAc) caused an upward shift in the dose-response curve under fixed-ratio schedule and increased the break point under progressive-ratio schedule, indicating enhanced motivation for self-administered drug. The effect of the HDAC inhibitor is attributed to the increased elevation of histone acetylation induced by chronic, but not acute, cocaine experience. In contrast, neutralizing the chronic cocaine-induced increase in histone modification by the bilateral overexpression of HDAC4 in the NAc shell reduced drug motivation. The association between the motivation for cocaine and the transcriptional activation of addiction-related genes by H3 acetylation in the NAc shell was analyzed. Among the genes activated by chronic cocaine experiences, the expression of CaMKIIalpha, but not CaMKIIbeta, correlated positively with motivation for the drug. Lentivirus-mediated shRNA knockdown experiments showed that CaMKIIalpha, but not CaMKIIbeta, in the NAc shell is essential for the maintenance of motivation to self-administered cocaine. These findings suggest that chronic drug-use-induced transcriptional activation of genes, such as CaMKIIalpha, modulated by H3 acetylation in the NAc is a critical regulatory mechanism underlying motivation for drug reinforcement.

  19. Behavioral momentum of cocaine self-administration: effects of frequency of reinforcement on resistance to extinction.

    Science.gov (United States)

    Quick, Stacey L; Shahan, Timothy A

    2009-07-01

    Persistent drug seeking is a defining property of substance abuse and is generally thought to depend, in part, on exposure to drug-associated contexts. Behavioral momentum theory provides a set of methods and a theoretical framework for understanding how stimulus contexts contribute to the persistence of operant behavior. Earlier research has extended behavioral momentum theory to alcohol self-administration, but not to intravenous drug self-administration. This experiment extended behavioral momentum theory to cocaine self-administration by examining the effects of frequency of cocaine reinforcement in a context on resistance to extinction. Rats self-administered 0.32 mg/kg infusions of cocaine in a multiple schedule of reinforcement arranging two distinct contexts. Responding in a Rich context was reinforced by cocaine infusions at a higher frequency (i.e. variable interval 120 s) and in a Lean context at a lower frequency (variable interval 360 s). After establishment of responding in the two contexts, resistance to extinction was examined. Preextinction response rates for cocaine were similar in the Rich and Lean contexts. Nonetheless, relative resistance to extinction was greater in the Rich context than in the Lean context. The difference in resistance to extinction in the two contexts was well described by a quantitative model of behavioral momentum. These results suggest that the frequency of drug reinforcement in a context contributes to the persistence of drug seeking in that context, and that behavioral momentum theory might be useful for understanding how drug-associated contexts contribute to the persistence of drug seeking.

  20. Differential Control of Cocaine Self-Administration by GABAergic and Glutamatergic CB1 Cannabinoid Receptors.

    Science.gov (United States)

    Martín-García, Elena; Bourgoin, Lucie; Cathala, Adeline; Kasanetz, Fernando; Mondesir, Miguel; Gutiérrez-Rodriguez, Ana; Reguero, Leire; Fiancette, Jean-François; Grandes, Pedro; Spampinato, Umberto; Maldonado, Rafael; Piazza, Pier Vincenzo; Marsicano, Giovanni; Deroche-Gamonet, Véronique

    2016-08-01

    The type 1 cannabinoid receptor (CB1) modulates numerous neurobehavioral processes and is therefore explored as a target for the treatment of several mental and neurological diseases. However, previous studies have investigated CB1 by targeting it globally, regardless of its two main neuronal localizations on glutamatergic and GABAergic neurons. In the context of cocaine addiction this lack of selectivity is critical since glutamatergic and GABAergic neuronal transmission is involved in different aspects of the disease. To determine whether CB1 exerts different control on cocaine seeking according to its two main neuronal localizations, we used mutant mice with deleted CB1 in cortical glutamatergic neurons (Glu-CB1) or in forebrain GABAergic neurons (GABA-CB1). In Glu-CB1, gene deletion concerns the dorsal telencephalon, including neocortex, paleocortex, archicortex, hippocampal formation and the cortical portions of the amygdala. In GABA-CB1, it concerns several cortical and non-cortical areas including the dorsal striatum, nucleus accumbens, thalamic, and hypothalamic nuclei. We tested complementary components of cocaine self-administration, separating the influence of primary and conditioned effects. Mechanisms underlying each phenotype were explored using in vivo microdialysis and ex vivo electrophysiology. We show that CB1 expression in forebrain GABAergic neurons controls mouse sensitivity to cocaine, while CB1 expression in cortical glutamatergic neurons controls associative learning processes. In accordance, in the nucleus accumbens, GABA-CB1 receptors control cocaine-induced dopamine release and Glu-CB1 receptors control AMPAR/NMDAR ratio; a marker of synaptic plasticity. Our findings demonstrate a critical distinction of the altered balance of Glu-CB1 and GABA-CB1 activity that could participate in the vulnerability to cocaine abuse and addiction. Moreover, these novel insights advance our understanding of CB1 neuropathophysiology.

  1. The brain-specific neural zinc finger transcription factor 2b (NZF-2b/7ZFMyt1 suppresses cocaine self-administration in rats

    Directory of Open Access Journals (Sweden)

    Vijay Chandrasekar

    2010-04-01

    Full Text Available Brain-specific neural-zinc-finger transcription factor-2b (NZF2b/7ZFMyt1 is induced in the mesolimbic dopaminergic region after chronic cocaine exposure and lentiviral-mediated expression of NZF2b/7ZFMyt1 in the nucleus accumbens results in decreased locomotor activity (Chandrasekar and Dreyer, 2009. In this study the role of NZF2b/7ZFMyt1 in active cocaine seeking and of its interaction with histone deacetylase on the altered behavior has been observed. Localized expression of NZF2b/7ZFMyt1 in the nucleus accumbens resulted in attenuated cocaine self-administration, whereas silencing this transcription factor with lentiviruses expressing siRNAs increased the animal′s motivation to self-infuse cocaine. Low doses of sodium butyrate, a potent inhibitor of histone deacetylase, were sufficient to reverse the NZF2b/7ZFMyt1-mediated decrease in cocaine self-administration. NZF2b/7ZFMyt1 expression resulted in strong induction of transcription factors REST1 and NAC1 and of the dopamine D2 receptor, with concomitant inhibition of BDNF and its receptor TrkB. We show that NZF2b/7ZFMyt1 colocalizes with histone deacetylase-2 (HDAC2, probably overcoming the suppression of transcriptional activity caused by Lingo1. These findings show that molecular adaptations mediated by NZF2b/7ZFMyt1 expression possibly lead to decreased responsiveness to the reinforcing properties of cocaine and play a prominent role in affecting the behavioral changes induced by the drug.

  2. Environmental enrichment, administered after establishment of cocaine self-administration, reduces lever pressing in extinction and during a cocaine context renewal test.

    Science.gov (United States)

    Ranaldi, Robert; Kest, Karen; Zellner, Margaret; Hachimine-Semprebom, Priscila

    2011-08-01

    The objective of this study was to test the hypothesis that environmental enrichment (EE) administered to rats previously trained to self-administer cocaine would reduce responding in extinction and in a cocaine-context renewal test. Long-Evans male rats were trained to press an active lever reinforced by cocaine (1.0 mg/kg/injection) under a fixed-ratio 1 schedule of reinforcement (inactive lever presses produced no consequences). After stable responding was established, all rats were given a 10-day break from the operant chambers followed by random assignment to EE (larger cages equipped with visual and auditory stimuli) or control (standard housing) group conditions in which they lived for the remainder of the experiment. Ten days after this move, rats were exposed to 10 extinction-responding sessions in a context different from the one in which self-administration occurred, followed by a context-renewal session occurring in the original self-administration context. The EE group responded significantly less in both the extinction and context-renewal sessions compared with the control group. These results suggest that EE reduces the ability of cocaine-associated stimuli to control cocaine-related responding.

  3. The effects of repeated opioid administration on locomotor activity: II. Unidirectional cross-sensitization to cocaine.

    Science.gov (United States)

    Smith, Mark A; Greene-Naples, Jennifer L; Felder, Jennifer N; Iordanou, Jordan C; Lyle, Megan A; Walker, Katherine L

    2009-08-01

    Sensitization refers to an increase in sensitivity to the effects of a drug and is believed to play a role in the etiology of substance use disorders. Cross-sensitization has been observed between drugs from different pharmacological classes and may play a role in the escalation of drug use in polydrug-abusing populations. The purpose of this study was to examine cross-sensitization between opioids and cocaine and to determine the extent to which cross-sensitization is mediated by an opioid's selectivity for mu, kappa, and delta receptors. Separate groups of rats were treated with opioid receptor agonists and antagonists every other day for 10 days, and the locomotor effects of cocaine were tested 8 days later. The mu agonists, morphine and buprenorphine, and the delta agonist, BW373U86 [(+/-)-4-[(R(*))-[(2S(*),5R(*))-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide hydrochloride], produced cross-sensitization to cocaine, such that repeated administration of these drugs over a 10-day period significantly enhanced cocaine's locomotor effects when tested later. Coadministration of the opioid antagonist naltrexone prevented morphine and buprenorphine from producing cross-sensitization. Coadministration of naltrexone, but not the delta antagonist naltrindole, also prevented BW373U86 from producing cross-sensitization. The kappa agonist spiradoline failed to produce cross-sensitization, but coadministration of spiradoline prevented morphine and buprenorphine from producing cross-sensitization. The ability of spiradoline to block cross-sensitization was itself blocked by the kappa antagonist nor-binaltorphimine. The mixed mu/kappa opioids butorphanol, nalbuphine, and nalorphine did not produce cross-sensitization under any condition examined. These data indicate that agonist activity at mu receptors positively modulates cross-sensitization between opioids and cocaine, whereas agonist activity at kappa receptors negatively modulates

  4. Novelty seeking, incentive salience and acquisition of cocaine self-administration in the rat.

    Science.gov (United States)

    Beckmann, Joshua S; Marusich, Julie A; Gipson, Cassandra D; Bardo, Michael T

    2011-01-01

    It has been suggested that incentive salience plays a major role in drug abuse and the development of addiction. Additionally, novelty seeking has been identified as a significant risk factor for drug abuse. However, how differences in the readiness to attribute incentive salience relate to novelty seeking and drug abuse vulnerability has not been explored. The present experiments examined how individual differences in incentive salience attribution relate to novelty seeking and acquisition of cocaine self-administration in a preclinical model. Rats were first assessed in an inescapable novelty task and a novelty place preference task (measures of novelty seeking), followed by a Pavlovian conditioned approach task for food (a measure of incentive salience attribution). Rats then were trained to self-administer cocaine (0.3 or 1.0 mg/kg/infusion) using an autoshaping procedure. The results demonstrate that animals that attributed incentive salience to a food-associated cue were higher novelty seekers and acquired cocaine self-administration more quickly at the lower dose. The results suggest that novelty-seeking behavior may be a mediator of incentive salience attribution and that incentive salience magnitude may be an indicator of drug reward.

  5. Chronic cocaine pretreatment facilitates Pavlovian sexual conditioning in male Japanese quail.

    Science.gov (United States)

    Levens, Neil; Akins, Chana K

    2004-11-01

    Repeated drug exposure that results in behavioral sensitization has been shown to enhance sex-seeking behaviors in rats as well as facilitate Pavlovian excitatory and inhibitory conditioning. In the present experiment, male Japanese quail were given repeated presentations of cocaine (10 mg/kg, i.p.) that resulted in increased locomotor activity relative to saline. After a 10-day withdrawal period, subjects received sexual conditioning trials that consisted of presentation of an object conditioned stimulus (CS) followed by sexual reinforcement. Results showed that birds that previously received chronic cocaine demonstrated more conditioned approach behavior to the CS object, a shorter latency to copulate with a female, and made more cloacal contacts (copulatory behavior) during sexual reinforcement than saline-treated birds. The findings suggest that chronic cocaine later facilitates Pavlovian conditioning in a sexual behavior paradigm. This may be the result of cocaine facilitating learning via the dopaminergic system. The findings are discussed in the context of the incentive sensitization theory and possible neuronal mechanisms.

  6. Effects of oral and intravenous administration of buspirone on food-cocaine choice in socially housed male cynomolgus monkeys.

    Science.gov (United States)

    Czoty, Paul W; Nader, Michael A

    2015-03-13

    Drugs acting at D3 dopamine receptors have been suggested as medications for cocaine dependence. These experiments examined the effects of intravenously and orally administered buspirone, a D2-like receptor antagonist with high affinity for D3 and D4 receptors, on the relative reinforcing strength of cocaine in group-housed male cynomolgus monkeys. Use of socially housed monkeys permitted the assessment of whether social status, known to influence D2-like receptor availability, modulates the behavioral effects of buspirone. Buspirone was administered acutely to monkeys self-administering cocaine under a food-drug choice procedure in which a cocaine self-administration dose-effect curve was determined daily. When administered by either route, buspirone significantly decreased cocaine choice in dominant-ranked monkeys. In subordinate monkeys, however, i.v. buspirone was ineffective on average, and oral buspirone increased choice of lower cocaine doses. The effects of buspirone only differed according to route of administration in subordinate monkeys. Moreover, it is noteworthy that the effects of buspirone were similar to those of the D3 receptor-selective antagonist PG01037 and qualitatively different than those of less selective drugs that act at D2-like or serotonin (5-HT)1A receptors, suggesting a D3 and possibly D4 receptor mechanism of action for buspirone. Taken together, the data support the utility of drugs targeting D3/D4 receptors as potential treatments for cocaine addiction, particularly in combination with enriching environmental manipulations.

  7. The effect of chronic cocaine exposure throughout pregnancy on maternal and infant outcomes in the rhesus monkey.

    Science.gov (United States)

    Morris, P; Binienda, Z; Gillam, M P; Klein, J; McMartin, K; Koren, G; Duhart, H M; Slikker, W; Paule, M G

    1997-01-01

    To explore the effects of gestational cocaine exposure in a nonhuman primate model, pregnant rhesus monkeys were either treated (N = 10) with escalating doses of cocaine up to 7.5 mg/kg (IM), three times per day, 5 consecutive days per week, prior to conception and throughout gestation, or were not treated (N = 10) with cocaine at all. Substantial levels of both cocaine and its major metabolite, benzoylecgonine, were observed in samples of hair taken at birth from mothers and infants of the cocaine-treated group. Despite these differences in cocaine exposure, the experimental groups did not differ significantly with respect to maternal outcome, as measured by body weight again during pregnancy and length of pregnancy. On the other hand, the experimental groups did differ significantly with respect to infant outcome, as measured at birth by body weight, overall length, and crown circumference, all of which were decreased in the cocaine-treated group. A variety of reflexes tested at birth were normal in the cocaine-treated group. It was concluded that, in a rhesus monkey model, chronic cocaine exposure throughout pregnancy had no significant effect on maternal outcome, but did significantly affect infant outcome as assessed in this investigation.

  8. Continuous intracerebroventricular infusion of the competitive NMDA receptor antagonist, LY235959, facilitates escalation of cocaine self-administration and increases break point for cocaine in Sprague-Dawley rats.

    Science.gov (United States)

    Allen, Richard M; Uban, Kristina A; Atwood, Elizabeth M; Albeck, David S; Yamamoto, Dorothy J

    2007-11-01

    Although escalation of consumption is an important characteristic of cocaine dependence, the neurobiological mechanisms that mediate this phenomenon have not been fully described. In this study, we used male, Sprague-Dawley rats to measure the effects of acute and continuous intracerebroventricular (ICV) administration of the competitive NMDA receptor antagonist, LY235959, on cocaine self-administration behavior under various schedules of reinforcement and access conditions. Single ICV infusions of LY235959 (0.03-0.3 microg/5 microl) produced dose-dependent and statistically significant decreases in the number of cocaine infusions earned under a progressive ratio schedule of reinforcement. In a second experiment, vehicle or LY235959 (0.2-0.3 microg/day) was continuously administered ICV to rats via surgically-implanted subcutaneous osmotic minipump/intracranial cannula assemblies. Both vehicle- and LY235959-treated rats significantly escalated cocaine self-administration over the 10 long access sessions; however, rats treated with LY235959 escalated cocaine self-administration faster and to a greater degree than vehicle-treated rats. There was a statistically significant increase in cocaine infusions earned under the PR schedule in LY235959-treated rats, but not vehicle-treated rats, after 10 long access cocaine self-administration sessions. These data support the hypothesis that escalation of cocaine consumption is mediated by hypo-glutamatergic tone in the central nervous system and this facilitation of escalation is associated with an increase in motivation to respond for cocaine.

  9. Sleep Regulates Incubation of Cocaine Craving.

    Science.gov (United States)

    Chen, Bo; Wang, Yao; Liu, Xiaodong; Liu, Zheng; Dong, Yan; Huang, Yanhua H

    2015-09-30

    After withdrawal from cocaine, chronic cocaine users often experience persistent reduction in total sleep time, which is accompanied by increased sleep fragmentation resembling chronic insomnia. This and other sleep abnormalities have long been speculated to foster relapse and further drug addiction, but direct evidence is lacking. Here, we report that after prolonged withdrawal from cocaine self-administration, rats exhibited persistent reduction in nonrapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep, as well as increased sleep fragmentation. In an attempt to improve sleep after cocaine withdrawal, we applied chronic sleep restriction to the rats during their active (dark) phase of the day, which selectively decreased the fragmentation of REM sleep during their inactive (light) phase without changing NREM or the total amount of daily sleep. Animals with improved REM sleep exhibited decreased incubation of cocaine craving, a phenomenon depicting the progressive intensification of cocaine seeking after withdrawal. In contrast, experimentally increasing sleep fragmentation after cocaine self-administration expedited the development of incubation of cocaine craving. Incubation of cocaine craving is partially mediated by progressive accumulation of calcium-permeable AMPA receptors (CP-AMPARs) in the nucleus accumbens (NAc). After withdrawal from cocaine, animals with improved REM sleep exhibited reduced accumulation of CP-AMPARs in the NAc, whereas increasing sleep fragmentation accelerated NAc CP-AMPAR accumulation. These results reveal a potential molecular substrate that can be engaged by sleep to regulate cocaine craving and relapse, and demonstrate sleep-based therapeutic opportunities for cocaine addiction. Significance statement: Sleep abnormalities are common symptoms in chronic drug users long after drug withdrawal. These withdrawal-associated sleep symptoms, particularly reduction in total sleep time and deteriorating sleep quality, have been

  10. Modeling Causal Relationship Between Brain Regions Within the Drug-Cue Processing Network in Chronic Cocaine Smokers.

    Science.gov (United States)

    Ray, Suchismita; Haney, Margaret; Hanson, Catherine; Biswal, Bharat; Hanson, Stephen José

    2015-12-01

    The cues associated with drugs of abuse have an essential role in perpetuating problematic use, yet effective connectivity or the causal interaction between brain regions mediating the processing of drug cues has not been defined. The aim of this fMRI study was to model the causal interaction between brain regions within the drug-cue processing network in chronic cocaine smokers and matched control participants during a cocaine-cue exposure task. Specifically, cocaine-smoking (15M; 5F) and healthy control (13M; 4F) participants viewed cocaine and neutral cues while in the scanner (a Siemens 3 T magnet). We examined whole brain activation, including activation related to drug-cue processing. Time series data extracted from ROIs determined through our General Linear Model (GLM) analysis and prior publications were used as input to IMaGES, a computationally powerful Bayesian search algorithm. During cocaine-cue exposure, cocaine users showed a particular feed-forward effective connectivity pattern between the ROIs of the drug-cue processing network (amygdala → hippocampus → dorsal striatum → insula → medial frontal cortex, dorsolateral prefrontal cortex, anterior cingulate cortex) that was not present when the controls viewed the cocaine cues. Cocaine craving ratings positively correlated with the strength of the causal influence of the insula on the dorsolateral prefrontal cortex in cocaine users. This study is the first demonstration of a causal interaction between ROIs within the drug-cue processing network in cocaine users. This study provides insight into the mechanism underlying continued substance use and has implications for monitoring treatment response.

  11. Extinction of cocaine self-administration reveals functionally and temporally distinct dopaminergic signals in the nucleus accumbens.

    Science.gov (United States)

    Stuber, Garret D; Wightman, R Mark; Carelli, Regina M

    2005-05-19

    While Pavlovian and operant conditioning influence drug-seeking behavior, the role of rapid dopamine signaling in modulating these processes is unknown. During self-administration of cocaine, two dopaminergic signals, measured with 100 ms resolution, occurred immediately before and after the lever press (termed pre- and post-response dopamine transients). Extinction of self-administration revealed that these two signals were functionally distinct. Pre-response transients, which could reflect the motivation to obtain the drug, did not decline during extinction. Remarkably, post-response dopamine transients attenuated as extinction progressed, suggesting that they encode the learned association between environmental cues and cocaine. A third type of dopamine transient, not time locked to overt stimuli, decreased in frequency during extinction and correlated with calculated cocaine concentrations. These results show that dopamine release transients involved in different aspects of cocaine self-administration are highly plastic--differentially governed by motivation, learned associations linked with environmental stimuli, and the pharmacological actions of cocaine.

  12. Gene expression changes in the medial prefrontal cortex and nucleus accumbens following abstinence from cocaine self-administration

    Directory of Open Access Journals (Sweden)

    Morgan Drake

    2010-02-01

    Full Text Available Abstract Background Many studies of cocaine-responsive gene expression have focused on changes occurring during cocaine exposure, but few studies have examined the persistence of these changes with cocaine abstinence. Persistent changes in gene expression, as well as alterations induced during abstinence may underlie long-lasting drug craving and relapse liability. Results Whole-genome expression analysis was conducted on a rat cocaine binge-abstinence model that has previously been demonstrated to engender increased drug seeking and taking with abstinence. Gene expression changes in two mesolimbic terminal fields (mPFC and NAc were identified in a comparison of cocaine-naïve rats with rats after 10 days of cocaine self-administration followed by 1, 10, or 100 days of enforced abstinence (n = 6-11 per group. A total of 1,461 genes in the mPFC and 414 genes in the NAc were altered between at least two time points (ANOVA, p Conclusions Together, these changes help to illuminate processes and networks involved in abstinence-induced behaviors, including synaptic plasticity, MAPK signaling, and TNF signaling.

  13. Methylphenidate treatment beyond adolescence maintains increased cocaine self-administration in the Spontaneously Hypertensive Rat model of Attention Deficit/Hyperactivity Disorder

    OpenAIRE

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

    2015-01-01

    Past research with the Spontaneously Hypertensive Rat (SHR) model of Attention Deficit/Hyperactivity Disorder showed that adolescent methylphenidate treatment enhanced cocaine abuse risk in SHR during adulthood. Acquisition of cocaine self-administration was faster, and cocaine dose-response functions were shifted upward under fixed-ratio and progressive ratio schedules compared to adult SHR that received adolescent vehicle treatment or to control strains that received adolescent methylphenid...

  14. Deficits in ventromedial prefrontal cortex group 1 metabotropic glutamate receptor function mediate resistance to extinction during protracted withdrawal from an extensive history of cocaine self-administration.

    Science.gov (United States)

    Ben-Shahar, Osnat; Sacramento, Arianne D; Miller, Bailey W; Webb, Sierra M; Wroten, Melissa G; Silva, Hannah E; Caruana, Amanda L; Gordon, Evan J; Ploense, Kyle L; Ditzhazy, Jennifer; Kippin, Tod E; Szumlinski, Karen K

    2013-01-01

    Anomalies in prefrontal cortex (PFC) function are posited to underpin difficulties in learning to suppress drug-seeking behavior during abstinence. Because group 1 metabotropic glutamate receptors (mGluRs) regulate drug-related learning, we assayed the consequences of extended access to intravenous cocaine (6 h/d; 0.25 mg/infusion for 10 d) on the PFC expression of group 1 mGluRs and the relevance of observed changes for cocaine seeking. After protracted withdrawal, cocaine-experienced animals exhibited a time-dependent intensification of cue-induced cocaine-seeking behavior and an impaired extinction of this behavior. These behavioral phenomena were associated with a time-dependent reduction in mGluR1/5 expression within ventromedial PFC (vmPFC) of cocaine-experienced animals exposed to extinction testing but not in untested ones. Interestingly, pharmacological manipulations of vmPFC mGluR1/5 produced no immediate effects on cue-induced cocaine-seeking behavior but produced residual effects on a subsequent test for cocaine seeking. At 3 d withdrawal, cocaine-experienced rats infused intra-vmPFC with mGluR1/5 antagonists, either before or after an initial test for cocaine seeking, persisted in their cocaine seeking akin to cocaine-experienced rats in protracted withdrawal. Conversely, cocaine-experienced rats infused with an mGluR1/5 agonist before the initial test for cocaine-seeking at 30 d withdrawal exhibited a facilitation of extinction learning. These data indicate that cue-elicited deficits in vmPFC group 1 mGluR function mediate resistance to extinction during protracted withdrawal from a history of extensive cocaine self-administration and pose pharmacological stimulation of these receptors as a potential approach to facilitate learned suppression of drug-seeking behavior that may aid drug abstinence.

  15. Differential regulation of MeCP2 and PP1 in passive or voluntary administration of cocaine or food.

    Science.gov (United States)

    Bodetto, Sarah Pol; Romieu, Pascal; Sartori, Maxime; Tesone-Coelho, Carolina; Majchrzak, Monique; Barbelivien, Alexandra; Zwiller, Jean; Anglard, Patrick

    2014-12-01

    Cocaine exposure induces changes in the expression of numerous genes, in part through epigenetic modifications. We have initially shown that cocaine increases the expression of the chromatin remodeling protein methyl-CpG binding protein 2 (MeCP2) and characterized the protein phosphatase-1Cβ (PP1Cβ) gene, as repressed by passive i.p. cocaine injections through a Mecp2-mediated mechanism involving de novo DNA methylation. Both proteins being involved in learning and memory processes, we investigated whether voluntary cocaine administration would similarly affect their expression using an operant self-administration paradigm. Passive and voluntary i.v. cocaine intake was found to induce Mecp2 and to repress PP1Cβ in the prefrontal cortex and the caudate putamen. This observation is consistent with the role of Mecp2 acting as a transcriptional repressor of PP1Cβ and shows that passive intake was sufficient to alter their expression. Surprisingly, striking differences were observed under the same conditions in food-restricted rats tested for food pellet delivery. In the prefrontal cortex and throughout the striatum, both proteins were induced by food operant conditioning, but remained unaffected by passive food delivery. Although cocaine and food activate a common reward circuit, changes observed in the expression of other genes such as reelin and GAD67 provide new insights into molecular mechanisms differentiating neuroadaptations triggered by each reinforcer. The identification of hitherto unknown genes differentially regulated by drugs of abuse and a natural reinforcer should improve our understanding of how two rewarding stimuli differ in their ability to drive behavior.

  16. Acute heroin intoxication in a baby chronically exposed to cocaine and heroin: a case report

    Directory of Open Access Journals (Sweden)

    Pichini Simona

    2011-07-01

    Full Text Available Abstract Introduction Acute intoxication with drugs of abuse in children is often only the tip of the iceberg, actually hiding chronic exposure. Analysis using non-conventional matrices such as hair can provide long-term information about exposure to recreational drugs. Case presentation We report the case of a one-month-old Caucasian boy admitted to our pediatric emergency unit with respiratory distress and neurological abnormalities. A routine urine test was positive for opiates, suggesting an acute opiate ingestion. No other drugs of misuse, such as cocaine, cannabis, amphetamines or derivatives, were detected in the baby's urine. Subsequently, hair samples from the baby and the parents were collected to evaluate the possibility of chronic exposure to drug misuse by segmental analysis. Opiates and cocaine metabolites were detected in hair samples from the baby boy and his parents. Conclusions In light of these and previous results, we recommend hair analysis in babies and children from risky environments to detect exposure to heroin and other drug misuse, which could provide the basis for specific social and health interventions.

  17. ELECTROPHYSIOLOGICAL CHARACTERISTICS OF PARAVENTRICULAR THALAMIC (PVT NEURONS IN RESPONSE TO CHRONIC COCAINE EXPOSURE: EFFECTS OF COCAINE- AND AMPHETAMINE-REGULATED TRANSCRIPT (CART

    Directory of Open Access Journals (Sweden)

    Jiann Wei eYeoh

    2014-08-01

    Full Text Available Recent work has established that the paraventricular thalamus (PVT is a central node in the brain reward-seeking pathway. This role is likely mediated in part through the dense projections to the PVT from hypothalamic peptide transmitter systems such as orexin, and cocaine- and amphetamine-regulated transcript (CART, both of which play key roles in drug-seeking behaviour. Consistent with this proposition, we previously found that inactivation of the PVT or infusions of CART into the PVT suppressed drug-seeking behaviour in an animal model of contingent cocaine self-administration. Despite this work, very few studies have assessed the basic physiological properties of PVT neurons and how these parameters are altered by exposure to drugs such as cocaine. We set out to address these questions by employing an electrophysiological approach to record from anterior PVT (aPVT neurons from cocaine-treated and control animals. First, we determined the excitability of aPVT neurons by injecting a series of depolarizing current steps and characterizing the resulting action potential (AP discharge properties. Second, we investigated the effects of CART on excitatory synaptic inputs to aPVT neurons. We found that the majority of aPVT neurons exhibited tonic firing (TF, and initial bursting (IB consistent with previous studies. However, we also identified PVT neurons that exhibited delayed firing (DF, single spiking (SS and reluctant firing (RF. Interestingly, cocaine exposure shifted the proportion of aPVT neurons that exhibited TF. Further, application of CART suppressed excitatory synaptic drive to PVT. This finding is consistent with our previous behavioural data, which showed that CART signaling in the PVT negatively regulates drug-seeking behaviour. Together, these studies support previous anatomical evidence that the PVT can integrate reward-relevant information and provides a putative mechanism through which drugs of abuse can dysregulate this system in

  18. Repeated intravenous administrations of teneurin-C terminal associated peptide (TCAP)-1 attenuates reinstatement of cocaine seeking by corticotropin-releasing factor (CRF) in rats.

    Science.gov (United States)

    Erb, Suzanne; McPhee, Matthew; Brown, Zenya J; Kupferschmidt, David A; Song, Lifang; Lovejoy, David A

    2014-08-01

    The teneurin c-terminal associated peptides (TCAP) have been implicated in the regulation of the stress response, possibly via a corticotropin-releasing factor (CRF)-related mechanism. We have previously shown that repeated intracerebroventricular (ICV) injections of TCAP-1 attenuate the reinstatement of cocaine seeking by CRF in rats. Here, we determined whether intravenous (IV) administrations of TCAP-1 would likewise attenuate CRF-induced reinstatement, and whether this effect would vary depending on the rat's history of cocaine self administration. Rats were trained to self-administer cocaine for 10 days, during once daily sessions that were either 3h ("short access"; ShA) or 6h ("long access"; LgA). Rats were then given five daily injections of TCAP-1 (0, 300, or 3,000 pmol, IV) in their home cage. Subsequently, they were returned to the self-administration chambers where extinction of cocaine seeking and testing for CRF-induced reinstatement of cocaine seeking was carried out. Repeated IV administrations of TCAP-1 were efficacious in attenuating CRF-induced reinstatement of cocaine seeking, but at different doses in ShA and LgA rats. Taken together, the findings extend previous work showing a consistent effect of repeated ICV TCAP-1 on CRF-induced reinstatement of cocaine seeking, and point to a potential therapeutic benefit of TCAP-1 in attenuating cocaine seeking behaviors.

  19. Changes in endocannabinoid and N-acylethanolamine levels in rat brain structures following cocaine self-administration and extinction training.

    Science.gov (United States)

    Bystrowska, Beata; Smaga, Irena; Frankowska, Małgorzata; Filip, Małgorzata

    2014-04-03

    Preclinical investigations have demonstrated that drugs of abuse alter the levels of lipid-based signalling molecules, including endocannabinoids (eCBs) and N-acylethanolamines (NAEs), in the rodent brain. In addition, several drugs targeting eCBs and/or NAEs are implicated in reward and/or seeking behaviours related to the stimulation of dopamine systems in the brain. In our study, the brain levels of eCBs (anandamide (AEA) and 2-arachidonoylglycerol (2-AG)) and NAEs (oleoylethanolamide (OEA) and palmitoylethanolamide (PEA)) were analyzed via an LC-MS/MS method in selected brain structures of rats during cocaine self-administration and after extinction training according to the "yoked" control procedure. Repeated (14days) cocaine (0.5mg/kg/infusion) self-administration and yoked drug delivery resulted in a significant decrease (ca. 52%) in AEA levels in the cerebellum, whereas levels of 2-AG increased in the frontal cortex, the hippocampus and the cerebellum and decreased in the hippocampus and the dorsal striatum. In addition, we detected increases (>150%) in the levels of OEA and PEA in the limbic areas in both cocaine treated groups, as well as an increase in the tissue levels of OEA in the dorsal striatum in only the yoked cocaine group and increases in the tissue levels of PEA in the dorsal striatum (both cocaine groups) and the nucleus accumbens (yoked cocaine group only). Compared to the yoked saline control group, extinction training (10days) resulted in a potent reduction in AEA levels in the frontal cortex, the hippocampus and the nucleus accumbens and in 2-AG levels in the hippocampus, the dorsal striatum and the cerebellum. The decreases in the limbic and subcortical areas were more apparent for rats that self-administered cocaine. Following extinction, there was a region-specific change in the levels of NAEs in rats previously injected with cocaine; a potent increase (ca. 100%) in the levels of OEA and PEA was detected in the prefrontal cortex and the

  20. Perseveration in the presence of punishment: the effects of chronic cocaine exposure and lesions to the prefrontal cortex.

    Science.gov (United States)

    Allen, Craig P; Leri, Francesco

    2014-03-15

    Perseveration is the repetition of a previously appropriate response in a manner, or context, which is detrimental to the individual. Although both cocaine exposure and prefrontal cortex (PFC) dysfunctions have been implicated in perseverative-like behaviours, the underlying nature of the impairments has been debated. The current study tested whether chronic cocaine exposure and PFC lesions induce perseverative-like behaviours by causing insensitivity to punishment. Food-restricted male Sprague-Dawley rats were trained to respond for sucrose on concurrent schedules of reinforcement. After initial training, rats received either a sensitizing regimen of cocaine exposure, or excitotoxic lesions to subregions of the PFC. The test of perseveration involved a choice of responding between two levers associated with fixed ratio and progressive ratio (PR) schedules. Responding on the PR lever was punished by a 1 min timeout period. It was found that, unlike control subjects, those exposed to chronic cocaine, or with lesions to the medial prefrontal cortex, were significantly slower in adapting their responding to avoid punishment. The current study provides evidence that both cocaine exposure and lesions to the prefrontal cortex can increase perseverative-like responding, although the magnitude and permanence of these effects are contingent on the nature of the task.

  1. Comparing injection and non-injection routes of administration for heroin, methamphetamine, and cocaine users in the United States.

    Science.gov (United States)

    Novak, Scott P; Kral, Alex H

    2011-01-01

    Research examining the demographic and substance use characteristics of illicit drug use in the United States has typically failed to consider differences in routes of administration or has exclusively focused on a single route of administration?injection drug use. Data from National Survey on Drug Use and Health were used to compare past-year injection drug users and non-injection drug users' routes of administration of those who use the three drugs most commonly injected in the United States: heroin, methamphetamine, and cocaine. Injection drug users were more likely than those using drugs via other routes to be older (aged 35 and older), unemployed, possess less than a high school education, and reside in rural areas. IDUs also exhibited higher rates of abuse/dependence, perceived need for substance abuse treatment, and co-occurring physical and psychological problems. Fewer differences between IDUs and non-IDUs were observed for heroin users compared with methamphetamine or cocaine users.

  2. High affinity binding of (/sup 3/H)cocaine to rat liver microsomes

    Energy Technology Data Exchange (ETDEWEB)

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

    1988-01-01

    )/sup 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 (/sup 3/H)cocaine binding. On the other hand, chronic administration of cocaine reduced (/sup 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 (/sup 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 (/sup 3/H)cocaine binding to liver with a different rank order of potency than their displacement of (/sup 3/H)cocaine binding to striatum. This high affinity (/sup 3/H)cocaine binding protein in liver is not likely to be monooxygenase, but may have a role in cocaine-induced hepatotoxicity

  3. Inactivation of the central nucleus of the amygdala reduces the effect of punishment on cocaine self-administration in rats

    OpenAIRE

    Xue, YueQiang; Steketee, Jeffery D.; Sun, Wenlin

    2012-01-01

    Continued cocaine use despite the negative consequences is a hallmark of cocaine addiction. One such consequence is punishment that is often used by society to curb cocaine use. Unfortunately, we know little about the mechanism involved in regulation by punishment of cocaine use. The fact that cocaine addicts continue cocaine use despite potential severe punishment suggests that the mechanism may be impaired. Such impairment is expected to critically contribute to compulsive cocaine use. This...

  4. DJ1 Expression Downregulates in Neuroblastoma Cells (SK-N-MC Chronically Exposed to HIV-1 and Cocaine.

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    Upal eRoy

    2015-07-01

    Full Text Available Background: HIV-associated neurological disorder (HAND has long been recognized as a consequence of Human Immunodeficiency Virus (HIV infection in the brain. The pathology of HAND gets more complicated with the recreational drug use such as cocaine. Recent studies have suggested multiple genetic influences involved in the pathology of addiction and HAND but only a fraction of the entire genetic risk has been investigated so far. In this regard, role of DJ1 protein (a gene linked to autosomal recessive early-onset Parkinson’s disease in regulating dopamine transmission and reactive oxygen species (ROS production in neuronal cells will be worth investigating in HIV-1 and cocaine exposed microenvironment. Being a very abundant protein in the brain, DJ1 could serve as a potential marker for early detection of HIV-1 and/or cocaine related neurological disorder.Methods: In vitro analysis was done to observe the effect of HIV-1 and/or cocaine on DJ1 protein expression in neuroblastoma cells (SK-N-MC. Gene expression and protein analysis of DJ1 was done on the HIV infected and/or cocaine treated SK-N-MC and compared to untreated cells using real time PCR, Western Blot and flow cytometry.Results: Gene expression and protein analysis indicated that there was a significant decrease in DJ1 expression in SK-N-MC chronically exposed to HIV-1 and/or cocaine.Conclusion: This is the first study to establish that DJ1 expression level in the neuronal cells significantly decreased in presence of HIV-1and/or cocaine indicating oxidative stress level of dopamine neurons.

  5. 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).

  6. Chronic loss of noradrenergic tone produces β-arrestin2-mediated cocaine hypersensitivity and alters cellular D2 responses in the nucleus accumbens.

    Science.gov (United States)

    Gaval-Cruz, Meriem; Goertz, Richard B; Puttick, Daniel J; Bowles, Dawn E; Meyer, Rebecca C; Hall, Randy A; Ko, Daijin; Paladini, Carlos A; Weinshenker, David

    2016-01-01

    Cocaine blocks plasma membrane monoamine transporters and increases extracellular levels of dopamine (DA), norepinephrine (NE) and serotonin (5-HT). The addictive properties of cocaine are mediated primarily by DA, while NE and 5-HT play modulatory roles. Chronic inhibition of dopamine β-hydroxylase (DBH), which converts DA to NE, increases the aversive effects of cocaine and reduces cocaine use in humans, and produces behavioral hypersensitivity to cocaine and D2 agonism in rodents, but the underlying mechanism is unknown. We found a decrease in β-arrestin2 (βArr2) in the nucleus accumbens (NAc) following chronic genetic or pharmacological DBH inhibition, and overexpression of βArr2 in the NAc normalized cocaine-induced locomotion in DBH knockout (Dbh -/-) mice. The D2/3 agonist quinpirole decreased excitability in NAc medium spiny neurons (MSNs) from control, but not Dbh -/- animals, where instead there was a trend for an excitatory effect. The Gαi inhibitor NF023 abolished the quinpirole-induced decrease in excitability in control MSNs, but had no effect in Dbh -/- MSNs, whereas the Gαs inhibitor NF449 restored the ability of quinpirole to decrease excitability in Dbh -/- MSNs, but had no effect in control MSNs. These results suggest that chronic loss of noradrenergic tone alters behavioral responses to cocaine via decreases in βArr2 and cellular responses to D2/D3 activation, potentially via changes in D2-like receptor G-protein coupling in NAc MSNs.

  7. Dopamine D3 receptor-preferring agonist enhances the subjective effects of cocaine in humans.

    Science.gov (United States)

    Newton, Thomas F; Haile, Colin N; Mahoney, James J; Shah, Ravi; Verrico, Christopher D; De La Garza, Richard; Kosten, Thomas R

    2015-11-30

    Pramipexole is a D3 dopamine receptor-preferring agonist indicated for the treatment of Parkinson disease. Studies associate pramipexole with pathological gambling and impulse control disorders suggesting a role for D3 receptors in reinforcement processes. Clinical studies showed pramipexole decreased cocaine craving and reversed central deficits in individuals with cocaine use disorder. Preclinical studies have shown acute administration of pramipexole increases cocaine's reinforcing effects whereas other reports suggest chronic pramipexole produces tolerance to cocaine. In a randomized, double-blind, placebo-controlled study we examined the impact of pramipexole treatment on the subjective effects produced by cocaine in volunteers with cocaine use disorder. Volunteers received pramipexole titrated up to 3.0mg/d or placebo over 15 days. Participants then received intravenous cocaine (0, 20 and 40mg) on day 15. Cardiovascular and subjective effects were obtained with visual analog scales at time points across the session. Pramipexole alone increased peak heart rate following saline and diastolic blood pressure following cocaine. Pramipexole produced upwards of two-fold increases in positive subjective effects ratings following cocaine. These results indicate that chronic D3 receptor activation increases the subjective effects of cocaine in humans. Caution should be used when prescribing pramipexole to patients that may also use cocaine.

  8. Aripiprazole blocks acute self-administration of cocaine and is not self-administered in mice

    DEFF Research Database (Denmark)

    Sørensen, Gunnar; Sager, Thomas N; Petersen, Jørgen H

    2008-01-01

    doses (0.03, 0.1, and 0.3 mg/kg/infusion) even caused significant decreases in nose-poking activity, possibly due to extrapyramidal side effects. CONCLUSIONS: These data are consistent with a potential role for aripiprazole in treatment of cocaine addiction without abuse potential per se....

  9. Cocaine Self-Administration Alters the Relative Effectiveness of Multiple Memory Systems during Extinction

    Science.gov (United States)

    Gabriele, Amanda; Setlow, Barry; Packard, Mark G.

    2009-01-01

    Rats were trained to run a straight-alley maze for an oral cocaine or sucrose vehicle solution reward, followed by either response or latent extinction training procedures that engage neuroanatomically dissociable "habit" and "cognitive" memory systems, respectively. In the response extinction condition, rats performed a runway approach response…

  10. Overexpression of CREB in the nucleus accumbens shell increases cocaine reinforcement in self-administering rats.

    Science.gov (United States)

    Larson, Erin B; Graham, Danielle L; Arzaga, Rose R; Buzin, Nicole; Webb, Joseph; Green, Thomas A; Bass, Caroline E; Neve, Rachael L; Terwilliger, Ernest F; Nestler, Eric J; Self, David W

    2011-11-09

    Chronic exposure to addictive drugs enhances cAMP response element binding protein (CREB)-regulated gene expression in nucleus accumbens (NAc), and these effects are thought to reduce the positive hedonic effects of passive cocaine administration. Here, we used viral-mediated gene transfer to produce short- and long-term regulation of CREB activity in NAc shell of rats engaging in volitional cocaine self-administration. Increasing CREB expression in NAc shell markedly enhanced cocaine reinforcement of self-administration behavior, as indicated by leftward (long-term) and upward (short-term) shifts in fixed ratio dose-response curves. CREB also increased the effort exerted by rats to obtain cocaine on more demanding progressive ratio schedules, an effect highly correlated with viral-induced modulation of BDNF protein in the NAc shell. CREB enhanced cocaine reinforcement when expressed either throughout acquisition of self-administration or when expression was limited to postacquisition tests, indicating a direct effect of CREB independent of reinforcement-related learning. Downregulating endogenous CREB in NAc shell by expressing a short hairpin RNA reduced cocaine reinforcement in similar tests, while overexpression of a dominant-negative CREB(S133A) mutant had no significant effect on cocaine self-administration. Finally, increasing CREB expression after withdrawal from self-administration enhanced cocaine-primed relapse, while reducing CREB levels facilitated extinction of cocaine seeking, but neither altered relapse induced by cocaine cues or footshock stress. Together, these findings indicate that CREB activity in NAc shell increases the motivation for cocaine during active self-administration or after withdrawal from cocaine. Our results also highlight that volitional and passive drug administration can lead to substantially different behavioral outcomes.

  11. Lesions of cholinergic pedunculopontine tegmental nucleus neurons fail to affect cocaine or heroin self-administration or conditioned place preference in rats.

    Directory of Open Access Journals (Sweden)

    Stephan Steidl

    Full Text Available Cholinergic input to the ventral tegmental area (VTA is known to contribute to reward. Although it is known that the pedunculopontine tegmental nucleus (PPTg provides an important source of excitatory input to the dopamine system, the specific role of PPTg cholinergic input to the VTA in cocaine reward has not been previously determined. We used a diphtheria toxin conjugated to urotensin-II (Dtx::UII, the endogenous ligand for urotensin-II receptors expressed by PPTg cholinergic but not glutamatergic or GABAergic cells, to lesion cholinergic PPTg neurons. Dtx::UII toxin infusion resulted in the loss of 95.78 (±0.65% of PPTg cholinergic cells but did not significantly alter either cocaine or heroin self-administration or the development of cocaine or heroin conditioned place preferences. Thus, cholinergic cells originating in PPTg do not appear to be critical for the rewarding effects of cocaine or of heroin.

  12. Cocaine and the nervous system.

    Science.gov (United States)

    Prakash, A; Das, G

    1993-12-01

    Cocaine abuse today has reached greater heights than it did during the first cocaine epidemic in the late nineteenth century. It is estimated that one out of every four Americans has used cocaine and some six million people in the US use it regularly. Although cocaine affects all systems in the body, the central nervous system (CNS) is the primary target. Cocaine blocks the reuptake of neurotransmitters in the neuronal synapses. Almost all CNS effects of cocaine can be attributed to this mechanism. Euphoria, pharmacological pleasure and intense cocaine craving share basis in this system. The effects of cocaine on other organ systems, in addition to its effects on the CNS, account for the majority of the complications associated with cocaine abuse. In this paper, the CNS effects following cocaine administration and their treatment are discussed.

  13. Cocaine self-administration alters the relative effectiveness of multiple memory systems during extinction

    OpenAIRE

    Gabriele, Amanda; Setlow, Barry; Packard, Mark G.

    2009-01-01

    Rats were trained to run a straight-alley maze for an oral cocaine or sucrose vehicle solution reward, followed by either response or latent extinction training procedures that engage neuroanatomically dissociable “habit” and “cognitive” memory systems, respectively. In the response extinction condition, rats performed a runway approach response to an empty fluid well. In the latent extinction condition, rats were placed at the empty fluid well without performing a runway approach response. R...

  14. Forced abstinence from cocaine self-administration is associated with DNA methylation changes in myelin genes in the corpus callosum: a preliminary study

    Directory of Open Access Journals (Sweden)

    David Andrew Nielsen

    2012-06-01

    Full Text Available Background: Human cocaine abuse is associated with alterations in white matter integrity revealed upon brain imaging, an observation that is recapitulated in an animal model of continuous cocaine exposure. The mechanism through which cocaine may affect white matter is unknown and the present study tested the hypothesis that cocaine self-administration results in changes in DNA methylation that could result in altered expression of several myelin genes that could contribute to the effects of cocaine on white matter integrity.Methods: In the present study, we examined the impact of forced abstinence from cocaine self-administration on chromatin-associated changes in white matter. To this end, rats were trained to self-administer cocaine (0.75 mg/kg/0.1 ml infusion for 14 days followed by forced abstinence for 1 day (N = 6 or 30 days (N = 6 before sacrifice. Drug-free, sham surgery controls (n = 7 were paired with the experimental groups. Global DNA methylation and DNA methylation at specific CpG sites in the promoter regions of myelin basic protein (Mbp, proteolipid protein-1 (Plp1, and SRY-related HMG-box-10 (Sox10 genes were analyzed in DNA extracted from corpus callosum.Results: Significant differences in the overall methylation patterns of the Sox10 promoter region were observed in the corpus callosum of rats at 30 days of forced abstinence from cocaine self-administration relative to sham controls; the -189, -142, -93 and -62 CpG sites were significantly hypomethylated point-wise at this time point. After correction for multiple comparisons, no differences in global methylation or the methylation patterns of Mbp or Plp1 were found.Conclusions: Forced abstinence from cocaine self-administration was associated with differences in DNA methylation at specific CpG sites in the promoter region of the Sox10 gene in corpus callosum. These changes may be related to reductions in normal age related changes in DNA methylation and could be a factor in

  15. Reinforcement-related regulation of AMPA glutamate receptor subunits in the ventral tegmental area enhances motivation for cocaine.

    Science.gov (United States)

    Choi, Kwang Ho; Edwards, Scott; Graham, Danielle L; Larson, Erin B; Whisler, Kimberly N; Simmons, Diana; Friedman, Allyson K; Walsh, Jessica J; Rahman, Zia; Monteggia, Lisa M; Eisch, Amelia J; Neve, Rachael L; Nestler, Eric J; Han, Ming-Hu; Self, David W

    2011-05-25

    Chronic cocaine use produces numerous biological changes in brain, but relatively few are functionally associated with cocaine reinforcement. Here we show that daily intravenous cocaine self-administration, but not passive cocaine administration, induces dynamic upregulation of the AMPA glutamate receptor subunits GluR1 and GluR2 in the ventral tegmental area (VTA) of rats. Increases in GluR1 protein and GluR1(S845) phosphorylation are associated with increased GluR1 mRNA in self-administering animals, whereas increased GluR2 protein levels occurred despite substantial decreases in GluR2 mRNA. We investigated the functional significance of GluR1 upregulation in the VTA on cocaine self-administration using localized viral-mediated gene transfer. Overexpression of GluR1(WT) in rat VTA primarily infected dopamine neurons (75%) and increased AMPA receptor-mediated membrane rectification in these neurons with AMPA application. Similar GluR1(WT) overexpression potentiated locomotor responses to intra-VTA AMPA, but not NMDA, infusions. In cocaine self-administering animals, overexpression of GluR1(WT) in the VTA markedly increased the motivation for cocaine injections on a progressive ratio schedule of cocaine reinforcement. In contrast, overexpression of protein kinase A-resistant GluR1(S845A) in the VTA reduced peak rates of cocaine self-administration on a fixed ratio reinforcement schedule. Neither viral vector altered sucrose self-administration, and overexpression of GluR1(WT) or GluR1(S845A) in the adjacent substantia nigra had no effect on cocaine self-administration. Together, these results suggest that dynamic regulation of AMPA receptors in the VTA during cocaine self-administration contributes to cocaine addiction by acting to facilitate subsequent cocaine use.

  16. Cutaneous Necrotizing Vasculitis and Leukopenia in a Cocaine User: Is Levamisole the Culprit?

    Directory of Open Access Journals (Sweden)

    Lara El Khoury

    2016-01-01

    Full Text Available Levamisole is an antihelminthic drug banned by the US Food and Drug Administration (FDA in 2000 because of its dangerous side effects. Over the past few years, it has been identified as an adulterant in cocaine and reported to cause cutaneous vasculitis in cocaine users. The health burden of levamisole is serious since it is estimated that over 5 million Americans use cocaine and that 70% of the cocaine used in the USA contains levamisole. In this paper we report the case of a 23-year-old female cocaine user that presented with purpuric rash and skin necrosis, found to have positive c-ANCA and anti-proteinase 3 antibodies. Her skin biopsy showed fibroconnective tissue with signs of necrosis, acute and chronic inflammation, and thrombus formation. She was diagnosed with levamisole-induced vasculitis and successfully treated with withdrawal of cocaine use and local wound care.

  17. Cutaneous Necrotizing Vasculitis and Leukopenia in a Cocaine User: Is Levamisole the Culprit?

    Science.gov (United States)

    El Khoury, Lara; Zeineddine, Nabil; Felix, Richard; Goldstein, Mark

    2016-01-01

    Levamisole is an antihelminthic drug banned by the US Food and Drug Administration (FDA) in 2000 because of its dangerous side effects. Over the past few years, it has been identified as an adulterant in cocaine and reported to cause cutaneous vasculitis in cocaine users. The health burden of levamisole is serious since it is estimated that over 5 million Americans use cocaine and that 70% of the cocaine used in the USA contains levamisole. In this paper we report the case of a 23-year-old female cocaine user that presented with purpuric rash and skin necrosis, found to have positive c-ANCA and anti-proteinase 3 antibodies. Her skin biopsy showed fibroconnective tissue with signs of necrosis, acute and chronic inflammation, and thrombus formation. She was diagnosed with levamisole-induced vasculitis and successfully treated with withdrawal of cocaine use and local wound care.

  18. COCAINE CARDIOMYOPATHY—A CASE REPORT

    OpenAIRE

    Georgiev Antonio; Zhivadinovik Julija

    2014-01-01

    Abstract: Cocaine is the second most common illicit drug used and the most frequent cause of drug related deaths. The use of cocaine is associated with both, acute and chronic complications, that may involve any system, but the most common system affected is cardiovascular one. Cocaine cardiomyopathy may result from the use of cocaine. This article presents a first case in Republic of Macedonia of 24-year-old male with reversible cocaine- related cardiomyopathy. Clinical presentation...

  19. Cocaine cardiomyopathy: A case report

    Directory of Open Access Journals (Sweden)

    Georgiev Antonio

    2014-12-01

    Full Text Available Cocaine is the second most common illicit drug used and the most frequent cause of drug related deaths. The use of cocaine is associated with both, acute and chronic complications, that may involve any system, but the most common system affected is cardiovascular one. Cocaine cardiomyopathy may result from the use of cocaine. This article presents a first case in Republic of Macedonia of 24-year-old male with reversible cocaine-related cardiomyopathy. Clinical presentation, laboratory, X-ray, ultrasound findings and treatment are reviewed.

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

    Science.gov (United States)

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

    2015-01-01

    Adolescents are highly vulnerable to addiction and are four times more likely to become addicted at first exposure than at any other age. The dopamine D1 receptor, which is typically overexpressed in the normal adolescent prefrontal cortex, is involved in drug cue responses and is associated with relapse in animal models. In human drug addicts, imaging methods have detected increased activation in response to drug cues in reward- and habit-associated brain regions. These same methods can be applied more quantitatively to rodent models. Here, changes in neuronal activation in response to cocaine-conditioned cues were observed using functional magnetic resonance imaging in juvenile rats that were made to over-express either D1 receptors or green fluorescent protein by viral-mediated transduction. Reduced activation was observed in the amygdala and dopamine cell body regions in the low cue-preferring/control juvenile rats in response to cocaine cues. In contrast, increased activation was observed in the dorsal striatum, nucleus accumbens, prefrontal cortex, and dopamine cell bodies in high cue-preferring/D1 juveniles. The increase in cue salience that is mediated by increased D1 receptor density, rather than excessive cocaine experience, appears to underlie the transition from aversion to reward in cue-induced neural response and may form the basis for habit-forming vulnerability. PMID:27006904

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

    Directory of Open Access Journals (Sweden)

    Steven B. Lowen

    2015-01-01

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

  2. Diazepam promotes choice of abstinence in cocaine self-administering rats.

    Science.gov (United States)

    Augier, Eric; Vouillac, Caroline; Ahmed, Serge H

    2012-03-01

    When facing a choice between cocaine and a potent, albeit inessential, non-drug alternative (i.e. water sweetened with saccharin), most cocaine self-administering rats abstain from cocaine in favor of the non-drug pursuit, regardless of the dose available and even after extended drug use. Only a minority continues to take the drug despite the opportunity of making a different choice and increasing stakes. This pattern of individual variation could suggest that the majority of rats are resilient to addiction, taking cocaine by default of other options. Only a minority would be vulnerable to addiction. This study tested the hypothesis that rats choose to refrain from cocaine self-administration because cocaine would be conflictual, having both rewarding and anxiogenic properties. Contrary to this hypothesis, however, we report here that diazepam-a broad-spectrum benzodiazepine anxiolytic-did not decrease, but instead, further increased cocaine abstinence. Interestingly, although diazepam decreased locomotion, rats adapted to this effect by spending more time near the lever associated with the preferred reward, a behavior that minimized the need for locomotion at the moment of choice. When responding for cocaine or saccharin was analyzed separately, we found that diazepam decreased responding for cocaine without affecting responding for saccharin. Finally, the abstinence-promoting effects of diazepam were also induced in cocaine-preferring rats treated chronically with diazepam. Overall, this study demonstrates that abstinence from cocaine cannot be explained away by the anxiogenic effects of cocaine, thereby reinforcing the notion of resilience to addiction. It also supports the use of benzodiazepines in the treatment of cocaine addiction.

  3. Estradiol as a mechanism for sex differences in the development of an addicted phenotype following extended access cocaine self-administration.

    Science.gov (United States)

    Ramôa, Carolina P; Doyle, Susan E; Naim, Diana W; Lynch, Wendy J

    2013-08-01

    Women progress more rapidly after initial cocaine use to addiction as compared with men. Similarly, female rats appear to require less cocaine exposure before developing an addicted phenotype with evidence implicating estradiol as a potential mechanism. The goals of this study were to determine whether there are sex differences in the magnitude of the addicted phenotype under optimized conditions that induce its development in both males and females and to determine the role of estradiol in this effect. Following acquisition, intact male and intact and ovariectomized (OVX) female rats with and without estradiol replacement were given access to cocaine (1.5 mg/kg per infusion) under either extended access (ExA; discrete trial procedure, 4 trials/h, 24 h/day, 10 days) or short access (ShA) conditions (20 infusions maximum/day, 3 days). Motivation to obtain cocaine (0.5 mg/kg/infusion), as assessed under a progressive-ratio schedule, was then examined following a 2-week abstinence period. Results showed that following ExA self-administration, both males and females developed an addicted phenotype, with 9 of 11 males and 8 of 10 females showing a greater than 15% increase in levels of motivation to obtain cocaine as compared with ShA controls. In contrast, within the OVX groups, responding was enhanced from control levels after ExA self-administration in estradiol-replaced rats only. These results suggest that while females may have an enhanced vulnerability to developing an addicted phenotype, they may be similar to males once addiction has developed. These results also suggest that estradiol is critically involved in the development of an addicted phenotype in females.

  4. Comparison of self-administration behavior and responsiveness to drug-paired cues in rats running an alley for intravenous heroin and cocaine

    OpenAIRE

    Su, Zu-In; Wenzel, Jennifer; Baird, Rebeccah; Ettenberg, Aaron

    2010-01-01

    Rationale Evidence suggests that responsiveness to a drug-paired cue is predicted by the reinforcing magnitude of the drug during prior self-administration. It remains unclear, however, if this principle holds true when comparisons are made across drug reinforcers. Objective The current study was therefore devised to test the hypothesis that differences in the animals’ responsiveness to a cocaine- or heroin-paired cue presented during extinction would reflect differences in the patterns of pr...

  5. Cocaine self-administration in mice with forebrain knock-down of trpc5 ion channels [v1; ref status: indexed, http://f1000r.es/pb

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    Matthew B Pomrenze

    2013-02-01

    Full Text Available Canonical transient receptor potential (TRPC channels are a family of non-selective cation channels that play a crucial role in modulating neuronal excitability due to their involvement in intracellular Ca2+ regulation and dendritic growth. TRPC5 channels a are one of the two most prevalent TRPC channels in the adult rodent brain; b are densely expressed in deep layer pyramidal neurons of the prefrontal cortex (PFC; and c modulate neuronal persistent activity necessary for working memory and attention. In order to evaluate the causal role of TRPC5 in motivation/reward-related behaviors, conditional forebrain TRPC5 knock-down (trpc5-KD mice were generated and trained to nose-poke for intravenous cocaine. Here we present a data set containing the first 6 days of saline or cocaine self-administration in wild type (WT and trpc5-KD mice. In addition, we also present a data set showing the dose-response to cocaine after both groups had achieved similar levels of cocaine self-administration. Compared to WT mice, trpc5-KD mice exhibited an apparent increase in self-administration on the first day of cocaine testing without prior operant training. There were no apparent differences between WT and trpc5-KD mice for saline responding on the first day of training. Both groups showed similar dose-response sensitivity to cocaine after several days of achieving similar levels of cocaine intake.

  6. Cocaine and "pharmacological kindling" in the rat.

    Science.gov (United States)

    Stripling, J S

    1983-11-01

    The concept of "pharmacological kindling" has been used to explain the behavioral sensitization to cocaine produced by repeated administration of subconvulsive doses. This idea was tested by the repeated administration of cocaine to rats followed by electrical kindling of the olfactory bulb (a site at which cocaine has prominent electrophysiologic effects). No significant effect of cocaine on kindling was found. The relationship of this finding to studies using other drugs is discussed.

  7. Chronic heroin and cocaine abuse is associated with decreased serum concentrations of the nerve growth factor and brain-derived neurotrophic factor.

    Science.gov (United States)

    Angelucci, Francesco; Ricci, Valerio; Pomponi, Massimiliano; Conte, Gianluigi; Mathé, Aleksander A; Attilio Tonali, Pietro; Bria, Pietro

    2007-11-01

    Chronic cocaine and heroin users display a variety of central nervous system (CNS) dysfunctions including impaired attention, learning, memory, reaction time, cognitive flexibility, impulse control and selective processing. These findings suggest that these drugs may alter normal brain functions and possibly cause neurotoxicity. Neurotrophins are a class of proteins that serve as survival factors for CNS neurons. In particular, nerve growth factor (NGF) plays an important role in the survival and function of cholinergic neurons while brain-derived neurotrophic factor (BDNF) is involved in synaptic plasticity and in the maintenance of midbrain dopaminergic and cholinergic neurons. In the present study, we measured by enzyme-linked immunosorbent assay (ELISA) the NGF and BDNF levels in serum of three groups of subjects: heroin-dependent patients, cocaine-dependent patients and healthy volunteers. Our goal was to identify possible change in serum neurotrophins in heroin and cocaine users. BDNF was decreased in heroin users whereas NGF was decreased in both heroin and cocaine users. These findings indicate that NGF and BDNF may play a role in the neurotoxicity and addiction induced by these drugs. In view of the neurotrophin hypothesis of schizophrenia the data also suggest that reduced level of neurotrophins may increase the risk of developing psychosis in drug users.

  8. Emotion recognition during cocaine intoxication.

    Science.gov (United States)

    Kuypers, K P C; Steenbergen, L; Theunissen, E L; Toennes, S W; Ramaekers, J G

    2015-11-01

    Chronic or repeated cocaine use has been linked to impairments in social skills. It is not clear whether cocaine is responsible for this impairment or whether other factors, like polydrug use, distort the observed relation. We aimed to investigate this relation by means of a placebo-controlled experimental study. Additionally, associations between stressor-related activity (cortisol, cardiovascular parameters) induced by the biological stressor cocaine, and potential cocaine effects on emotion recognition were studied. Twenty-four healthy recreational cocaine users participated in this placebo-controlled within-subject study. Participants were tested between 1 and 2 h after treatment with oral cocaine (300 mg) or placebo. Emotion recognition of low and high intensity expressions of basic emotions (fear, anger, disgust, sadness, and happiness) was tested. Findings show that cocaine impaired recognition of negative emotions; this was mediated by the intensity of the presented emotions. When high intensity expressions of Anger and Disgust were shown, performance under influence of cocaine 'normalized' to placebo-like levels while it made identification of Sadness more difficult. The normalization of performance was most notable for participants with the largest cortisol responses in the cocaine condition compared to placebo. It was demonstrated that cocaine impairs recognition of negative emotions, depending on the intensity of emotion expression and cortisol response.

  9. Metabolomics of cocaine: implications in toxicity.

    Science.gov (United States)

    Dinis-Oliveira, Ricardo Jorge

    2015-01-01

    Cocaine is the most commonly used illicit drug among those seeking care in Emergency Departments or drug detoxification centers. Cocaine, chemically known as benzoylmethylecgonine, is a naturally occurring substance found in the leaves of the Erythroxylum coca plant. The pharmacokinetics of cocaine is dependent on multiple factors, such as physical/chemical form, route of administration, genetics and concurrent consumption of alcohol. This review aims to discuss metabolomics of cocaine, namely by presenting all known metabolites of cocaine and their roles in the cocaine-mediated toxic effects.

  10. Clinical potential of methylphenidate in the treatment of cocaine addiction: a review of the current evidence

    Directory of Open Access Journals (Sweden)

    Dürsteler KM

    2015-06-01

    Full Text Available Kenneth M Dürsteler,1,2 Eva-Maria Berger,1 Johannes Strasser,1 Carlo Caflisch,2 Jochen Mutschler,2 Marcus Herdener,2 Marc Vogel1 1Center for Addictive Disorders, Psychiatric University Clinics Basel, Basel, Switzerland; 2Center for Addictive Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland Background: Cocaine use continues to be a public health problem, yet there is no proven effective pharmacotherapy for cocaine dependence. A promising approach to treating cocaine dependence may be agonist-replacement therapy, which is already used effectively in the treatment of opioid and tobacco dependence. The replacement approach for cocaine dependence posits that administration of a long-acting stimulant medication should normalize the neurochemical and behavioral perturbations resulting from chronic cocaine use. One potential medication to be substituted for cocaine is methylphenidate (MPH, as this stimulant possesses pharmacobehavioral properties similar to those of cocaine. Aim: To provide a qualitative review addressing the rationale for the use of MPH as a cocaine substitute and its clinical potential in the treatment of cocaine dependence. Methods: We searched MEDLINE for clinical studies using MPH in patients with cocaine abuse/dependence and screened the bibliographies of the articles found for pertinent literature. Results: MPH, like cocaine, increases synaptic dopamine by inhibiting dopamine reuptake. The discriminative properties, reinforcing potential, and subjective effects of MPH and cocaine are almost identical and, importantly, MPH has been found to substitute for cocaine in animals and human volunteers under laboratory conditions. When taken orally in therapeutic doses, its abuse liability, however, appears low, which is especially true for extended-release MPH preparations. Though there are promising data in the literature, mainly from case reports and

  11. SIRT1-FOXO3a regulate cocaine actions in the nucleus accumbens.

    Science.gov (United States)

    Ferguson, Deveroux; Shao, Ningyi; Heller, Elizabeth; Feng, Jian; Neve, Rachael; Kim, Hee-Dae; Call, Tanessa; Magazu, Samantha; Shen, Li; Nestler, Eric J

    2015-02-18

    Previous studies have shown that chronic cocaine administration induces SIRT1, a Class III histone deacetylase, in the nucleus accumbens (NAc), a key brain reward region, and that such induction influences the gene regulation and place conditioning effects of cocaine. To determine the mechanisms by which SIRT1 mediates cocaine-induced plasticity in NAc, we used chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq), 1 d after 7 daily cocaine (20 mg/kg) or saline injections, to map SIRT1 binding genome-wide in mouse NAc. Our unbiased results revealed two modes of SIRT1 action. First, despite its induction in NAc, chronic cocaine causes depletion of SIRT1 from most affected gene promoters in concert with enrichment of H4K16ac (itself a deacetylation target of SIRT1), which is associated with increased expression of these genes. Second, we deduced the forkhead transcription factor (FOXO) family to be a downstream mechanism through which SIRT1 regulates cocaine action. We proceeded to demonstrate that SIRT1 induction causes the deacetylation and activation of FOXO3a in NAc, which leads to the induction of several known FOXO3a gene targets in other systems. Finally, we directly establish a role for FOXO3a in promoting cocaine-elicited behavioral responses by use of viral-mediated gene transfer: we show that overexpressing FOXO3a in NAc enhances cocaine place conditioning. The discovery of these two actions of SIRT1 in NAc in the context of behavioral adaptations to cocaine represents an important step forward in advancing our understanding of the molecular adaptations underlying cocaine action.

  12. Withdrawal from Cocaine Self-Administration Produces Long-Lasting Deficits in Orbitofrontal-Dependent Reversal Learning in Rats

    Science.gov (United States)

    Calu, Donna J.; Stalnaker, Thomas A.; Franz, Theresa M.; Singh, Teghpal; Shaham, Yavin; Schoenbaum, Geoffrey

    2007-01-01

    Drug addicts make poor decisions. These decision-making deficits have been modeled in addicts and laboratory animals using reversal-learning tasks. However, persistent reversal-learning impairments have been shown in rats and monkeys only after noncontingent cocaine injections. Current thinking holds that to represent the human condition…

  13. 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.

  14. Acute brain metabolic effects of cocaine in rhesus monkeys with a history of cocaine use.

    Science.gov (United States)

    Henry, Porche' Kirkland; Murnane, Kevin S; Votaw, John R; Howell, Leonard L

    2010-12-01

    Cocaine addiction involves an escalation in drug intake which alters many brain functions. The present study documented cocaine-induced changes in brain metabolic activity as a function of cocaine self-administration history. Experimentally naive rhesus monkeys (N = 6) were given increasing access to cocaine under a fixed-ratio schedule of intravenous (i.v.) drug self-administration. PET imaging with F-18 labeled fluorodeoxyglucose (FDG) was used to measure acute intramuscular (i.m.) cocaine-induced changes in brain metabolism in the cocaine-naïve state, following 60 sessions under limited-access conditions (1 h/day), following 60 sessions under extended-access conditions (4 h/day), and following 4 weeks of drug withdrawal. In the cocaine-naïve state, cocaine-induced increases in brain metabolism were restricted to the prefrontal cortex. As cocaine exposure increased from limited to extended access, metabolic effects expanded throughout the frontal cortex and were induced within the striatum. Conversely, cocaine-induced activation was far less robust following withdrawal. The results highlight a progressive expansion of the metabolic effects of cocaine to include previously unaffected dopamine innervated brain regions as a consequence of cocaine self-administration history. The identification of brain regions progressively influenced by drug exposure may be highly relevant toward efforts to develop treatments for cocaine addiction.

  15. 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.

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

    OpenAIRE

    Radley, Jason J.; 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 ...

  17. 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.

  18. Cocaine addiction as a homeostatic reinforcement learning disorder.

    Science.gov (United States)

    Keramati, Mehdi; Durand, Audrey; Girardeau, Paul; Gutkin, Boris; Ahmed, Serge H

    2017-03-01

    Drug addiction implicates both reward learning and homeostatic regulation mechanisms of the brain. This has stimulated 2 partially successful theoretical perspectives on addiction. Many important aspects of addiction, however, remain to be explained within a single, unified framework that integrates the 2 mechanisms. Building upon a recently developed homeostatic reinforcement learning theory, the authors focus on a key transition stage of addiction that is well modeled in animals, escalation of drug use, and propose a computational theory of cocaine addiction where cocaine reinforces behavior due to its rapid homeostatic corrective effect, whereas its chronic use induces slow and long-lasting changes in homeostatic setpoint. Simulations show that our new theory accounts for key behavioral and neurobiological features of addiction, most notably, escalation of cocaine use, drug-primed craving and relapse, individual differences underlying dose-response curves, and dopamine D2-receptor downregulation in addicts. The theory also generates unique predictions about cocaine self-administration behavior in rats that are confirmed by new experimental results. Viewing addiction as a homeostatic reinforcement learning disorder coherently explains many behavioral and neurobiological aspects of the transition to cocaine addiction, and suggests a new perspective toward understanding addiction. (PsycINFO Database Record

  19. Quantitative {sup 123}I IMP and {sup 99m}Tc HMPAO imaging in the dog following cocaine administration

    Energy Technology Data Exchange (ETDEWEB)

    Susskind, Herbert; Weber, David A.; Ivanovic, Marija; Wong, Christopher T.C.; Haan, Constance E. de; Gavin, Patrick R

    1996-04-01

    SPECT and associated imaging procedures were used in beagle dogs to evaluate the uptake, distribution, and clearance properties of i.v.-injected {sup 123}I IMP (IMP) and {sup 99m}Tc HMPAO (HMPAO) in the brain, lungs, liver, and kidneys; (2) quantify the acute effects (after 15 sec) of very low doses (0.5 or 1.0 mg/kg) cocaine on the kinetics and localization properties of IMP and HMPAO; and (3) evaluate comparative imaging properties of IMP and HMPAO for measuring regional cerebral blood flow (rCBF). Regional and global uptake and localization of IMP or HMPAO were evaluated in control studies using dynamic planar (0-30 min) and SPECT imaging (at 35 min). The regional distribution properties of IMP and HMPAO in the brain were estimated from regions of interest (ROIs) drawn around anatomic structures on MR slices and manually registered with corresponding SPECT slices. Cocaine significantly reduced the 30-min IMP uptake in the brain and lungs by {approx}15%, but only slightly changed HMPAO uptake in the brain and other organs. In the control studies, the respective uptakes of IMP in the brain and lungs were 9 and 39% greater (p < 0.01) than those of HMPAO. In control SPECT studies, the highest uptake of IMP was observed in the thalamus and progressively less activity was observed in the parietal lobe, frontal lobe, cerebellum, occipital lobe, and entire brain; activity in the olfactory bulb was lower than in all other regions. Cocaine reduced IMP uptake in the cerebellum (p < 0.01), occipital lobe (p < 0.01), and entire brain (p < 0.05). IMP uptake (cpm/pixel-mCi) in the different brain regions was 1.3 to 2.1 times greater than that of HMPAO (p < 0.001). HMPAO uptake was more homogeneous throughout the gray matter of the brain; no significant uptake differences were observed among flagged regions. Results indicate that single, acute doses of cocaine, 0.5 and 1.0 mg/kg, significantly altered the uptake and localization properties of IMP in the dog's brain, lungs

  20. Plasma profile of pro-inflammatory cytokines and chemokines in cocaine users under outpatient treatment: influence of cocaine symptom severity and psychiatric co-morbidity.

    Science.gov (United States)

    Araos, Pedro; Pedraz, María; Serrano, Antonia; Lucena, Miguel; Barrios, Vicente; García-Marchena, Nuria; Campos-Cloute, Rafael; Ruiz, Juan J; Romero, Pablo; Suárez, Juan; Baixeras, Elena; de la Torre, Rafael; Montesinos, Jorge; Guerri, Consuelo; Rodríguez-Arias, Marta; Miñarro, José; Martínez-Riera, Roser; Torrens, Marta; Chowen, Julie A; Argente, Jesús; Mason, Barbara J; Pavón, Francisco J; Rodríguez de Fonseca, Fernando

    2015-07-01

    The treatment for cocaine use constitutes a clinical challenge because of the lack of appropriate therapies and the high rate of relapse. Recent evidence indicates that the immune system might be involved in the pathogenesis of cocaine addiction and its co-morbid psychiatric disorders. This work examined the plasma pro-inflammatory cytokine and chemokine profile in abstinent cocaine users (n = 82) who sought outpatient cocaine treatment and age/sex/body mass-matched controls (n = 65). Participants were assessed with the diagnostic interview Psychiatric Research Interview for Substance and Mental Diseases according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Tumor necrosis factor-alpha, chemokine (C-C motif) ligand 2/monocyte chemotactic protein-1 and chemokine (C-X-C motif) ligand 12 (CXCL12)/stromal cell-derived factor-1 (SDF-1) were decreased in cocaine users, although all cytokines were identified as predictors of a lifetime pathological use of cocaine. Interleukin-1 beta (IL-1β), chemokine (C-X3-C motif) ligand 1 (CX3CL1)/fractalkine and CXCL12/SDF-1 positively correlated with the cocaine symptom severity when using the DSM-IV-TR criteria for cocaine abuse/dependence. These cytokines allowed the categorization of the outpatients into subgroups according to severity, identifying a subgroup of severe cocaine users (9-11 criteria) with increased prevalence of co-morbid psychiatric disorders [mood (54%), anxiety (32%), psychotic (30%) and personality (60%) disorders]. IL-1β was observed to be increased in users with such psychiatric disorders relative to those users with no diagnosis. In addition to these clinical data, studies in mice demonstrated that plasma IL-1β, CX3CL1 and CXCL12 were also affected after acute and chronic cocaine administration, providing a preclinical model for further research. In conclusion, cocaine exposure modifies the circulating levels of pro-inflammatory mediators. Plasma

  1. Modafinil: a useful medication for cocaine addiction? Review of the evidence from neuropharmacological, experimental and clinical studies.

    Science.gov (United States)

    Martínez-Raga, Jose; Knecht, Carlos; Cepeda, Sonsoles

    2008-06-01

    Cocaine addiction is a chronic relapsing disorder associated with severe medical and psychosocial complications. However, there are no approved medications for cocaine dependent individuals. Modafinil, a medication that differs chemically and pharmacologically from other central nervous system stimulants, has been suggested to be potentially useful for this complex disorder. The present paper aims to critically review the published evidence from laboratory and clinical studies on modafinil for cocaine addiction, including discussion of its pharmacological characteristics and how it may relate with cocaine neurobiology. Whilst its exact mechanism of action remains to be elucidated, different neurotransmitter systems have been implicated, including modulation on dopamine, glutamate/GABA, noradrenaline and the hypocretin/orexin system, but it is possible that modafinil acts by a synergistic combination of mechanisms. With a favourable pharmacokinetic profile, it appears to have a low abuse potential. Laboratory and clinical studies provide consistent, albeit preliminary, evidence of the potential usefulness of modafinil for cocaine dependent patients. Not only there is no evidence of pharmacokinetic interactions between modafinil and cocaine, but in addition cocaine induced euphoria and cardiovascular effects appear to be attenuated by modafinil. Furthermore, modafinil has been shown to decrease cocaine self-administration. In addition, modafinil treated patient are more likely to achieve protracted abstinence than placebo treated patients. However, further research is needed to confirm these findings.

  2. Arteriopatía periférica crónica inducida por cocaína Chronic peripheral arterial disease induced by cocaine

    Directory of Open Access Journals (Sweden)

    Sonia Pankl

    2012-02-01

    Full Text Available La trombosis periférica aguda inducida por cocaína ha sido descripta en la literatura, siendo una complicación poco común. Si bien existen comunicaciones que reflejan los efectos crónicos de la cocaína sobre el sistema arterial periférico, no hay casos publicados de tal complicación en ausencia de otros factores de riesgo. Se presenta el caso de una mujer de 22 años de edad con antecedentes de consumo de cocaína intranasal de 3 gramos por semana durante un año, que consultó por claudicación intermitente a los 200 metros asociada a dolor y parestesias en miembro inferior izquierdo de 2 meses de evolución. El ecodoppler arterial evidenció una estenosis mayor del 70% en la arteria femoral superficial izquierda. Se realizaron estudios complementarios descartando otras etiologías probables. Se inició tratamiento con ácido acetilsalicílico, cilostazol y ejercicio reglado, asociado a terapia de apoyo para mantenimiento del cese del consumo de cocaína, con buena respuesta. Se destaca la importancia de la difusión de información a los pacientes, dado que la mayoría de la población desconoce las complicaciones cardiovasculares de dicha adicción. Es indispensable indagar sobre el consumo de cocaína en pacientes jóvenes con arteriopatía sin factores de riesgo aparentes.Cocaine induced acute peripheral thrombosis, though a rare complication, has been described in the literature. Although there are reports describing the chronic effects of cocaine on the peripheral arterial system, there are no published cases of this complication when other risk factors are lacking. We report on a 22 year old female patient, with intranasal consumption of 3 grams of cocaine per week for a year, who consulted for intermittent claudication at 200 meters, associated to left lower limb pain and paresthesiae for the last two months. Arterial Doppler ultrasonography showed a stenosis greater than 70% in the superficial left femoral artery. Other

  3. Acute and chronic tramadol administration impair spatial memory in rat

    Science.gov (United States)

    Hosseini-Sharifabad, Ali; Rabbani, Mohammad; Sharifzadeh, Mohammad; Bagheri, Narges

    2016-01-01

    Tramadol hydrochloride, a synthetic opioid, acts via a multiple mechanism of action. Tramadol can potentially change the behavioral phenomena. The present study evaluates the effect of tramadol after single or multiple dose/s on the spatial memory of rat using object recognition task (ORT). Tramadol, 20 mg/kg, was injected intraperitoneally (i.p) as a single dose or once a day for 21 successive days considered as acute or chronic treatment respectively. After treatment, animals underwent two trials in the ORT. In the first trial (T1), animals encountered with two identical objects for exploration in a five-minute period. After 1 h, in the T2 trial, the animals were exposed to a familiar and a nonfamiliar object. The exploration times and frequency of the exploration for any objects were recorded. The results showed that tramadol decreased the exploration times for the nonfamiliar object in the T2 trial when administered either as a single dose (P<0.001) or as the multiple dose (P<0.05) compared to the respective control groups. Both acute and chronic tramadol administration eliminated the different frequency of exploration between the familiar and nonfamiliar objects. Our findings revealed that tramadol impaired memory when administered acutely or chronically. Single dose administration of tramadol showed more destructive effect than multiple doses of tramadol on the memory. The observed data can be explained by the inhibitory effects of tramadol on the wide range of neurotransmitters and receptors including muscarinic, N-methyl D-aspartate, AMPA as well as some second messenger like cAMP and cGMP or its stimulatory effect on the opioid, gama amino butyric acid, dopamine or serotonin in the brain. PMID:27051432

  4. The relationship between cocaine-induced increases in NAC1 and behavioral sensitization.

    Science.gov (United States)

    Wang, P J; Stromberg, Michael; Replenski, Stephen; Snyder-Mackler, Alexander; Mackler, Scott A

    2003-04-01

    Repeated exposure to cocaine can cause long-term behavioral changes in mammals, including an augmented locomotor response known as behavioral sensitization. A major goal of research is the identification of molecules associated with these behaviors. NAC1, a member of the POZ/BTB transcription factor family, exhibited increased mRNA levels in the nucleus accumbens of the rat weeks after cocaine use. NAC1 exists as two isoforms, each demonstrating the ability to inhibit transcription, but to different extents. The present experiments examined the time course for both NAC1 isoforms after five consecutive days of systemic cocaine administration in male rats. Tissues were collected from several central nervous system regions and underwent Western blot analysis. There was significantly greater expression of the long isoform, lNAC1 (cocaine 1.341+/-0.641; saline 1+/-0.321; P=.044), and the short isoform, sNAC1 (cocaine 3.038+/-2.816; saline 1+/-0.720; P=.001), in the nucleus accumbens of cocaine-treated rats. The olfactory tubercle also showed a significant increase, but only in sNAC1 expression and at only one time period. No other significant differences were observed for either isoform of NAC1 in any other brain region. The expression of lNAC1 exhibited an inverse relationship with behavioral sensitization in rats 1-3 months following repeated cocaine injections predicting approximately 40% of the variance in the behavior variables (R(2)=.387; and P=.031 for distance and P=.025 for ambulatory count). These results indicate that NAC1 expression is increased for a period of several months after chronic cocaine exposure. Furthermore, these data suggest that NAC1 may function as an endogenous inhibitor of behavioral sensitization. NAC1 represents a target for future studies examining cocaine-induced behavioral changes.

  5. Cocaine tolerance in honey bees.

    Directory of Open Access Journals (Sweden)

    Eirik Søvik

    Full Text Available Increasingly invertebrates are being used to investigate the molecular and cellular effects of drugs of abuse to explore basic mechanisms of addiction. However, in mammals the principle factors contributing to addiction are long-term adaptive responses to repeated drug use. Here we examined whether adaptive responses to cocaine are also seen in invertebrates using the honey bee model system. Repeated topical treatment with a low dose of cocaine rendered bees resistant to the deleterious motor effects of a higher cocaine dose, indicating the development of physiological tolerance to cocaine in bees. Cocaine inhibits biogenic amine reuptake transporters, but neither acute nor repeated cocaine treatments caused measurable changes in levels of biogenic amines measured in whole bee brains. Our data show clear short and long-term behavioural responses of bees to cocaine administration, but caution that, despite the small size of the bee brain, measures of biogenic amines conducted at the whole-brain level may not reveal neurochemical effects of the drug.

  6. Using the self-administration of apomorphine and cocaine to measure the pharmacodynamic potencies and pharmacokinetics of competitive dopamine receptor antagonists.

    Science.gov (United States)

    Norman, Andrew B; Tabet, Michael R; Norman, Mantana K; Tsibulsky, Vladimir L

    2011-01-15

    Competitive dopamine receptor antagonists accelerate psychomotor stimulant self-administration. According to pharmacological theory of competitive antagonism antagonists raise the equiactive agonist concentration. In the self-administration paradigm this is assumed to be the satiety threshold or C(min). The magnitude of the proportional increase in satiety threshold (agonist concentration ratio) as a function of antagonist dose should reflect the antagonist pharmacodynamic potency. The time course of this effect should reflect the rate of change of antagonist occupancy of receptors and, therefore, antagonist concentration, i.e. pharmacokinetics. Rats self-administered apomorphine or cocaine at a stable rate and were then injected i.v. with one of four competitive D₁-like or D₂-like dopamine receptor antagonists and the session continued. The agonist concentrations at the time of each self-administration (satiety thresholds) were calculated during the session. The antagonists accelerated self-administration of both agonists with a concomitant increase in the calculated satiety thresholds. The maximum agonist concentration ratio was proportional to the dose of antagonist. The time courses of the changes in agonist concentration ratio were independent of the agonist and of the dose of antagonist. Schild analysis of the maximum agonist concentration ratio as a function of the antagonist dose allowed apparent pA₂ (or K(dose)) to be measured. Antagonist K(dose) values should provide a quantitative basis for receptor identification in behavioral pharmacology. The assay system may also measure the pharmacokinetics of antagonist elimination from the brain. Agonist self-administration represents a sensitive in vivo pharmacological assay system that provides information useful for pharmacokinetic/pharmacodynamic modeling of antagonist effects.

  7. Glutamate transporter GLT-1 mediates N-acetylcysteine inhibition of cocaine reinstatement.

    Science.gov (United States)

    Reissner, Kathryn J; Gipson, Cassandra D; Tran, Phuong K; Knackstedt, Lori A; Scofield, Michael D; Kalivas, Peter W

    2015-03-01

    Both pre-clinical and clinical studies indicate that N-acetylcysteine (NAC) may be useful in treating relapse to addictive drug use. Cocaine self-administration in rats reduces both cystine-glutamate exchange and glutamate transport via GLT-1 in the nucleus accumbens, and NAC treatment normalizes these two glial processes critical for maintaining glutamate homeostasis. However, it is not known if one or both of these actions by NAC is needed to inhibit relapse to cocaine seeking. To determine whether the restoration of GLT-1 and/or cystine-glutamate exchange is required for NAC to inhibit cue-induced reinstatement of cocaine seeking, we utilized the rat self-administration/extinction/reinstatement model of cocaine relapse. Rats were pre-treated in the nucleus accumbens with vivo-morpholino antisense oligomers targeting either GLT-1 or xCT (catalytic subunit of the cystine-glutamate exchanger) overlapping with daily NAC administration during extinction (100 mg/kg, i.p. for the last 5 days). Rats then underwent cue-induced reinstatement of active lever pressing in the absence of NAC, to determine if preventing NAC-induced restoration of one or the other protein was sufficient to block the capacity of chronic NAC to inhibit reinstatement. The vivo-morpholino suppression of xCT reduced cystine-glutamate exchange but did not affect NAC-induced reduction of reinstated cocaine seeking. In contrast, suppressing NAC-induced restoration of GLT-1 not only prevented NAC from inhibiting reinstatement, but augmented the capacity of cues to reinstate cocaine seeking. We hypothesized that the increased reinstatement after inhibiting NAC induction of GLT-1 resulted from increased extracellular glutamate, and show that augmented reinstatement is prevented by blocking mGluR5. Restoring GLT-1, not cystine-glutamate exchange, is a key mechanism whereby daily NAC reduces cue-induced cocaine reinstatement.

  8. Behavioural, biochemical and molecular changes induced by chronic crack-cocaine inhalation in mice: The role of dopaminergic and endocannabinoid systems in the prefrontal cortex.

    Science.gov (United States)

    Areal, Lorena B; Rodrigues, Livia C M; Andrich, Filipe; Moraes, Livia S; Cicilini, Maria A; Mendonça, Josideia B; Pelição, Fabricio S; Nakamura-Palacios, Ester M; Martins-Silva, Cristina; Pires, Rita G W

    2015-09-01

    Crack-cocaine addiction has increasingly become a public health problem worldwide, especially in developing countries. However, no studies have focused on neurobiological mechanisms underlying the severe addiction produced by this drug, which seems to differ from powder cocaine in many aspects. This study investigated behavioural, biochemical and molecular changes in mice inhaling crack-cocaine, focusing on dopaminergic and endocannabinoid systems in the prefrontal cortex. Mice were submitted to two inhalation sessions of crack-cocaine a day (crack-cocaine group) during 11 days, meanwhile the control group had no access to the drug. We found that the crack-cocaine group exhibited hyperlocomotion and a peculiar jumping behaviour ("escape jumping"). Blood collected right after the last inhalation session revealed that the anhydroecgonine methyl ester (AEME), a specific metabolite of cocaine pyrolysis, was much more concentrated than cocaine itself in the crack-cocaine group. Most genes related to the endocannabinoid system, CB1 receptor and cannabinoid degradation enzymes were downregulated after 11-day crack-cocaine exposition. These changes may have decreased dopamine and its metabolites levels, which in turn may be related with the extreme upregulation of dopamine receptors and tyrosine hydroxylase observed in the prefrontal cortex of these animals. Our data suggest that after 11 days of crack-cocaine exposure, neuroadaptive changes towards downregulation of reinforcing mechanisms may have taken place as a result of neurochemical changes observed on dopaminergic and endocannabinoid systems. Successive changes like these have never been described in cocaine hydrochloride models before, probably because AEME is only produced by cocaine pyrolysis and this metabolite may underlie the more aggressive pattern of addiction induced by crack-cocaine.

  9. Low startle magnitude may be a behavioral marker of vulnerability to cocaine addiction.

    Science.gov (United States)

    Wheeler, Marina G; Duncan, Erica; Davis, Michael

    2017-01-01

    Cocaine addicted men have low startle magnitude persisting during prolonged abstinence. Low startle rats show greater cocaine self-administration than high startle rats. Low startle may be a marker of a vulnerability to heightened cocaine-related behaviors in rats and similarly may be a marker of vulnerability to cocaine addiction in humans.

  10. Stimulation of 5-HT(1B) receptors enhances cocaine reinforcement yet reduces cocaine-seeking behavior.

    Science.gov (United States)

    Pentkowski, Nathan S; Acosta, Jazmin I; Browning, Jenny R; Hamilton, Elizabeth C; Neisewander, Janet L

    2009-09-01

    Paradoxically, stimulation of 5-HT(1B) receptors (5-HT(1B)Rs) enhances sensitivity to the reinforcing effects of cocaine but attenuates incentive motivation for cocaine as measured using the extinction/reinstatement model. We revisited this issue by examining the effects of a 5-HT(1B)R agonist, CP94253, on cocaine reinforcement and cocaine-primed reinstatement, predicting that CP94253 would enhance cocaine-seeking behavior reinstated by a low priming dose, similar to its effect on cocaine reinforcement. Rats were trained to self-administer cocaine (0.75 mg/kg, i.v.) paired with light and tone cues. For reinstatement experiments, they then underwent daily extinction training to reduce cocaine-seeking behavior (operant responses without cocaine reinforcement). Next, they were pre-treated with CP94253 (3-10 mg/kg, s.c.) and either tested for cocaine-primed (10 or 2.5 mg/kg, i.p.) or cue-elicited reinstatement of extinguished cocaine-seeking behavior. For reinforcement, effects of CP94253 (5.6 mg/kg) across a range of self-administered cocaine doses (0-1.5 mg/kg, i.v.) were examined. Cocaine dose-dependently reinstated cocaine-seeking behavior, but contrary to our prediction, CP94253 reduced reinstatement with both priming doses. Similarly, CP94253 reduced cue-elicited reinstatement. In contrast, CP94253 shifted the self-administration dose-effect curve leftward, consistent with enhanced cocaine reinforcement. When saline was substituted for cocaine, CP94253 reduced response rates (i.e. cocaine-seeking behavior). In subsequent control experiments, CP94253 decreased open-arm exploration in an elevated plus-maze suggesting an anxiogenic effect, but had no effect on locomotion or sucrose reinforcement. These results provide strong evidence that stimulation of 5-HT(1B)Rs produces opposite effects on cocaine reinforcement and cocaine-seeking behavior, and further suggest that 5-HT(1B)Rs may be a novel target for developing medications for cocaine dependence.

  11. Mind Over Matter: Cocaine

    Science.gov (United States)

    ... Term(s): Teachers / NIDA Teaching Guide / Mind Over Matter Teaching Guide and Series / Cocaine Print Mind Over Matter: Cocaine Order Free Publication in: English Spanish Download PDF 806.08 KB Cocaine is ...

  12. Water metabolism in rats subjected to chronic alcohol administration

    DEFF Research Database (Denmark)

    Parlesak, Alexandr; Pohl, C.; Bode, J.C.;

    2004-01-01

    AIM: While the diuretic action of acute ingestion of alcohol has been studied extensively, the effect of chronic alcohol consumption has received less attention. The aim of the present study was to investigate the effect of chronic alcohol consumption on the balance of water intake and excretion ...

  13. A comparison of motivations for use among users of crack cocaine and cocaine powder in a sample of simultaneous cocaine and alcohol users.

    Science.gov (United States)

    Martin, Gina; Macdonald, Scott; Pakula, Basia; Roth, Eric A

    2014-03-01

    This study examined the motivations for using cocaine and alcohol comparing those who primarily smoked crack and those who primarily used cocaine powder when using simultaneously with alcohol. Motivations examined included: 1) to cope with a negative affect, 2) enhancement, 3) to be social and 4) to conform. The research design was a cross-sectional study in which clients in treatment for cocaine and alcohol problems completed a self-administered questionnaire about their substance use. Among those who primarily smoked crack or snorted cocaine when also using alcohol (n=153), there were 93 participants who reported primarily snorting cocaine and 60 participants who primarily reported smoking crack. Bivariate analyses found that those who primarily smoked crack reported lower social motivations to use alcohol and cocaine. When adjusting for other covariates in a multivariate analysis, social motivation was still significantly different between groups. Additionally, those who primarily smoked crack were more likely to be older, report higher cocaine dependence severity, be unemployed and were less likely to have completed some post-secondary education, than those who primarily snorted cocaine. No differences were found in enhancement, coping or conformity motivations between the two groups. These results suggest that simultaneous cocaine and alcohol use may have social importance to those who primarily snort cocaine, but that this importance is less evident to those who smoke crack. Consequently, future studies examining motivations for simultaneous cocaine and alcohol use should distinguish between different routes of cocaine administration.

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

    Science.gov (United States)

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

    2014-04-01

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

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

    Science.gov (United States)

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

    2014-01-01

    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. PMID:24440755

  16. Effects of cocaine on honey bee dance behaviour.

    Science.gov (United States)

    Barron, Andrew B; Maleszka, Ryszard; Helliwell, Paul G; Robinson, Gene E

    2009-01-01

    The role of cocaine as an addictive drug of abuse in human society is hard to reconcile with its ecological role as a natural insecticide and plant-protective compound, preventing herbivory of coca plants (Erythroxylum spp.). This paradox is often explained by proposing a fundamental difference in mammalian and invertebrate responses to cocaine, but here we show effects of cocaine on honey bees (Apis mellifera L.) that parallel human responses. Forager honey bees perform symbolic dances to advertise the location and value of floral resources to their nest mates. Treatment with a low dose of cocaine increased the likelihood and rate of bees dancing after foraging but did not otherwise increase locomotor activity. This is consistent with cocaine causing forager bees to overestimate the value of the floral resources they collected. Further, cessation of chronic cocaine treatment caused a withdrawal-like response. These similarities likely occur because in both insects and mammals the biogenic amine neuromodulator systems disrupted by cocaine perform similar roles as modulators of reward and motor systems. Given these analogous responses to cocaine in insects and mammals, we propose an alternative solution to the paradox of cocaine reinforcement. Ecologically, cocaine is an effective plant defence compound via disruption of herbivore motor control but, because the neurochemical systems targeted by cocaine also modulate reward processing, the reinforcing properties of cocaine occur as a ;side effect'.

  17. Cocaine. Specialized Information Service.

    Science.gov (United States)

    Do It Now Foundation, Phoenix, AZ.

    This compilation of journal articles on cocaine includes a report describing cocaine as the recreational drug of the middle class, statistics from the United States Department of Health on health consequences of cocaine use, an article on "speedballing" (use of cocaine and heroin in combination), and a discussion of the various ways…

  18. 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.

  19. Role of personality traits in cocaine craving throughout an outpatient psychosocial treatment program

    Directory of Open Access Journals (Sweden)

    Flávia Ismael

    2014-03-01

    Full Text Available Objective: Cocaine dependence is a major international public health concern. Its chronically relapsing nature is possibly related to craving intensity, which can be influenced by diverse biological and psychological aspects. This study aimed to evaluate the role of different personality traits in craving measured throughout a psychosocial treatment program. Method: The sample comprised 66 cocaine-dependent outpatients who were enrolled in an individual and manualized cognitive-behavioral therapy program. The influence of personality traits on craving intensity, frequency, and duration was analyzed using a generalized estimating equations model with an autoregressive correlation structure. Results: Craving varied during treatment. The personality traits of novelty seeking, reward dependence, and harm avoidance interacted with craving intensity, and the personality trait of persistence interacted with craving duration throughout the treatment period. Furthermore, there were significant interactions between drug use and craving intensity, and between different routes of administration and craving intensity. Participants who used cocaine/crack while in treatment and concurrent users of crack (i.e., freebase cocaine and powder cocaine also had a higher craving intensity. Conclusion: The extent of craving variation can depend on certain personality styles. This study shows that craving is influenced by personality traits, and this may presumably change clinical expression involved in disease.

  20. 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

    2017-02-21

    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.Molecular Psychiatry advance online publication, 21 February 2017; doi:10.1038/mp.2017.8.

  1. Precise simultaneous quantification of methadone and cocaine in rat serum and brain tissue samples following their successive i.p. administration.

    Science.gov (United States)

    Nakhla, David S; Hussein, Lobna A; Magdy, N; Abdallah, Inas A; Hassan, Hazem E

    2017-03-24

    A sensitive high-performance liquid chromatography (HPLC) assay with dual UV detection has been developed and validated for the simultaneous quantification of methadone and cocaine in rat serum and brain tissue samples. Liquid-liquid extraction using hexanes was applied for samples extraction with Levo-Tetrahydropalmatine (L-THP) as the internal standard. Chromatographic separation of the analytes was achieved on a reversed-phase Waters Symmetry(®) C18 column (150mm×4.6mm, 5μm). A gradient elution was employed with a mobile phase consisting of 5mM potassium phosphate containing 0.1% triethylamine (pH=6.5) (A) and acetonitrile (B) with a flow rate of 1mL/min. UV detection was employed at 215nm and 235nm for the determination of methadone and cocaine, respectively. The calibration curves were linear over the range of 0.05-10μg/mL for both methadone and cocaine. The assay was validated according to FDA guidelines for bioanalytical method validation and results were satisfactory and met FDA criteria. Inter-day accuracy values of serum and brain samples ranged from 96.97 to 105.59% while intra-day accuracy values ranged from 91.49 to 111.92%. Stability assays showed that both methadone and cocaine were stable during sample storage, preparation, and analytical procedures. The method was successfully used to analyze biological samples obtained from a drug- drug interaction pharmacokinetics (PK) study conducted in rats to investigate the effect of methadone on cocaine PK. Our method not only can be used for bioanalysis of samples obtained from rats but also can potentially be applied to human biological serum samples to monitor compliance to methadone maintenance therapy (MMT) and to detect possible cocaine-methadone co-abuse.

  2. The Effects of Concurrent Administration of (±)3,4-Methylenedioxymethamphetamine and Cocaine on Conditioned Place Preference in the Adult Male Rat

    OpenAIRE

    Diller, Anna J.; Rocha, Angelica; Aaron L. Cardon; Valles, Rodrigo; Wellman, Paul J.; Nation, Jack R.

    2007-01-01

    Conditioned place preference (CPP), a commonly used model for studying the role of contextual cues in drug reward and drug seeking, was employed to explore possible behavioral interactions between (±)3,4-methylenedioxymethamphetamine (MDMA; “ecstasy”) and cocaine. On each of four occasions, adult male rats received one of three doses of MDMA (0 mg/kg, 5 mg/kg, 10 mg/kg; administered subcutaneously [s.c.]) combined with one of three doses of cocaine (0 mg/kg, 2.5 mg/kg, 5 mg/kg; administered i...

  3. AAVrh.10-Mediated Expression of an Anti-Cocaine Antibody Mediates Persistent Passive Immunization That Suppresses Cocaine-Induced Behavior

    Science.gov (United States)

    Rosenberg, Jonathan B.; Hicks, Martin J.; De, Bishnu P.; Pagovich, Odelya; Frenk, Esther; Janda, Kim D.; Wee, Sunmee; Koob, George F.; Hackett, Neil R.; Kaminsky, Stephen M.; Worgall, Stefan; Tignor, Nicole; Mezey, Jason G.

    2012-01-01

    Abstract Cocaine addiction is a major problem affecting all societal and economic classes for which there is no effective therapy. We hypothesized an effective anti-cocaine vaccine could be developed by using an adeno-associated virus (AAV) gene transfer vector as the delivery vehicle to persistently express an anti-cocaine monoclonal antibody in vivo, which would sequester cocaine in the blood, preventing access to cognate receptors in the brain. To accomplish this, we constructed AAVrh.10antiCoc.Mab, an AAVrh.10 gene transfer vector expressing the heavy and light chains of the high affinity anti-cocaine monoclonal antibody GNC92H2. Intravenous administration of AAVrh.10antiCoc.Mab to mice mediated high, persistent serum levels of high-affinity, cocaine-specific antibodies that sequestered intravenously administered cocaine in the blood. With repeated intravenous cocaine challenge, naive mice exhibited hyperactivity, while the AAVrh.10antiCoc.Mab-vaccinated mice were completely resistant to the cocaine. These observations demonstrate a novel strategy for cocaine addiction by requiring only a single administration of an AAV vector mediating persistent, systemic anti-cocaine passive immunity. PMID:22486244

  4. Effect of chronic pain on fentanyl self-administration in mice.

    Directory of Open Access Journals (Sweden)

    Carrie L Wade

    Full Text Available The development of opioid addiction in subjects with established chronic pain is an area that is poorly understood. It is critically important to clearly understand the neurobiology associated with propensity toward conversion to addiction under conditions of chronic pain. To pose the question whether the presence of chronic pain influences motivation to self-administer opioids for reward, we applied a combination of rodent models of chronic mechanical hyperalgesia and opioid self-administration. We studied fentanyl self-administration in mice under three conditions that induce chronic mechanical hyperalgesia: inflammation, peripheral nerve injury, and repeated chemotherapeutic injections. Responding for fentanyl was compared among these conditions and their respective standard controls (naïve condition, vehicle injection or sham surgery. Acquisition of fentanyl self-administration behavior was reduced or absent in all three conditions of chronic hyperalgesia relative to control mice with normal sensory thresholds. To control for potential impairment in ability to learn the lever-pressing behavior or perform the associated motor tasks, all three groups were evaluated for acquisition of food-maintained responding. In contrast to the opioid, chronic hyperalgesia did not interfere with the reinforcing effect of food. These studies indicate that the establishment of chronic hyperalgesia is associated with reduced or ablated motivation to seek opioid reward in mice.

  5. An overview of cocaethylene, an alcohol-derived, psychoactive, cocaine metabolite.

    Science.gov (United States)

    Landry, M J

    1992-01-01

    Cocaethylene is a psychoactive ethyl homologue of cocaine, and is formed exclusively during the coadministration of cocaine and alcohol. Not a natural alkaloid of the coca leaf, cocaethylene can be identified in the urine, blood, hair, and neurological and liver tissue samples of individuals who have consumed both cocaine and alcohol. With a pharmacologic profile similar to cocaine, it can block the dopamine transporter on dopaminergic presynaptic nerve terminals in the brain. It increases dopamine synaptic content, provoking enhanced postsynaptic receptor stimulation, resulting in euphoria, reinforcement, and self-administration. Equipotent to cocaine with regard to dopamine transporter affinity, cocaethylene appears to be far less potent than cocaine with regard to serotonin transporter binding. Lacking the serotonergic-related inhibitory mechanism, cocaethylene appears to be more euphorigenic and rewarding than cocaine. Synthesized and administered cocaethylene has a behavioral stimulation profile similar to cocaine. Cocaethylene has been shown to be less potent and equipotent to cocaine, and alcohol plus cocaine produces more stimulatory locomotor behavior in mice than either drug alone. Equipotent to cocaine with regard to primate reinforcement and self-administration, cocaethylene can substitute for cocaine in drug discrimination studies, and can produce stimulation of operant conditioning in rats. With regard to lethality, cocaethylene has been shown to be more potent than cocaine in mice and rats. The combination of cocaine and alcohol appears to exert more cardiovascular toxicity than either drug alone in humans. Alcohol appears to potentiate cocaine hepatotoxicity in both humans and mice.

  6. Chronic Cannabinoid Administration in Vivo Compromises Extinction of Fear Memory

    Science.gov (United States)

    Lin, Hui-Ching; Mao, Sheng-Chun; Chen, Po-See; Gean, Po-Wu

    2008-01-01

    Endocannabinoids are critically involved in the extinction of fear memory. Here we examined the effects of repeated cannabinoid administration on the extinction of fear memory in rats and on inhibitory synaptic transmission in medial prefrontal cortex (mPFC) slices. Rats were treated with the CB1 receptor agonist WIN55212-2 (WIN 10 mg/kg, i.p.)…

  7. 5-lipoxygenase expression in a brain damage model induced by chronic oral administration of aluminum

    Institute of Scientific and Technical Information of China (English)

    Yongquan Pan; Peng Zhang; Junqing Yang; Qiang Su

    2010-01-01

    A preliminary study has found that the 5-lipoxygenase inhibitor, caffeic acid, has a marked protective effect on acute brain injury induced by intracerebroventricular microinjection of aluminum.In this experiment, chronic brain injury and neuronal degeneration model was established in rats by chronic oral administration of aluminum, and then intervened using caffeic acid. Results showed that caffeic acid can downregulate chronic aluminum overload-induced 5-lipoxygenase mRNA and protein expression, and repair the aluminum overload-induced hippocampal neuronal damage andspatial orientation impairment. It is suggested that direct intervention of 5-lipoxygenase expression has a neuroprotective role in the degeneration induced by chronic aluminum overload brain injury model.

  8. Relative Timing Between Kappa Opioid Receptor Activation and Cocaine Determines the Impact on Reward and Dopamine Release

    Science.gov (United States)

    Chartoff, Elena H; Ebner, Shayla R; Sparrow, Angela; Potter, David; Baker, Phillip M; Ragozzino, Michael E; Roitman, Mitchell F

    2016-01-01

    Negative affective states can increase the rewarding value of drugs of abuse and promote drug taking. Chronic cocaine exposure increases levels of the neuropeptide dynorphin, an endogenous ligand at kappa opioid receptors (KOR) that suppresses dopamine release in the nucleus accumbens (NAc) and elicits negative affective states upon drug withdrawal. However, there is evidence that the effects of KOR activation on affective state are biphasic: immediate aversive effects are followed by delayed increases in reward. The impact of KOR-induced affective states on reward-related effects of cocaine over time is not known. We hypothesize that the initial aversive effects of KOR activation increase, whereas the delayed rewarding effects decrease, the net effects of cocaine on reward and dopamine release. We treated rats with cocaine at various times (15 min to 48 h) after administration of the selective KOR agonist salvinorin A (salvA). Using intracranial self-stimulation and fast scan cyclic voltammetry, we found that cocaine-induced increases in brain stimulation reward and evoked dopamine release in the NAc core were potentiated when cocaine was administered within 1 h of salvA, but attenuated when administered 24 h after salvA. Quantitative real-time PCR was used to show that KOR and prodynorphin mRNA levels were decreased in the NAc, whereas tyrosine hydroxylase and dopamine transporter mRNA levels and tissue dopamine content were increased in the ventral tegmental area 24 h post-salvA. These findings raise the possibility that KOR activation—as occurs upon withdrawal from chronic cocaine—modulates vulnerability to cocaine in a time-dependent manner. PMID:26239494

  9. Chronic administration of Abarema cochliacarpos attenuates colonic inflammation in rats

    Directory of Open Access Journals (Sweden)

    Maria Silene da Silva

    Full Text Available Inflammatory bowel diseases are characterized by a chronic clinical course of relapse and remission associated with self-destructive inflammation of the gastrointestinal tract. Active extracts from plants have emerged as natural potential candidates for its treatment. Abarema cochliacarpos (Gomes Barneby & Grimes, Fabaceae (Barbatimão, is a native medicinal plant in to Brazil. Previously we have demonstrated in an acute colitis model a marked protective effect of a butanolic extract, so we decided to assess its anti-inflammatory effect in a chronic ulcerative colitis model induced by trinitrobenzensulfonic acid (TNBS. Abarema cochliacarpos (150 mg/day, v.o. was administered for fourteen consecutive days. This treatment decreased significantly macroscopic damage as compared with TNBS. Histological analysis showed that the extract improved the microscopic structure. Myeloperoxidase activity (MPO was significantly decreased. Study of cytokines showed that TNF-α was diminished and IL-10 level was increased after Abarema cochliacarpos treatment. In order to elucidate inflammatory mechanisms, expression of cyclooxygenase (COX-2 and nitric oxide synthase (iNOS were studied showing a significant downregulation. In addition, there was reduction in the JNK and p-38 activation. Finally, IκB degradation was blocked by Abarema cochliacarpos treatment being consistent with an up-regulation of the NF-kappaB-binding activity. These results reinforce the anti-inflammatory effects described previously suggesting that Abarema cochliacarpos could provide a source for the search for new anti-inflammatory compounds useful in ulcerative colitis treatment.

  10. Examination of cocaine dose in a preclinical model of natural reward devaluation by cocaine.

    Science.gov (United States)

    Green, Jennifer L; Dykstra, Linda A; Carelli, Regina M

    2015-06-01

    In a preclinical model of natural reward devaluation by cocaine, taste cues elicit aversive taste reactivity when they predict impending but delayed cocaine self-administration. Here, we investigated this negative affective state as a function of cocaine dose. Male, Sprague-Dawley rats were given 45 brief intraoral infusions of a 0.15% saccharin solution before 2 h cocaine self-administration for 14 days. Rats were video recorded; taste reactivity and patterns of self-administration were quantified on the first and last days. On day 14, a significant decrease in appetitive taste reactivity and increase in aversive taste reactivity was observed (compared with day 1) that did not vary as a function of cocaine dose. In contrast, patterns of cocaine self-administration (i.e. the total number of lever presses and load-up behavior) varied as a function of dose across days. Further, load-up behavior was positively correlated with aversive taste reactivity (i.e. gapes) on day 14 across all doses tested. Collectively, these findings indicate that the emergence of negative affect in this preclinical model is not dependent on cocaine dose.

  11. Effects of contingent and non-contingent cocaine on drug-seeking behavior measured using a second-order schedule of cocaine reinforcement in rats.

    Science.gov (United States)

    Markou, A; Arroyo, M; Everitt, B J

    1999-06-01

    Rats were trained to respond with intravenous cocaine as the reinforcer under a fixed interval 15-min schedule, during which conditioned stimuli paired with cocaine were presented contingent on completion of a fixed ratio of 10 responses (i.e., second-order schedule of reinforcement). The effects of contingent and noncontingent cocaine were investigated. The results show that pretreatment with noncontingent (i.e., experimenter-administered) cocaine led to a satiation-like effect that was reflected in decreased numbers of responses and a tendency for an increased latency to initiate responding when the doses of cocaine administered were similar to or higher than the training/maintenance dose of cocaine. By contrast, noncontingent administration of cocaine doses lower than the training/maintenance dose, and response-contingent cocaine administration, led to increased drug-seeking behavior, as reflected in increased numbers of responses. The present data indicate that at least two factors determine whether administration of cocaine would lead to drug-seeking behavior: whether the cocaine administration is contingent or noncontingent, and the relative magnitude of the cocaine dose administered in relation to the training/maintenance dose of cocaine.

  12. Neurochemical Effects of Chronic Administration of Calcitriol in Rats

    Directory of Open Access Journals (Sweden)

    Pei Jiang

    2014-12-01

    Full Text Available Despite accumulating data showing the various neurological actions of vitamin D (VD, its effects on brain neurochemistry are still far from fully understood. To further investigate the neurochemical influence of VD, we assessed neurotransmitter systems in the brain of rats following 6-week calcitriol (1,25-dihydroxyvitamin D administration (50 ng/kg/day or 100 ng/kg/day. Both the two doses of calcitriol enhanced VDR protein level without affecting serum calcium and phosphate status. Rats treated with calcitriol, especially with the higher dose, exhibited elevated γ-aminobutyric acid (GABA status. Correspondingly, the mRNA expression of glutamate decarboxylase (GAD 67 was increased. 100 ng/kg of calcitriol administration also increased glutamate and glutamine levels in the prefrontal cortex, but did not alter glutamine synthetase (GS expression. Additionally, calcitriol treatment promoted tyrosine hydroxylase (TH and tryptophan hydroxylase 2 (TPH2 expression without changing dopamine and serotonin status. However, the concentrations of the metabolites of dopamine and serotonin were increased and the drug use also resulted in a significant rise of monoamine oxidase A (MAOA expression, which might be responsible to maintain the homeostasis of dopaminergic and serotonergic neurotransmission. Collectively, the present study firstly showed the effects of calcitriol in the major neurotransmitter systems, providing new evidence for the role of VD in brain function.

  13. Vaccine administration in children with chronic kidney disease.

    Science.gov (United States)

    Esposito, Susanna; Mastrolia, Maria Vincenza; Prada, Elisabetta; Pietrasanta, Carlo; Principi, Nicola

    2014-11-20

    Pediatric patients with severe chronic kidney disease (CKD) on conservative treatment, on dialysis, and those with renal transplantation are at a higher risk for infectious diseases as the result of impaired immune responses against infectious agents. Infections in these patients can have drastic consequences for disease morbidity and mortality. Immunization is a crucial preventive strategy for disease management in this pediatric population. However, vaccination coverage among children with CKD remains low due to safety concerns and doubts about vaccine immunogenicity and efficacy. In this study, we reviewed why children with CKD are at higher risk of infections, the importance of vaccinations among these children, barriers to vaccinations, and recommend the best vaccination schedules. Overall, vaccines have acceptable immunogenicity, efficacy, and safety profiles in children with CKD. However, in some cases, the protective antibody levels induced by vaccines and the benefits and risks of booster vaccine doses must be individually managed. Furthermore, close contacts and household members of these children should complete age-appropriate vaccination schedules to increase the child's indirect protection.

  14. Reinstatement in a Cocaine vs. Food Choice Situation: Reversal of Preference between Drug and Non-Drug Rewards

    OpenAIRE

    Brendan J. Tunstall; Kearns, David N.

    2013-01-01

    Recent studies (for review see Ahmed, 2010; 2012) show that when given a mutually exclusive choice between cocaine and food, rats almost exclusively choose food. The present experiment investigated potential shifts in preference between levers associated with either food or cocaine which might occur during extinction (food and cocaine no longer available) and during footshock-induced, cocaine-primed, and food-primed reinstatement. During self-administration sessions where food and cocaine wer...

  15. Chronic administration of quercetin prevent spatial learning and memory deficits provoked by chronic stress in rats.

    Science.gov (United States)

    Mohammadi, Hadis Said; Goudarzi, Iran; Lashkarbolouki, Taghi; Abrari, Kataneh; Elahdadi Salmani, Mahmoud

    2014-08-15

    There are several reports that cognitive impairment is observed in stress related disorders and chronic stress impairs learning and memory. However, very few studies have looked into the possible ways of preventing this stress-induced deficit. This research study was conducted to evaluate the effects of quercetin, a natural flavonoid, with strong antioxidant and free radical scavenger properties, on chronic stress induced learning and memory deficits and oxidative stress in hippocampus. For chronic stress, rats were restrained daily for 6h/day (from 9:00 to 15:00) for 21 days in well-ventilated plexiglass tubes without access to food and water. The animals were injected with quercetin or vehicle 60 min before restraint stress over a period of 21 days. Then, rats trained with six trials per day for 6 consecutive days in the water maze. On day 28, a probe test was done to measure memory retention. In addition, oxidative stress markers in the hippocampus were evaluated. Results of this study demonstrated that chronic stress exposure rats exhibited higher escape latency during training trials and reduced time spent in target quadrant, higher escape location latency and average proximity in probe trial test. Quercetin (50mg/kg) treatment during restraint stress (21 days) markedly decreased escape latency and increased time spent in target quadrant during Morris water maze task. In comparison to vehicle treated group, chronic-stress group had significantly higher malondialdehyde (MDA) levels, significantly higher superoxide dismutase (SOD) activity and significantly lower glutathione peroxidase (GPx) activity in the hippocampus. Quercetin treatment caused a significant decrease in the hippocampus MDA levels and improves SOD and GPx activities in stressed animals. Finally, quercetin significantly decreased plasma corticosterone levels in stressed animals. Based on results of this study, chronic stress has detrimental effects on learning and memory and quercetin treatment

  16. Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: a histopathological study.

    Science.gov (United States)

    Zlatković, Jelena; Todorović, Nevena; Tomanović, Nada; Bošković, Maja; Djordjević, Snežana; Lazarević-Pašti, Tamara; Bernardi, Rick E; Djurdjević, Aleksandra; Filipović, Dragana

    2014-08-01

    Chronic exposure to stress contributes to the etiology of mood disorders, and the liver as a target organ of antidepressant and antipsychotic drug metabolism is vulnerable to drug-induced toxicity. We investigated the effects of chronic administration of fluoxetine (15mg/kg/day) or clozapine (20mg/kg/day) on liver injury via the measurement of liver enzymes, oxidative stress and histopathology in rats exposed to chronic social isolation (21days), an animal model of depression, and controls. The activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the liver content of carbonyl groups, malonyldialdehyde (MDA), reduced glutathione (GSH), cytosolic glutathione S-transferase (GST) and nitric oxide (NO) metabolites were determined. We also characterized nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2) and CuZn-superoxide dismutase (CuZnSOD) protein expression as well as histopathological changes. Increased serum ALT activity in chronically-isolated and control animals treated with both drugs was found while increased AST activity was observed only in fluoxetine-treated rats (chronically-isolated and controls). Increased carbonyl content, MDA, GST activity and decreased GSH levels in drug-treated controls/chronically-isolated animals suggest a link between drugs and hepatic oxidative stress. Increased NO levels associated with NF-κB activation and the concomitant increased COX-2 expression together with compromised CuZnSOD expression in clozapine-treated chronically-isolated rats likely reinforce oxidative stress, observed by increased lipid peroxidation and GSH depletion. In contrast, fluoxetine reduced NO levels in chronically-isolated rats. Isolation induced oxidative stress but histological changes were similar to those observed in vehicle-treated controls. Chronic administration of fluoxetine in both chronically-isolated and control animals resulted in more or less normal hepatic architecture, while clozapine in both groups

  17. Pathogenesis of nephrogenic diabetes insipidus due to chronic administration of lithium in rats.

    OpenAIRE

    S. Christensen; Kusano, E; Yusufi, A N; Murayama, N; Dousa, T P

    1985-01-01

    A polyuric syndrome with nephrogenic diabetes insipidus (NDI) is a frequent consequence of prolonged administration of lithium (Li) salts. Studies in the past, mainly the acute and in vitro experiments, indicated that Li ions can inhibit hydroosmotic effect of [8-arginine]vasopressin (AVP) at the step of cAMP generation in vitro. However, the pathogenesis of the NDI due to chronic oral administration of low therapeutic doses of Li salts is not yet clarified. We conducted a comprehensive study...

  18. Evaluation of Krebs cycle enzymes in the brain of rats after chronic administration of antidepressants.

    Science.gov (United States)

    Scaini, Giselli; Santos, Patricia M; Benedet, Joana; Rochi, Natália; Gomes, Lara M; Borges, Lislaine S; Rezin, Gislaine T; Pezente, Daiana P; Quevedo, João; Streck, Emilio L

    2010-05-31

    Several works report brain impairment of metabolism as a mechanism underlying depression. Citrate synthase and succinate dehydrogenase are enzymes localized within cells in the mitochondrial matrix and are important steps of Krebs cycle. In addition, citrate synthase has been used as a quantitative enzyme marker for the presence of intact mitochondria. Thus, we investigated citrate synthase and succinate dehydrogenase activities from rat brain after chronic administration of paroxetine, nortriptiline and venlafaxine. Adult male Wistar rats received daily injections of paroxetine (10mg/kg), nortriptiline (15mg/kg), venlafaxine (10mg/kg) or saline in 1.0mL/kg volume for 15 days. Twelve hours after the last administration, the rats were killed by decapitation, the hippocampus, striatum and prefrontal cortex were immediately removed, and activities of citrate synthase and succinate dehydrogenase were measured. We verified that chronic administration of paroxetine increased citrate synthase activity in the prefrontal cortex, hippocampus, striatum and cerebral cortex of adult rats; cerebellum was not affected. Chronic administration of nortriptiline and venlafaxine did not affect the enzyme activity in these brain areas. Succinate dehydrogenase activity was increased by chronic administration of paroxetine and nortriptiline in the prefrontal cortex, hippocampus, striatum and cerebral cortex of adult rats; cerebellum was not affected either. Chronic administration of venlafaxine increased succinate dehydrogenase activity in prefrontal cortex, but did not affect the enzyme activity in cerebellum, hippocampus, striatum and cerebral cortex. Considering that metabolism impairment is probably involved in the pathophysiology of depressive disorders, an increase in these enzymes by antidepressants may be an important mechanism of action of these drugs.

  19. Effects of chronic corticosterone and imipramine administration on panic and anxiety-related responses.

    Science.gov (United States)

    Diniz, L; Dos Reis, B B; de Castro, G M; Medalha, C C; Viana, M B

    2011-10-01

    It is known that chronic high levels of corticosterone (CORT) enhance aversive responses such as avoidance and contextual freezing. In contrast, chronic CORT does not alter defensive behavior induced by the exposure to a predator odor. Since different defense-related responses have been associated with specific anxiety disorders found in clinical settings, the observation that chronic CORT alters some defensive behaviors but not others might be relevant to the understanding of the neurobiology of anxiety. In the present study, we investigated the effects of chronic CORT administration (through surgical implantation of a 21-day release 200 mg pellet) on avoidance acquisition and escape expression by male Wistar rats (200 g in weight at the beginning of the experiments, N = 6-10/group) tested in the elevated T-maze (ETM). These defensive behaviors have been associated with generalized anxiety and panic disorder, respectively. Since the tricyclic antidepressant imipramine is successfully used to treat both conditions, the effects of combined treatment with chronic imipramine (15 mg, ip) and CORT were also investigated. Results showed that chronic CORT facilitated avoidance performance, an anxiogenic-like effect (P Imipramine significantly reversed the anxiogenic effect of CORT (P imipramine inhibited escape responses, a panicolytic-like effect. Unlike chronic CORT, imipramine also decreased locomotor activity in an open field. These data suggest that chronic CORT specifically altered ETM avoidance, a fact that should be relevant to a better understanding of the physiopathology of generalized anxiety and panic disorder.

  20. Cocaine and automaintained responding in pigeons: rate-reducing effects and tolerance thereto with different durations of food delivery.

    Science.gov (United States)

    Durgin, Amy; Porter, Lindsay K; Bradley, Kelly P; Laraway, Sean; Poling, Alan

    2009-10-01

    Pigeons were exposed to an automaintenance procedure in which 6-s key illuminations in one color (red or white) were immediately followed by 3-s food deliveries and key illuminations in the other color were followed by 9-s food deliveries. Both conditions engendered consistent responding. With both durations of food delivery, acute and chronic cocaine administrations (1.0-17.8 mg/kg) produced dose-dependent decreases in mean percent trials (key illuminations) with a response and mean total response per session. Tolerance developed to the disruptive effects of cocaine on both response measures. Food duration did not significantly affect either response measure or significantly interact with cocaine dose or drug regimen. The orderliness of the present findings, like those of a related study examining whether probability of food delivery modulated the effects of cocaine on automaintained responding [Porritt, M., Arnold, M., Poling, A., Cocaine and automaintained responding in pigeons: rate-reducing effects and tolerance thereto with different CS-US pairing probabilities. Pharmacol Biochem Behav 2007; 87:405-411.], suggests that the automaintenance procedure is a useful assay for examining tolerance to drug effects on classically-conditioned responding. Unlike the results of that study, however, the present findings are inconsistent with a behavioral momentum analysis of drug effects on such responding.

  1. Dopamine D3 Receptor Antagonist (GSK598809) Potentiates the Hypertensive Effects of Cocaine in Conscious, Freely-Moving Dogs.

    Science.gov (United States)

    Appel, Nathan M; Li, Shou-Hua; Holmes, Tyson H; Acri, Jane B

    2015-09-01

    The chronic and relapsing nature of addiction presents unique challenges for ensuring the safety of a potential medication. A patient may use cocaine, for example, while taking the medication or take more medication than prescribed. Thus, a potential medication must be safe and not exacerbate the effects of cocaine. Multiple published studies support antagonism of brain dopamine D3 receptor function as a potential mechanism of action for an anti-addiction medication. Dopamine D3 receptors are widely distributed outside the central nervous system, however; for example, dopamine D3 receptors in the kidneys are implicated in regulating blood pressure. The selective dopamine D3 receptor antagonist GSK598809 [1-(2-fluoro-4-trifluoromethyl-phenyl)-3-{3-[4-methyl-5-(4-methyl-oxazol-5-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-propyl}-3-aza-bicyclo[3.1.0]hexane] has been proposed as a medication to treat cocaine and other substance use disorders. The US Food and Drug Administration has established guidelines recommending safety studies to investigate potential undesirable pharmacodynamic effects of a substance in relation to exposure in the therapeutic range and above. Hence, we assessed the interaction between this selective dopamine D3 receptor antagonist and cocaine on hemodynamics and cardiac function in freely-moving, telemetered dogs before conducting a clinical trial. GSK598809 increased the hemodynamic effect of cocaine in this model. Thus, the increase in blood pressure after intravenous cocaine was greater in animals that had been pretreated with GSK598809 compared with vehicle. This finding suggests that GSK598809 in particular, and perhaps dopamine D3 receptor antagonists as a class, may produce unacceptable cardiovascular risks as medications to treat cocaine use disorder.

  2. The role of ventral and dorsal striatum mGluR5 in relapse to cocaine-seeking and extinction learning.

    Science.gov (United States)

    Knackstedt, Lori A; Trantham-Davidson, Heather L; Schwendt, Marek

    2014-01-01

    Cocaine addiction is a chronic, relapsing disease characterized by an inability to regulate drug-seeking behavior. Here we investigated the role of mGluR5 in the ventral and dorsal striatum in regulating cocaine-seeking following both abstinence and extinction. Animals underwent 2 weeks of cocaine self-administration followed by 3 weeks of home-cage abstinence. Animals were then reintroduced to the operant chamber for a context-induced relapse test, followed by 7-10 days of extinction training. Once responding was extinguished, cue-primed reinstatement test was conducted. Both drug-seeking tests were conducted in the presence of either mGluR5 negative allosteric modulator, MTEP or vehicle infused into either the nucleus accumbens (NA) core or dorsolateral striatum (dSTR). We found that MTEP infused in the NA core attenuated both context-induced relapse following abstinence and cue-primed reinstatement following extinction training. Blocking dSTR mGluR5 had no effect on context- or cue-induced cocaine-seeking. However, the intra-dSTR MTEP infusion on the context-induced relapse test day attenuated extinction learning for 4 days after the infusion. Furthermore, mGluR5 surface expression was reduced and LTD was absent in dSTR slices of animals undergoing 3 weeks of abstinence from cocaine but not sucrose self-administration. LTD was restored by bath application of VU-29, a positive allosteric modulator of mGluR5. Bath application of MTEP prevented the induction of LTD in dSTR slices from sucrose animals. Taken together, this data indicates that dSTR mGluR5 plays an essential role in extinction learning but not cocaine relapse, while NA core mGluR5 modulates drug-seeking following both extinction and abstinence from cocaine self-administration.

  3. Activin receptor signaling regulates cocaine-primed behavioral and morphological plasticity.

    Science.gov (United States)

    Gancarz, Amy M; Wang, Zi-Jun; Schroeder, Gabrielle L; Damez-Werno, Diane; Braunscheidel, Kevin M; Mueller, Lauren E; Humby, Monica S; Caccamise, Aaron; Martin, Jennifer A; Dietz, Karen C; Neve, Rachael L; Dietz, David M

    2015-07-01

    Activin receptor signaling, including the transcription factor Smad3, was upregulated in the rat nucleus accumbens (NAc) shell following withdrawal from cocaine. Direct genetic and pharmacological manipulations of this pathway bidirectionally altered cocaine seeking while governing morphological plasticity in NAc neurons. Thus, Activin/Smad3 signaling is induced following withdrawal from cocaine, and such regulation may be a key molecular mechanism underlying behavioral and cellular plasticity in the brain following cocaine self-administration.

  4. Psychostimulant-Induced Testicular Toxicity in Mice: Evidence of Cocaine and Caffeine Effects on the Local Dopaminergic System.

    Directory of Open Access Journals (Sweden)

    Candela R González

    Full Text Available Several organ systems can be affected by psychostimulant toxicity. However, there is not sufficient evidence about the impact of psychostimulant intake on testicular physiology and catecholaminergic systems. The aim of the present study was to further explore potential toxic consequences of chronic exposure to cocaine, caffeine, and their combination on testicular physiology. Mice were injected with a 13-day chronic binge regimen of caffeine (3x5mg/kg, cocaine (3×10mg/kg, or combined administration. Mice treated with cocaine alone or combined with caffeine showed reduced volume of the seminiferous tubule associated to a reduction in the number of spermatogonia. Cocaine-only and combined treatments induced increased lipid peroxidation evaluated by TBARS assay and decreased glutathione peroxidase mRNA expression. Importantly, caffeine-cocaine combination potentiated the cocaine-induced germ cell loss, and induced pro-apoptotic BAX protein expression and diminished adenosine receptor A1 mRNA levels. We analyzed markers of dopaminergic function in the testis and detected the presence of tyrosine hydroxylase (TH in the cytoplasm of androgen-producing Leydig cells, but also in meiotic germs cells within seminiferous tubules. Moreover, using transgenic BAC-Drd1a-tdTomato and D2R-eGFP mice, we report for the first time the presence of dopamine receptors (DRs D1 and D2 in testicular mouse Leydig cells. Interestingly, the presence of DRD1 was also detected in the spermatogonia nearest the basal lamina of the seminiferous tubules, which did not show TH staining. We observed that psychostimulants induced downregulation of DRs mRNA expression and upregulation of TH protein expression in the testis. These findings suggest a potential role of the local dopaminergic system in psychostimulant-induced testicular pathology.

  5. Evidence for habitual and goal-directed behavior following devaluation of cocaine: a multifaceted interpretation of relapse.

    Directory of Open Access Journals (Sweden)

    David H Root

    Full Text Available BACKGROUND: Cocaine addiction is characterized as a chronically relapsing disorder. It is believed that cues present during self-administration become learned and increase the probability that relapse will occur when they are confronted during abstinence. However, the way in which relapse-inducing cues are interpreted by the user has remained elusive. Recent theories of addiction posit that relapse-inducing cues cause relapse habitually or automatically, bypassing processing information related to the consequences of relapse. Alternatively, other theories hypothesize that relapse-inducing cues produce an expectation of the drug's consequences, designated as goal-directed relapse. Discrete discriminative stimuli signaling the availability of cocaine produce robust cue-induced responding after thirty days of abstinence. However, it is not known whether cue-induced responding is a goal-directed action or habit. METHODOLOGY/PRINCIPAL FINDINGS: We tested whether cue-induced responding is a goal-directed action or habit by explicitly pairing or unpairing cocaine with LiCl-induced sickness (n = 7/group, thereby decreasing or not altering the value of cocaine, respectively. Following thirty days of abstinence, no difference in responding between groups was found when animals were reintroduced to the self-administration environment alone, indicating habitual behavior. However, upon discriminative stimulus presentations, cocaine-sickness paired animals exhibited decreased cue-induced responding relative to unpaired controls, indicating goal-directed behavior. In spite of the difference between groups revealed during abstinent testing, no differences were found between groups when animals were under the influence of cocaine. CONCLUSIONS/SIGNIFICANCE: Unexpectedly, both habitual and goal-directed responding occurred during abstinent testing. Furthermore, habitual or goal-directed responding may have been induced by cues that differed in their correlation

  6. Prepubertal chronic stress and ketamine administration to rats as a neurodevelopmental model of schizophrenia symptomatology.

    Science.gov (United States)

    Ram, Edward; Raphaeli, Shani; Avital, Avi

    2013-11-01

    Increased vulnerability to psychiatric disorders, such as schizophrenia, has been associated with higher levels of stress. In the early development of the central nervous system, changes in function of glutamatergic N-Methyl-D-aspartate (NMDA) receptors can possibly result in the development of psychosis, cognitive impairment and emotional dysfunction in adulthood. Thus, in this study we examined the behavioural consequences of the exposure of male rats to chronic stress (postnatal days 30-60) and ketamine administration (postnatal days 41-45); both during a sensitive developmental time window. We found that the locomotor activity of both ketamine and ketamine+chronic stress groups was significantly higher compared with that of the control rats. In contrast, the locomotor activity of the chronic stress group was significantly lower compared with all other groups. Examining anhedonia in the sucrose preference test we found a significantly decreased sucrose intake in both ketamine+chronic stress and the chronic stress groups compared with the control rats. No significant differences were observed in sucrose intake between the control and the ketamine group. The object recognition test revealed that the attention to the novel object was significantly impaired in the ketamine+chronic stress group. Similarly, the ketamine+chronic stress group showed the poorest learning ability in the eight-arm radial maze, starting on the 8th day. Finally, throughout the different pre-pulse intensities, the ketamine+chronic stress group showed impaired PPI compared with all other groups. The results indicate that the combination of prepubertal onset of chronic stress and ketamine may serve as a valid novel animal model for schizophrenia-like symptoms.

  7. A case of chronic progressive radiation myelopathy treated with long-time corticosteroid administration

    Energy Technology Data Exchange (ETDEWEB)

    Hirota, Saeko; Soejima, Toshinori; Higashino, Takanori; Obayashi, Kayoko; Takada, Yoshiki [Hyogo Medical Center for Adults, Akashi (Japan); Hishikawa, Yoshio

    1998-05-01

    This is a report of one patient who developed chronic progressive radiation myelopathy at a gap of two portals 31 months after 40 Gy irradiation. He presented an unusual clinical course with over 5 years and 6 months administration of oral corticosteroid, very slow progression and long-lasting presentation of Gd-DTPA enhanced area in the suffered cord by MRI. It is suggested that corticosteroid administration from initial onset for a long period may change the natural course of radiation myelopathy, that is, may delay progress of it. (author)

  8. 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.

  9. Oral administration of synthetic human urogastrone promotes healing of chronic duodenal ulcers in rats

    DEFF Research Database (Denmark)

    Poulsen, Steen Seier; Nexø, Ebba

    1986-01-01

    The effect of oral administration of synthetic human epidermal growth factor/urogastrone (EGF/URO) on healing of chronic duodenal ulcers induced by cysteamine in rats was investigated and compared with that of cimetidine, a H2-receptor antagonist. After 25 and 50 days of treatment, synthetic human...... EGF/URO significantly increased healing of chronic duodenal ulcers to the same extent as cimetidine. Combined treatment with synthetic human EGF/URO and cimetidine for 25 days was more effective than synthetic human EGF/URO given alone, whereas combined treatment for 50 days was significantly more...... effective than cimetidine alone. These results show that a combination of an agent inhibiting gastric acid secretion and the cytoprotective and growth-stimulating peptide EGF/URO seems to be more effective with regard to duodenal ulcer healing than individual administration of the two substances. Synthetic...

  10. Effects of chronic corticosterone and imipramine administration on panic and anxiety-related responses

    Directory of Open Access Journals (Sweden)

    L. Diniz

    2011-10-01

    Full Text Available It is known that chronic high levels of corticosterone (CORT enhance aversive responses such as avoidance and contextual freezing. In contrast, chronic CORT does not alter defensive behavior induced by the exposure to a predator odor. Since different defense-related responses have been associated with specific anxiety disorders found in clinical settings, the observation that chronic CORT alters some defensive behaviors but not others might be relevant to the understanding of the neurobiology of anxiety. In the present study, we investigated the effects of chronic CORT administration (through surgical implantation of a 21-day release 200 mg pellet on avoidance acquisition and escape expression by male Wistar rats (200 g in weight at the beginning of the experiments, N = 6-10/group tested in the elevated T-maze (ETM. These defensive behaviors have been associated with generalized anxiety and panic disorder, respectively. Since the tricyclic antidepressant imipramine is successfully used to treat both conditions, the effects of combined treatment with chronic imipramine (15 mg, ip and CORT were also investigated. Results showed that chronic CORT facilitated avoidance performance, an anxiogenic-like effect (P < 0.05, without changing escape responses. Imipramine significantly reversed the anxiogenic effect of CORT (P < 0.05, although the drug did not exhibit anxiolytic effects by itself. Confirming previous observations, imipramine inhibited escape responses, a panicolytic-like effect. Unlike chronic CORT, imipramine also decreased locomotor activity in an open field. These data suggest that chronic CORT specifically altered ETM avoidance, a fact that should be relevant to a better understanding of the physiopathology of generalized anxiety and panic disorder.

  11. [The role of chronic gastritis in past medical history with NSAID administration in patients with osteoarthrosis].

    Science.gov (United States)

    Zak, M Iu

    2014-11-01

    122 patients with osteoarthrosis, who have in the past medical history verified chronic gastritis (50 males and 72 females) at the age from 42 to 64 have been examined. Control group was comprised of 40 patients with osteoarthrosis without gastroduodenal zone pathology in the past medical history. For arthralgia relief patients were prescribed meloxicam (average dose--12.5 - 1.39 mg daily) or nimesulide (average dose--150 ± 14.91 mg daily). As a result of this research it was determined that administration of selective NSAID (meloxicam and nimesulide) in patients with chronic gastritis in the past medical history raised the risk of NSAID gastropathy/dyspepsia 2.9 times (P 0.05) of erosive gastropathy. Patients with chronic gastritis in the past medical history when taking NSAID with the purpose of gastropathy prevention are recommended to undergo gastroprotective therapy.

  12. Oral administration of aflatoxin G₁ induces chronic alveolar inflammation associated with lung tumorigenesis.

    Science.gov (United States)

    Liu, Chunping; Shen, Haitao; Yi, Li; Shao, Peilu; Soulika, Athena M; Meng, Xinxing; Xing, Lingxiao; Yan, Xia; Zhang, Xianghong

    2015-02-03

    Our previous studies showed oral gavage of aflatoxin G₁ (AFG₁) induced lung adenocarcinoma in NIH mice. We recently found that a single intratracheal administration of AFG₁ caused chronic inflammatory changes in rat alveolar septum. Here, we examine whether oral gavage of AFG₁ induces chronic lung inflammation and how it contributes to carcinogenesis. We evaluated chronic lung inflammatory responses in Balb/c mice after oral gavage of AFG₁ for 1, 3 and 6 months. Inflammatory responses were heightened in the lung alveolar septum, 3 and 6 months after AFG₁ treatment, evidenced by increased macrophages and lymphocytes infiltration, up-regulation of NF-κB and p-STAT3, and cytokines production. High expression levels of superoxide dismutase (SOD-2) and hemoxygenase-1 (HO-1), two established markers of oxidative stress, were detected in alveolar epithelium of AFG₁-treated mice. Promoted alveolar type II cell (AT-II) proliferation in alveolar epithelium and angiogenesis, as well as increased COX-2 expression were also observed in lung tissues of AFG₁-treated mice. Furthermore, we prolonged survival of the mice in the above model for another 6 months to examine the contribution of AFG₁-induced chronic inflammation to lung tumorigenesis. Twelve months later, we observed that AFG₁ induced alveolar epithelial hyperplasia and adenocarcinoma in Balb/c mice. Up-regulation of NF-κB, p-STAT3, and COX-2 was also induced in lung adenocarcinoma, thus establishing a link between AFG₁-induced chronic inflammation and lung tumorigenesis. This is the first study to show that oral administration of AFG₁ could induce chronic lung inflammation, which may provide a pro-tumor microenvironment to contribute to lung tumorigenesis.

  13. Chronic central administration of Ghrelin increases bone mass through a mechanism independent of appetite regulation.

    Directory of Open Access Journals (Sweden)

    Hyung Jin Choi

    Full Text Available Leptin plays a critical role in the central regulation of bone mass. Ghrelin counteracts leptin. In this study, we investigated the effect of chronic intracerebroventricular administration of ghrelin on bone mass in Sprague-Dawley rats (1.5 μg/day for 21 days. Rats were divided into control, ghrelin ad libitum-fed (ghrelin ad lib-fed, and ghrelin pair-fed groups. Ghrelin intracerebroventricular infusion significantly increased body weight in ghrelin ad lib-fed rats but not in ghrelin pair-fed rats, as compared with control rats. Chronic intracerebroventricular ghrelin infusion significantly increased bone mass in the ghrelin pair-fed group compared with control as indicated by increased bone volume percentage, trabecular thickness, trabecular number and volumetric bone mineral density in tibia trabecular bone. There was no significant difference in trabecular bone mass between the control group and the ghrelin ad-lib fed group. Chronic intracerebroventricular ghrelin infusion significantly increased the mineral apposition rate in the ghrelin pair-fed group as compared with control. In conclusion, chronic central administration of ghrelin increases bone mass through a mechanism that is independent of body weight, suggesting that ghrelin may have a bone anabolic effect through the central nervous system.

  14. Action of a chronic administration of mescaline in dynamic behavioural situations.

    Science.gov (United States)

    Fundaro', A; Molinengo, L; Cassone, M C; Orsetti, M

    1986-01-01

    The modifications of the rat behaviour caused by a chronic administration of mescaline were studied in two schedules of operant conditioning. In the "periodic conditioning" test, the schedule of reinforcement was changed from a fixed ratio to a fixed interval schedule. Mescaline (4 mg/kg/day and 10 mg/kg/day) caused no modification of the ability of the rat to adapt its behaviour to the new experimental situation. In the "reversal test" the contingency for food delivery was switched from one lever, where responses were previously reinforced to the other lever where responses had no programmed consequences. A chronic administration of mescaline (4 mg/kg/day) caused a total incapacity of the rat to switch to the lever which became reinforced in the reversal trial. A chronic administration of 9 mg/kg/day of mescaline had an excitatory effect and the number of reinforced responses in the II and III reversals exceeded the unreinforced responses in a measure greater than in the controls.

  15. Disrupted Functional Connectivity with Dopaminergic Midbrain in Cocaine Abusers

    Energy Technology Data Exchange (ETDEWEB)

    Tomasi, D.; Tomasi, D.; Volkow, N.D.; Wang, R.; Carrillo, J.; Maloney, T.; Alia-Klein, N.; Woicik, P.A.; Telang, F.; Goldstein, R.Z.

    2010-06-01

    Chronic cocaine use is associated with disrupted dopaminergic neurotransmission but how this disruption affects overall brain function (other than reward/motivation) is yet to be fully investigated. Here we test the hypothesis that cocaine addicted subjects will have disrupted functional connectivity between the midbrain (where dopamine neurons are located) and cortical and subcortical brain regions during the performance of a sustained attention task. We measured brain activation and functional connectivity with fMRI in 20 cocaine abusers and 20 matched controls. When compared to controls, cocaine abusers had lower positive functional connectivity of midbrain with thalamus, cerebellum, and rostral cingulate, and this was associated with decreased activation in thalamus and cerebellum and enhanced deactivation in rostral cingulate. These findings suggest that decreased functional connectivity of the midbrain interferes with the activation and deactivation signals associated with sustained attention in cocaine addicts.

  16. An animal model of schizophrenia based on chronic LSD administration: old idea, new results.

    Science.gov (United States)

    Marona-Lewicka, Danuta; Nichols, Charles D; Nichols, David E

    2011-09-01

    Many people who take LSD experience a second temporal phase of LSD intoxication that is qualitatively different, and was described by Daniel Freedman as "clearly a paranoid state." We have previously shown that the discriminative stimulus effects of LSD in rats also occur in two temporal phases, with initial effects mediated by activation of 5-HT(2A) receptors (LSD30), and the later temporal phase mediated by dopamine D2-like receptors (LSD90). Surprisingly, we have now found that non-competitive NMDA antagonists produced full substitution in LSD90 rats, but only in older animals, whereas in LSD30, or in younger animals, these drugs did not mimic LSD. Chronic administration of low doses of LSD (>3 months, 0.16 mg/kg every other day) induces a behavioral state characterized by hyperactivity and hyperirritability, increased locomotor activity, anhedonia, and impairment in social interaction that persists at the same magnitude for at least three months after cessation of LSD treatment. These behaviors, which closely resemble those associated with psychosis in humans, are not induced by withdrawal from LSD; rather, they are the result of neuroadaptive changes occurring in the brain during the chronic administration of LSD. These persistent behaviors are transiently reversed by haloperidol and olanzapine, but are insensitive to MDL-100907. Gene expression analysis data show that chronic LSD treatment produced significant changes in multiple neurotransmitter system-related genes, including those for serotonin and dopamine. Thus, we propose that chronic treatment of rats with low doses of LSD can serve as a new animal model of psychosis that may mimic the development and progression of schizophrenia, as well as model the established disease better than current acute drug administration models utilizing amphetamine or NMDA antagonists such as PCP.

  17. Suppression of activity-regulated cytoskeleton-associated gene expression in the dorsal striatum attenuates extinction of cocaine-seeking.

    Science.gov (United States)

    Hearing, Matthew C; Schwendt, Marek; McGinty, Jacqueline F

    2011-07-01

    The caudate putamen (CPu) has been implicated in habit learning and neuroadaptive changes that mediate the compulsive nature of drug-seeking following chronic cocaine self-administration. Re-exposure to an operant chamber previously associated with cocaine, but not yoked-saline, increases activity-regulated cytoskeleton-associated (Arc) gene mRNA expression within the dorsolateral (dl) CPu following prolonged abstinence. In this study, we tested the hypothesis that antisense gene knockdown of Arc within the dlCPu would alter cocaine-seeking. Initial studies showed that a single infusion of Arc antisense oligodeoxynucleotide (ODN) into the dlCPu significantly attenuated the induction of Arc mRNA and Arc protein by a single cocaine exposure (20 mg/kg i.p.) compared to scrambled-ODN-infused controls. In cocaine self-administering rats, infusion of Arc antisense ODN into the dlCPu 3 h prior to a test of context-driven drug-seeking significantly attenuated Arc protein induction, but failed to alter responding during testing, suggesting striatal Arc does not facilitate context-induced drug-seeking following prolonged abstinence. However, Arc antisense ODN infusion blunted the decrease in responding during subsequent 1-h extinction tests 24 and 48 h later. Following re-exposure to a cocaine-paired context, surface expression of the AMPA-type glutamate receptor GluR1 was significantly reduced whereas GluR2 was significantly increased in the dlCPu, independent of Arc antisense ODN infusion. Together, these findings indicate an important role for Arc in neuroadaptations within brain regions responsible for drug-seeking after abstinence and direct attention to changes occurring within striatal circuitry that are necessary to break down the habitual behaviour that leads to relapse.

  18. [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.

  19. A Thermally Stable Form of Bacterial Cocaine Esterase: A Potential Therapeutic Agent for Treatment of Cocaine Abuse

    Energy Technology Data Exchange (ETDEWEB)

    Brim, Remy L.; Nance, Mark R.; Youngstrom, Daniel W.; Narasimhan, Diwahar; Zhan, Chang-Guo; Tesmer, John J.G.; Sunahara, Roger K.; Woods, James H. (Michigan); (Michigan-Med); (Kentucky)

    2010-09-03

    Rhodococcal cocaine esterase (CocE) is an attractive potential treatment for both cocaine overdose and cocaine addiction. CocE directly degrades cocaine into inactive products, whereas traditional small-molecule approaches require blockade of the inhibitory action of cocaine on a diverse array of monoamine transporters and ion channels. The usefulness of wild-type (wt) cocaine esterase is hampered by its inactivation at 37 C. Herein, we characterize the most thermostable form of this enzyme to date, CocE-L169K/G173Q. In vitro kinetic analyses reveal that CocE-L169K/G173Q displays a half-life of 2.9 days at 37 C, which represents a 340-fold improvement over wt and is 15-fold greater than previously reported mutants. Crystallographic analyses of CocE-L169K/G173Q, determined at 1.6-{angstrom} resolution, suggest that stabilization involves enhanced domain-domain interactions involving van der Waals interactions and hydrogen bonding. In vivo rodent studies reveal that intravenous pretreatment with CocE-L169K/G173Q in mice provides protection from cocaine-induced lethality for longer time periods before cocaine administration than wt CocE. Furthermore, intravenous administration (pretreatment) of CocE-L169K/G173Q prevents self-administration of cocaine in a time-dependent manner. Termination of the in vivo effects of CoCE seems to be dependent on, but not proportional to, its clearance from plasma as its half-life is approximately 2.3 h and similar to that of wt CocE (2.2 h). Taken together these data suggest that CocE-L169K/G173Q possesses many of the properties of a biological therapeutic for treating cocaine abuse but requires additional development to improve its serum half-life.

  20. Brain injury markers (S100B and NSE in chronic cocaine dependents Marcadores de lesão cerebral (S100B e NSE em dependentes crônicos de cocaína

    Directory of Open Access Journals (Sweden)

    Felix Henrique Paim Kessler

    2007-06-01

    Full Text Available OBJECTIVE: Studies have shown signs of brain damage caused by different mechanisms in cocaine users. The serum neuron specific enolase and S100B protein are considered specific biochemical markers of neuronal and glial cell injury. This study aimed at comparing blood levels of S100B and NSE in chronic cocaine users and in volunteers who did not use cocaine or other illicit drugs. METHOD: Twenty subjects dependent on cocaine but not on alcohol or marijuana, and 20 non-substance using controls were recruited. Subjects were selected by consecutive and non-probabilistic sampling. Neuron specific enolase and S100B levels were determined by luminescence assay. RESULTS: Cocaine users had significantly higher scores than controls in all psychiatric dimensions of the SCL-90 and had cognitive deficits in the subtest cubes of WAIS and the word span. Mean serum S100B level was 0.09 ± 0.04 µg/l among cocaine users and 0.08 ± 0.04 µg/l among controls. Mean serum neuron specific enolase level was 9.7 ± 3.5 ng/l among cocaine users and 8.3 ± 2.6 ng/l among controls. CONCLUSIONS: In this first study using these specific brain damage markers in cocaine users, serum levels of S100B and neuron specific enolase were not statistically different between cocaine dependent subjects and controls.OBJETIVO: Estudos têm demonstrado sinais de lesão cerebral causadas por diferentes mecanismos em usuários de cocaína. A enolase sérica neurônio-específica e a proteína S100B são consideradas marcadores bioquímicos específicos de lesão neuronal e glial. Este estudo objetivou comparar os níveis sangüíneos de S100B e enolase sérica neurônio-específica em usuários crônicos de cocaína e em voluntários que não usam cocaína ou outras drogas ilícitas. MÉTODO: Vinte sujeitos dependentes de cocaína, mas não dependentes de álcool, maconha ou outra droga, e 20 sujeitos controles não usuários de drogas foram recrutados. Os sujeitos foram selecionados por

  1. Prophylactic Chronic Zinc Administration Increases Neuroinflammation in a Hypoxia-Ischemia Model

    Directory of Open Access Journals (Sweden)

    Constantino Tomas-Sanchez

    2016-01-01

    Full Text Available Acute and subacute administration of zinc exert neuroprotective effects in hypoxia-ischemia animal models; yet the effect of chronic administration of zinc still remains unknown. We addressed this issue by injecting zinc at a tolerable dose (0.5 mg/kg weight, i.p. for 14 days before common carotid artery occlusion (CCAO in a rat. After CCAO, the level of zinc was measured by atomic absorption spectrophotometry, nitrites were determined by Griess method, lipoperoxidation was measured by Gerard-Monnier assay, and mRNA expression of 84 genes coding for cytokines, chemokines, and their receptors was measured by qRT-PCR, whereas nitrotyrosine, chemokines, and their receptors were assessed by ELISA and histopathological changes in the temporoparietal cortex-hippocampus at different time points. Long-term memory was evaluated using Morris water maze. Following CCAO, a significant increase in nitrosative stress, inflammatory chemokines/receptors, and cell death was observed after 8 h, and a 2.5-fold increase in zinc levels was detected after 7 days. Although CXCL12 and FGF2 protein levels were significantly increased, the long-term memory was impaired 12 days after reperfusion in the Zn+CCAO group. Our data suggest that the chronic administration of zinc at tolerable doses causes nitrosative stress, toxic zinc accumulation, and neuroinflammation, which might account for the neuronal death and cerebral dysfunction after CCAO.

  2. Prophylactic Chronic Zinc Administration Increases Neuroinflammation in a Hypoxia-Ischemia Model

    Science.gov (United States)

    Tomas-Sanchez, Constantino; Blanco-Alvarez, Victor Manuel; Gonzalez-Barrios, Juan Antonio; Martinez-Fong, Daniel; Garcia-Robles, Guadalupe; Soto-Rodriguez, Guadalupe; Torres-Soto, Maricela; Gonzalez-Vazquez, Alejandro; Aguilar-Peralta, Ana Karina; Garate-Morales, José-Luis; Aguilar-Carrasco, Luis-Angel; Limón, Daniel I.; Cebada, Jorge

    2016-01-01

    Acute and subacute administration of zinc exert neuroprotective effects in hypoxia-ischemia animal models; yet the effect of chronic administration of zinc still remains unknown. We addressed this issue by injecting zinc at a tolerable dose (0.5 mg/kg weight, i.p.) for 14 days before common carotid artery occlusion (CCAO) in a rat. After CCAO, the level of zinc was measured by atomic absorption spectrophotometry, nitrites were determined by Griess method, lipoperoxidation was measured by Gerard-Monnier assay, and mRNA expression of 84 genes coding for cytokines, chemokines, and their receptors was measured by qRT-PCR, whereas nitrotyrosine, chemokines, and their receptors were assessed by ELISA and histopathological changes in the temporoparietal cortex-hippocampus at different time points. Long-term memory was evaluated using Morris water maze. Following CCAO, a significant increase in nitrosative stress, inflammatory chemokines/receptors, and cell death was observed after 8 h, and a 2.5-fold increase in zinc levels was detected after 7 days. Although CXCL12 and FGF2 protein levels were significantly increased, the long-term memory was impaired 12 days after reperfusion in the Zn+CCAO group. Our data suggest that the chronic administration of zinc at tolerable doses causes nitrosative stress, toxic zinc accumulation, and neuroinflammation, which might account for the neuronal death and cerebral dysfunction after CCAO. PMID:27635404

  3. Mapping cocaine binding sites in human and baboon brain in vivo.

    Science.gov (United States)

    Fowler, J S; Volkow, N D; Wolf, A P; Dewey, S L; Schlyer, D J; Macgregor, R R; Hitzemann, R; Logan, J; Bendriem, B; Gatley, S J

    1989-01-01

    The first direct measurements of cocaine binding in the brain of normal human volunteers and baboons have been made by using positron emission tomography (PET) and tracer doses of [N-11C-methyl]-(-)-cocaine ([11C]cocaine). Cocaine's binding and release from brain are rapid with the highest regional uptake of carbon-11 occurring in the corpus striatum at 4-10 minutes after intravenous injection of labeled cocaine. This was followed by a clearance to half the peak value at about 25 minutes with the overall time course paralleling the previously documented time course of the euphoria experienced after intravenous cocaine administration. Blockade of the dopamine reuptake sites with nomifensine reduced the striatal but not the cerebellar uptake of [11C]cocaine in baboons indicating that cocaine binding is associated with the dopamine reuptake site in the corpus striatum. A comparison of labeled metabolites of cocaine in human and baboon plasma showed that while cocaine is rapidly metabolized in both species, the profile of labeled metabolites is different, with baboon plasma containing significant amounts of labeled carbon dioxide, and human plasma containing no significant labeled carbon dioxide. These studies demonstrate the feasibility of using [11C]cocaine and PET to map binding sites for cocaine in human brain, to monitor its kinetics, and to characterize its binding mechanism by using appropriate pharmacological challenges.

  4. Elevated dopamine in the medial prefrontal cortex suppresses cocaine seeking via D1 receptor overstimulation.

    Science.gov (United States)

    Devoto, Paola; Fattore, Liana; Antinori, Silvia; Saba, Pierluigi; Frau, Roberto; Fratta, Walter; Gessa, Gian Luigi

    2016-01-01

    Previous investigations indicate that the dopamine-β-hydroxylase (DBH) inhibitors disulfiram and nepicastat suppress cocaine-primed reinstatement of cocaine self-administration behaviour. Moreover, both inhibitors increase dopamine release in the rat medial prefrontal cortex (mPFC) and markedly potentiate cocaine-induced dopamine release in this region. This study was aimed to clarify if the suppressant effect of DBH inhibitors on cocaine reinstatement was mediated by the high extracellular dopamine in the rat mPFC leading to a supra-maximal stimulation of D1 receptors in the dorsal division of mPFC, an area critical for reinstatement of cocaine-seeking behaviour. In line with previous microdialysis studies in drug-naïve animals, both DBH inhibitors potentiated cocaine-induced dopamine release in the mPFC, in the same animals in which they also suppressed reinstatement of cocaine seeking. Similar to the DBH inhibitors, L-DOPA potentiated cocaine-induced dopamine release in the mPFC and suppressed cocaine-induced reinstatement of cocaine-seeking behaviour. The bilateral microinfusion of the D1 receptor antagonist SCH 23390 into the dorsal mPFC not only prevented cocaine-induced reinstatement of cocaine seeking but also reverted both disulfiram- and L-DOPA-induced suppression of reinstatement. Moreover, the bilateral microinfusion of the D1 receptor agonist chloro-APB (SKF 82958) into the dorsal mPFC markedly attenuated cocaine-induced reinstatement of cocaine seeking. These results suggest that stimulation of D1 receptors in the dorsal mPFC plays a crucial role in cocaine-induced reinstatement of cocaine seeking, whereas the suppressant effect of DBH inhibitors and L-DOPA on drug-induced reinstatement is mediated by a supra-maximal stimulation of D1 receptors leading to their inactivation.

  5. Hypocretin-1 receptors regulate the reinforcing and reward-enhancing effects of cocaine: Pharmacological and behavioral genetics evidence

    Directory of Open Access Journals (Sweden)

    Jonathan eHollander

    2012-07-01

    Full Text Available Considerable evidence suggests that transmission at hypocretin-1 (orexin-1 receptors (Hcrt-R1 plays an important role in the reinstatement of extinguished cocaine-seeking behaviors in rodents. However, far less is known about the role for hypocretin transmission in regulating ongoing cocaine-taking behavior. Here, we investigated the effects of the selective Hcrt-R1 antagonist SB-334867 on cocaine intake, as measured by intravenous (IV cocaine self-administration in rats. The stimulatory effects of cocaine on brain reward systems contribute to the establishment and maintenance of cocaine-taking behaviors. Therefore, we also assessed the effects of SB-334867 on the reward-enhancing properties of cocaine, as measured by cocaine-induced lowering of intracranial self-stimulation (ICSS thresholds. Finally, to definitively establish a role for Hcrt-R1 in regulating cocaine intake, we assessed IV cocaine self-administration in Hcrt-R1 knockout mice. We found that SB-334867 (1-4 mg/kg dose-dependently decreased cocaine (0.5 mg/kg/infusion self-administration in rats but did not alter responding for food rewards under the same schedule of reinforcement. This suggests that SB-334867 decreased cocaine reinforcement without negatively impacting operant performance. SB-334867 (1-4 mg/kg also dose-dependently attenuated the stimulatory effects of cocaine (10 mg/kg on brain reward systems, as measured by reversal of cocaine-induced lowering of ICSS thresholds in rats. Finally, we found that Hcrt-R1 knockout mice self-administered far less cocaine than wildtype mice across the entire dose-response function. These data demonstrate that Hcrt-R1 play an important role in regulating the reinforcing and reward-enhancing properties of cocaine, and suggest that hypocretin transmission is likely essential for establishing and maintaining the cocaine habit in human addicts.

  6. Ascertainment of chronic diseases using population health data: a comparison of health administrative data and patient self-report

    OpenAIRE

    Muggah Elizabeth; Graves Erin; Bennett Carol; Manuel Douglas G

    2013-01-01

    Abstract Background Health administrative data is increasingly being used for chronic disease surveillance. This study explored agreement between administrative and survey data for ascertainment of seven key chronic diseases, using individually linked data from a large population of individuals in Ontario, Canada. Methods All adults who completed any one of three cycles of the Canadian Community Health Survey (2001, 2003 or 2005) and agreed to have their responses linked to provincial health ...

  7. Enhanced regional brain metabolic responses to benzodiazepines in cocaine abusers

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D.; Wang, G.J.; Fowler, J.S. [Brookhaven National Lab., Upton, NY (United States)] [and others

    1997-05-01

    While dopamine (DA) appears to be crucial for cocaine reinforcement, its involvement in cocaine addiction is much less clear. Using PET we have shown persistent reductions in striatal DA D2 receptors (which arc predominantly located on GABA cells) in cocaine abusers. This finding coupled to GABA`s role as an effector for DA led us to investigate if there were GABAergic abnormalities in cocaine abusers. In this study we measured regional brain metabolic responses to lorazepam, to indirectly assess GABA function (benzodiazepines facilitate GABAergic neurotransmission). Methods: The experimental subjects consisted of 12 active cocaine abusers and 32 age matched controls. Each subject underwent two PET FDG scans obtained within 1 week of each other. The first FDG scan was obtained after administration of placebo (3 cc of saline solution) given 40-50 minutes prior to FDG; and the second after administration of lorazepam (30 {mu}g/kg) given 40-50 minutes prior to FDG. The subjects were blind to the drugs received. Results: Lorazepam-induced sleepiness was significantly greater in abusers than in controls (p<0.001). Lorazepam-induced decreases in brain glucose metabolism were significantly larger in cocaine abusers than in controls. Whereas in controls whole brain metabolism decreased 13{+-}7 %, in cocaine abusers it decreased 21{+-}13 % (p < 0.05). Lorazepam-induced decrements in regional metabolism were significantly larger in striatum (p < 0.0 1), thalamus (p < 0.01) and cerebellum (p < 0.005) of cocaine abusers than of controls (ANOVA diagnosis by condition (placebo versus lorazepam) interaction effect). The only brain region for which the absolute metabolic changes-induced by lorazepam in cocaine abusers were equivalent to those in controls was the orbitofrontal cortex. These results document an accentuated sensitivity to benzodiazepines in cocaine abusers which is compatible with disrupted GABAergic function in these patients.

  8. Cocaine-induced neuroadaptations in the dorsal striatum: glutamate dynamics and behavioral sensitization.

    Science.gov (United States)

    Parikh, Vinay; Naughton, Sean X; Shi, Xiangdang; Kelley, Leslie K; Yegla, Brittney; Tallarida, Christopher S; Rawls, Scott M; Unterwald, Ellen M

    2014-09-01

    Recent evidence suggests that diminished ability to control cocaine seeking arises from perturbations in glutamate homeostasis in the nucleus accumbens. However, the neurochemical substrates underlying cocaine-induced neuroadaptations in the dorsal striatum and how these mechanisms link to behavioral plasticity is not clear. We employed glutamate-sensitive microelectrodes and amperometry to study the impact of repeated cocaine administration on glutamate dynamics in the dorsolateral striatum of awake freely-moving rats. Depolarization-evoked glutamate release was robustly increased in cocaine-pretreated rats challenged with cocaine. Moreover, the clearance of glutamate signals elicited either by terminal depolarization or blockade of non-neuronal glutamate transporters slowed down dramatically in cocaine-sensitized rats. Repeated cocaine exposure also reduced the neuronal tone of striatal glutamate. Ceftriaxone, a β-lactam antibiotic that activates the astrocytic glutamate transporter, attenuated the effects of repeated cocaine exposure on synaptic glutamate release and glutamate clearance kinetics. Finally, the antagonism of AMPA glutamate receptors in the dorsolateral striatum blocked the development of behavioral sensitization to repeated cocaine administration. Collectively, these data suggest that repeated cocaine exposure disrupts presynaptic glutamate transmission and transporter-mediated clearance mechanisms in the dorsal striatum. Moreover, such alterations produce an over activation of AMPA receptors in this brain region leading to the sensitized behavioral response to repeated cocaine.

  9. Investigating the Potential Influence of Cause of Death and Cocaine Levels on the Differential Expression of Genes Associated with Cocaine Abuse

    Science.gov (United States)

    Bannon, Michael J.; Savonen, Candace L.; Hartley, Zachary J.; Johnson, Magen M.; Schmidt, Carl J.

    2015-01-01

    The development of new therapeutic strategies for the treatment of complex brain disorders such as drug addiction is likely to be advanced by a more complete understanding of the underlying molecular pathophysiology. Although the study of postmortem human brain represents a unique resource in this regard, it can be challenging to disentangle the relative contribution of chronic pathological processes versus perimortem events to the observed changes in gene expression. To begin to unravel this issue, we analyzed by quantitative PCR the midbrain expression of numerous candidate genes previously associated with cocaine abuse. Data obtained from chronic cocaine abusers (and matched control subjects) dying of gunshot wounds were compared with a prior study of subjects with deaths directly attributable to cocaine abuse. Most of the genes studied (i.e., tyrosine hydroxylase, dopamine transporter, forkhead box A2, histone variant H3 family 3B, nuclear factor kappa B inhibitor alpha, growth arrest and DNA damage-inducible beta) were found to be differentially expressed in chronic cocaine abusers irrespective of immediate cause of death or perimortem levels of cocaine, suggesting that these may represent core pathophysiological changes arising with chronic drug abuse. On the other hand, chemokine C-C motif ligand 2 and jun proto-oncogene expression were unaffected in cocaine-abusing subjects dying of gunshot wounds, in contrast to the differential expression previously reported in cocaine-related fatalities. The possible influence of cause of death and other factors on the cocaine-responsiveness of these genes is discussed. PMID:25658879

  10. Self-Administered Cocaine Causes Long-Lasting Increases in Impulsive Choice in a Delay Discounting Task

    OpenAIRE

    Mendez, Ian A.; Nicholas W Simon; Hart, Nigel; Mitchell, Marci R.; Nation, Jack R.; Wellman, Paul J.; Setlow, Barry

    2010-01-01

    Cocaine use is associated with high levels of impulsive choice (preference for immediate over delayed rewards), but it is not clear whether cocaine use causes elevated impulsive choice, or whether elevated impulsive choice is solely a predisposing factor for cocaine use. This study examined the effects of prior cocaine self-administration on rats performing a delay discounting task commonly used to measure impulsive choice. Male Long-Evans rats were implanted with intravenous catheters, and f...

  11. Chronic morphine administration enhances nociceptive sensitivity and local cytokine production after incision

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    Angst Martin S

    2008-02-01

    Full Text Available Abstract Background - The chronic use of opioids prior to surgery leads to lowered pain thresholds and exaggerated pain levels after these procedures. Several mechanisms have been proposed to explain this heightened sensitivity commonly termed opioid-induced hyperalgesia (OIH. Most of these proposed mechanisms involve plastic events in the central or peripheral nervous systems. Alterations in the abundance of peripheral mediators of nociception have not previously been explored. Results - In these experiments mice were treated with saline (control or ascending daily doses of morphine to generate a state of OIH followed by hind paw incision. In other experiments morphine treatment was initiated at the time of incision. Both mechanical allodynia and peri-incisional skin cytokine levels were measured. Myeloperoxidase (MPO assays were used to determine neutrophil activity near the wounds. The cytokine production inhibitor pentoxifylline was used to determine the functional significance of the excess cytokines in previously morphine treated animals. Mice treated chronically treated with morphine prior to incision were found to have enhanced skin levels of IL-1β, IL-6, G-CSF, KC and TNFα after incision at one or more time points compared to saline pretreated controls. The time courses of individual cytokines followed different patterns. There was no discernable effect of chronic morphine treatment on wound area neutrophil infiltration. Pentoxifylline reduced cytokine levels and reversed the excess mechanical sensitization caused by chronic morphine administration prior to incision. Morphine treatment initiated at the time of incision did not lead to a generalized enhancement of cytokine production or nociceptive sensitization in excess of the levels observed after incision alone. Conclusion - The enhanced level of nociceptive sensitization seen after incision in animals chronically exposed to morphine is associated with elevated levels of several

  12. Short- and long-term cognitive effects of chronic cannabinoids administration in late-adolescence rats.

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    Hila Abush

    Full Text Available The use of cannabis can impair cognitive function, especially short-term memory. A controversial question is whether long-term cannabis use during the late-adolescence period can cause irreversible deficits in higher brain function that persist after drug use stops. In order to examine the short- and long-term effects of chronic exposure to cannabinoids, rats were administered chronic i.p. treatment with the CB1/CB2 receptor agonist WIN55,212-2 (WIN; 1.2 mg/kg for two weeks during the late adolescence period (post-natal days 45-60 and tested for behavioral and electrophysiological measures of cognitive performance 24 hrs, 10 and 30 days after the last drug injection. The impairing effects of chronic WIN on short-term memory in the water maze and the object recognition tasks as well as long-term potentiation (LTP in the ventral subiculum (vSub-nucleus accumbens (NAc pathway were temporary as they lasted only 24 h or 10 d after withdrawal. However, chronic WIN significantly impaired hippocampal dependent short-term memory measured in the object location task 24 hrs, 10, 30, and 75 days after the last drug injection. Our findings suggest that some forms of hippocampal-dependent short-term memory are sensitive to chronic cannabinoid administration but other cognitive impairments are temporary and probably result from a residue of cannabinoids in the brain or acute withdrawal effects from cannabinoids. Understanding the effects of cannabinoids on cognitive function may provide us with tools to overcome these impairments and for cannabinoids to be more favorably considered for clinical use.

  13. 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.

  14. Glycine transporter-1 inhibition preceding extinction training inhibits reacquisition of cocaine seeking.

    Science.gov (United States)

    Achat-Mendes, Cindy; Nic Dhonnchadha, Bríd Á; Platt, Donna M; Kantak, Kathleen M; Spealman, Roger D

    2012-12-01

    Cognitive enhancers that act by increasing glycine transmission might be useful adjuncts to cocaine-cue extinction training to deter relapse. The study investigated the effects of combining treatments of the glycine transporter-1 (GlyT-1) inhibitor, Org24598, with extinction training on the subsequent reacquisition of cocaine self-administration. Squirrel monkeys and rats were trained to self-administer cocaine under a second-order schedule of intravenous drug injection in which responding was maintained by cocaine injections and a cocaine-paired visual stimulus. During three weekly extinction sessions, saline was substituted for cocaine but responding still produced the cocaine-paired stimulus. Subjects were treated with Org24598 or vehicle, either before or after each extinction session. One week later, cocaine injections were restored, and reacquisition of cocaine self-administration was evaluated over 15 sessions. Compared with vehicle, administration of Org24598 (1.0 mg/kg in monkeys; 3.0 or 7.5 mg/kg in rats) before each extinction session significantly inhibited reacquisition of cocaine self-administration in each species. In contrast, administration of Org24598 (1.0 mg/kg in monkeys) following, rather than preceding, each extinction session did not affect reacquisition compared with vehicle. When extinction training was replaced by cocaine self-administration or abstinence control conditions, treatment with the same doses of Org24598 resulted in reacquisition that was significantly more rapid than the reacquisition observed when Org24598 was administered before extinction training sessions. The results support the potential clinical utility of GlyT-1 inhibitor pretreatments combined with cocaine-cue extinction training to inhibit relapse.

  15. Acetylcholine release in the mesocorticolimbic dopamine system during cocaine seeking: conditioned and unconditioned contributions to reward and motivation.

    Science.gov (United States)

    You, Zhi-Bing; Wang, Bin; Zitzman, Dawnya; Wise, Roy A

    2008-09-03

    Microdialysis was used to assess the contribution to cocaine seeking of cholinergic input to the mesocorticolimbic dopamine system in ventral tegmental area (VTA). VTA acetylcholine (ACh) was elevated in animals lever pressing for intravenous cocaine and in cocaine-experienced and cocaine-naive animals passively receiving similar "yoked" injections. In cocaine-trained animals, the elevations comprised an initial (first hour) peak to approximately 160% of baseline and a subsequent plateau of 140% of baseline for the rest of the cocaine intake period. In cocaine-naive animals, yoked cocaine injections raised ACh levels to the 140% plateau but did not cause the initial 160% peak. In cocaine-trained animals that received unexpected saline (extinction conditions) rather than the expected cocaine, the initial peak was seen but the subsequent plateau was absent. VTA ACh levels played a causal role and were not just a correlate of cocaine seeking. Blocking muscarinic input to the VTA increased cocaine intake; the increase in intake offset the decrease in cholinergic input, resulting in the same VTA dopamine levels as were seen in the absence of the ACh antagonists. Increased VTA ACh levels (resulting from 10 microM VTA neostigmine infusion) increased VTA dopamine levels and reinstated cocaine seeking in cocaine-trained animals that had undergone extinction; these effects were strongly attenuated by local infusion of a muscarinic antagonist and weakly attenuated by a nicotinic antagonist. These findings identify two cholinergic responses to cocaine self-administration, an unconditioned response to cocaine itself and a conditioned response triggered by cocaine-predictive cues, and confirm that these cholinergic responses contribute to the control of cocaine seeking.

  16. Life-threatening haematological complication occurring in a cat after chronic carbimazole administration

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    Andrea Mosca

    2016-09-01

    Full Text Available Case summary An 11-year-old spayed female domestic shorthair cat with a history of hyperthyroidism treated with carbimazole for 7 months was presented for a check-up after a few episodes of vomiting. The cat had been receiving prednisolone at 0.5 mg/kg PO q12h for recent pancreatitis and concurrent inflammation of liver and small intestines confirmed by biopsies. Clinical examination revealed pale mucous membranes with a capillary refill time of 120 s and fibrinogen serum concentration (3.5 g/l. Morphological changes of thrombocytes in the absence of thrombocytopenia were also noted. In-saline agglutination test was positive. Abdominal radiographic and ultrasonographic examinations excluded the presence of organ abnormalities and peritoneal effusion. Blood biochemistry was unremarkable. Feline leukaemia virus and feline immunodeficiency virus tests were negative. On the basis of these findings, immune-mediated anaemia secondary to chronic carbimazole administration was suspected. Prednisolone was increased to 2 mg/kg PO q24h and carbimazole tablets were stopped. Despite close monitoring and intensive care, the cat died the same evening of admission to the hospital. Relevance and novel information This report suggests that severe haemotoxicity may occur as a sequel of chronic carbimazole administration in cats. Routine bloodwork and accurate follow-up of cats under treatment with thyrotoxic therapy may be advisable, in order to detect haematological changes before lethal complications occur.

  17. Differential regulation of the period genes in striatal regions following cocaine exposure.

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    Edgardo Falcon

    Full Text Available Several studies have suggested that disruptions in circadian rhythms contribute to the pathophysiology of multiple psychiatric diseases, including drug addiction. In fact, a number of the genes involved in the regulation of circadian rhythms are also involved in modulating the reward value for drugs of abuse, like cocaine. Thus, we wanted to determine the effects of chronic cocaine on the expression of several circadian genes in the Nucleus Accumbens (NAc and Caudate Putamen (CP, regions of the brain known to be involved in the behavioral responses to drugs of abuse. Moreover, we wanted to explore the mechanism by which these genes are regulated following cocaine exposure. Here we find that after repeated cocaine exposure, expression of the Period (Per genes and Neuronal PAS Domain Protein 2 (Npas2 are elevated, in a somewhat regionally selective fashion. Moreover, NPAS2 (but not CLOCK (Circadian Locomotor Output Cycles Kaput protein binding at Per gene promoters was enhanced following cocaine treatment. Mice lacking a functional Npas2 gene failed to exhibit any induction of Per gene expression after cocaine, suggesting that NPAS2 is necessary for this cocaine-induced regulation. Examination of Per gene and Npas2 expression over twenty-four hours identified changes in diurnal rhythmicity of these genes following chronic cocaine, which were regionally specific. Taken together, these studies point to selective disruptions in Per gene rhythmicity in striatial regions following chronic cocaine treatment, which are mediated primarily by NPAS2.

  18. Cocaine-induced hyperactivity and sensitization are dependent on GSK3.

    Science.gov (United States)

    Miller, Jonathan S; Tallarida, Ronald J; Unterwald, Ellen M

    2009-06-01

    Glycogen synthase kinase 3 (GSK3) is a critical mediator of many intracellular signaling systems. The activity of GSK3 is regulated by several kinases, with inactivation occurring via phosphorylation of the inhibitory serine-21 (alpha-isoform) and serine-9 (beta-isoform) residues. Here, we investigated whether acute cocaine administration regulates GSK3 activity and if inhibition of GSK3 by valproate or the selective GSK3 inhibitor SB 216763 would attenuate cocaine-induced behaviors in mice. Mice injected with cocaine (20 mg/kg, i.p.) showed a reduction in the phosphorylation of GSK3beta in the caudate putamen, reflecting an increase in the activity of the kinase. To assess the role of GSK3 in cocaine-induced hyperactivity, mice were pretreated with valproate (50-300 mg/kg, i.p.), SB 216763 (0.25-7.5 mg/kg, i.p.), or the appropriate vehicle prior to saline or cocaine (20 mg/kg, i.p.). Valproate or SB 216763 produced significant dose-dependent reductions in cocaine-induced ambulatory and stereotypic activity. Repeated administration of cocaine can result in an augmentation of the locomotor-stimulatory effects of the drug, a phenomenon referred to as sensitization. Mice pretreated with SB 216763 (2.5 mg/kg, i.p.) prior to daily cocaine (20 mg/kg, i.p.) for 5 days showed a significant attenuation of the development of cocaine-induced behavioral sensitization following a cocaine challenge on day 13. These results indicate that cocaine activated GSK3beta in the caudate putamen and that pharmacological inhibition of GSK3 reduced both the acute behavioral responses to cocaine and the long-term neuroadaptations produced by repeated cocaine, therefore suggesting a role for GSK3 in the behavioral and neurochemical manifestations associated with cocaine exposure.

  19. Therapeutic serum phenobarbital concentrations obtained using chronic transdermal administration of phenobarbital in healthy cats.

    Science.gov (United States)

    Delamaide Gasper, Joy A; Barnes Heller, Heidi L; Robertson, Michelle; Trepanier, Lauren A

    2015-04-01

    Seizures are a common cause of neurologic disease, and phenobarbital (PB) is the most commonly used antiepileptic drug. Chronic oral dosing can be challenging for cat owners, leading to poor compliance. The purpose of this study was to determine if the transdermal administration of PB could achieve serum PB concentrations of between 15 and 45 μg/ml in healthy cats. Nineteen healthy cats were enrolled in three groups. Transdermal PB in pluronic lecithin organogel (PLO) was applied to the pinnae for 14 days at a dosage of 3 mg/kg q12h in group 1 (n = 6 cats) and 9 mg/kg q12h in group 2 (n = 7 cats). Transdermal PB in Lipoderm Activemax was similarly applied at 9 mg/kg q12h for 14 days in group 3 (n = 6 cats). Steady-state serum PB concentrations were measured at trough, and at 2, 4 and 6 h after the morning dose on day 15. In group 1, median concentrations ranged from 6.0-7.5 μg/ml throughout the day (observed range 0-11 μg/ml). Group 2 median concentrations were 26.0 μg/ml (observed range 18.0-37.0 μg/ml). For group 3, median concentrations ranged from 15.0-17.0 μg/ml throughout the day (range 5-29 μg/ml). Side effects were mild. One cat was withdrawn from group 2 owing to ataxia and sedation. These results show therapeutic serum PB concentrations can be achieved in cats following chronic transdermal administration of PB in PLO at a dosage of 9 mg/kg q12h. More individual variation was noted using Lipoderm Activemax. Transdermal administration may be an alternative for cats that are difficult to medicate orally.

  20. Opponent process properties of self-administered cocaine.

    Science.gov (United States)

    Ettenberg, Aaron

    2004-01-01

    Over the past decade, data collected in our laboratory have demonstrated that self-administered cocaine produces Opponent-Process-like behavioral effects. Animals running a straight alley once each day for IV cocaine develop over trials an approach-avoidance conflict about re-entering the goal box. This conflict behavior is characterized by a stop in forward locomotion (usually at the very mouth of the goal box) followed by a turn and 'retreat' back toward the goal box. The results of a series of studies conducted over the past decade collectively suggest that the behavioral ambivalence exemplified by rats running the alley for IV cocaine stems from concurrent and opponent positive (rewarding) and negative (anxiogenic) properties of the drug--both of which are associated with the goal box. These opponent properties of cocaine have been shown to result from temporally distinct affective states. Using a conditioned place preference test, we have been able to demonstrate that while the initial immediate effects of IV cocaine are reinforcing, the state present 15 min post-injection is aversive. In our most recent work, the co-administration of IV cocaine with either oral ethanol or IV heroin was found to greatly diminish the development and occurrence of retreat behaviors in the runway. It may therefore be that the high incidence of co-abuse of cocaine with either ethanol or heroin, stems from the users' motivation to alleviate some of the negative side effects of cocaine. It would seem then that the Opponent Process Theory has provided a useful conceptual framework for the study of the behavioral consequences of self-administered cocaine including the notion that both positive and negative reinforcement mechanisms are involved in the development and maintenance of cocaine abuse.

  1. Proinflammatory cytokines differentially influence adult hippocampal cell proliferation depending upon the route and chronicity of administration

    Directory of Open Access Journals (Sweden)

    Julie Anne Seguin

    2008-12-01

    Full Text Available Julie Anne Seguin, Jordan Brennan, Emily Mangano, Shawn HayleyInstitute of Neuroscience, Carleton University, Ottawa, Ontario, CanadaAbstract: Disturbances of hippocampal plasticity, including impaired dendritic branching and reductions of neurogenesis, are provoked by stressful insults and may occur in depression. Although corticoids likely contribute to stressor-induced reductions of neurogenesis, other signaling messengers, including pro-inflammatory cytokines might also be involved. Accordingly, the present investigation assessed whether three proinflammatory cytokines, namely interleukin-1β (IL-1β, IL-6, and tumor necrosis factor-α (TNF-α (associated with depression influenced cellular proliferation within the hippocampus. In this regard, systemic administration of TNF-α reduced 5-bromo-2-deoxyuridine (BrdU labeling within the hippocampus, whereas IL-1β and IL-6 had no such effect. However, repeated but not a single intra-hippocampal infusion of IL-6 and IL-1β actually increased cellular proliferation and IL-6 infusion also enhanced microglial staining within the hippocampus. Yet, no changes in doublecortin expression were apparent, suggesting that the cytokine did not influence the birth of cells destined to become neurons. Essentially, the route of administration and chronicity of cytokine administration had a marked influence upon the nature of hippocampal alterations provoked, suggesting that cytokines may differentially regulate hippocampal plasticity in neuropsychiatric conditions.Keywords: cytokine, depression, neuroplasticity, hippocampus, stressor

  2. Proinflammatory cytokines differentially influence adult hippocampal cell proliferation depending upon the route and chronicity of administration.

    Science.gov (United States)

    Seguin, Julie Anne; Brennan, Jordan; Mangano, Emily; Hayley, Shawn

    2009-01-01

    Disturbances of hippocampal plasticity, including impaired dendritic branching and reductions of neurogenesis, are provoked by stressful insults and may occur in depression. Although corticoids likely contribute to stressor-induced reductions of neurogenesis, other signaling messengers, including pro-inflammatory cytokines might also be involved. Accordingly, the present investigation assessed whether three proinflammatory cytokines, namely interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) (associated with depression) influenced cellular proliferation within the hippocampus. In this regard, systemic administration of TNF-alpha reduced 5-bromo-2-deoxyuridine (BrdU) labeling within the hippocampus, whereas IL-1beta and IL-6 had no such effect. However, repeated but not a single intra-hippocampal infusion of IL-6 and IL-1beta actually increased cellular proliferation and IL-6 infusion also enhanced microglial staining within the hippocampus. Yet, no changes in doublecortin expression were apparent, suggesting that the cytokine did not influence the birth of cells destined to become neurons. Essentially, the route of administration and chronicity of cytokine administration had a marked influence upon the nature of hippocampal alterations provoked, suggesting that cytokines may differentially regulate hippocampal plasticity in neuropsychiatric conditions.

  3. Antihypertensive effect of auraptene, a monoterpene coumarin from the genus Citrus, upon chronic administration

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    Bibi Marjan Razavi

    2015-02-01

    Full Text Available Objective(s: Auraptene, a monoterpene coumarin from Citrus species, exhibits cardioprotective effects.In this study, the effects of auraptene administration were investigated on blood pressure of normotensive and desoxycorticosterone acetate (DOCA salt induced hypertensive rats. Materials and Methods: Five weeks administration of auraptene (2, 4, 8 and 16 mg/kg/day and nifedipine (0.25, 0.5, 1, 2 and 4 mg/kg/day in different groups of normotensive and hypertensive rats (at the end of 3 weeks treatment by DOCA salt was carried out and their effects on mean systolic blood pressure (MSBP and mean heart rate (MHR were evaluated using tail cuff method. Results: Our results indicated that chronic administration of auraptene (2, 4, 8 and 16 mg/kg/day significantly reduced the MSBP in DOCA salt treated rats in a dose and time dependent manner. The percent of decreases in MSBP levels by the highest dose of auraptene (16 mg/kg at the end of 4 th to 8 th weeks, were 7.00%, 10.78%, 16.07%, 21.28% and 27.54% respectively(P

  4. Cocaine is low on the value ladder of rats: possible evidence for resilience to addiction.

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    Lauriane Cantin

    Full Text Available BACKGROUND: Assessing the relative value of cocaine and how it changes with chronic drug use represents a long-standing goal in addiction research. Surprisingly, recent experiments in rats--by far the most frequently used animal model in this field--suggest that the value of cocaine is lower than previously thought. METHODOLOGY/PRINCIPAL FINDINGS: Here we report a series of choice experiments that better define the relative position of cocaine on the value ladder of rats (i.e., preference rank-ordering of different rewards. Rats were allowed to choose either taking cocaine or drinking water sweetened with saccharin--a nondrug alternative that is not biologically essential. By systematically varying the cost and concentration of sweet water, we found that cocaine is low on the value ladder of the large majority of rats, near the lowest concentrations of sweet water. In addition, a retrospective analysis of all experiments over the past 5 years revealed that no matter how heavy was past cocaine use most rats readily give up cocaine use in favor of the nondrug alternative. Only a minority, fewer than 15% at the heaviest level of past cocaine use, continued to take cocaine, even when hungry and offered a natural sugar that could relieve their need of calories. CONCLUSIONS/SIGNIFICANCE: This pattern of results (cocaine abstinence in most rats; cocaine preference in few rats maps well onto the epidemiology of human cocaine addiction and suggests that only a minority of rats would be vulnerable to cocaine addiction while the large majority would be resilient despite extensive drug use. Resilience to drug addiction has long been suspected in humans but could not be firmly established, mostly because it is difficult to control retrospectively for differences in drug self-exposure and/or availability in human drug users. This conclusion has important implications for preclinical research on the neurobiology of cocaine addiction and for future medication

  5. 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.

  6. Neuropeptide Y Y5 receptor antagonism attenuates cocaine-induced effects in mice

    DEFF Research Database (Denmark)

    Sørensen, Gunnar; Jensen, Morten; Weikop, Pia

    2012-01-01

    Rationale Several studies suggest a role for neuropeptide Y (NPY) in addiction to drugs of abuse, including cocaine. However, the NPY receptors mediating addiction-related effects remain to be determined. Objectives To explore the potential role of Y5 NPY receptors in cocaine-induced behavioural...... effects. Methods The Y5 antagonist L-152,804 and Y5-knockout (Y5-KO) mice were tested in two models of cocaine addiction-related behaviour: acute self-administration and cocaine-induced hyperactivity. We also studied effects of Y5 receptor antagonism on cocaine-induced c-fos expression and extracellular...... dopamine with microdialysis as well as dopamine transporter-mediated uptake of dopamine in vitro. Immunocytochemistry was used to determine whether dopamine neurons express Y5-like immunoreactivity. Results In self-administration, L-152,804 prominently decreased nose-poking for the peak dose of cocaine...

  7. Chronic cladribine administration increases amyloid beta peptide generation and plaque burden in mice.

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    Crystal D Hayes

    Full Text Available BACKGROUND: The clinical uses of 2-chloro-2'-deoxyadenosine (2-CDA or cladribine which was initially prescribed to patients with hematological and lymphoid cancers is now extended to treat patients with multiple sclerosis (MS. Previous data has shown that 2-CDA has high affinity to the brain and readily passes through the blood brain barrier reaching CSF concentrations 25% of that found in plasma. However, whether long-term administration of 2-CDA can lead to any adverse effects in patients or animal models is not yet clearly known. METHODOLOGY: Here we show that exposure of 2-CDA to CHO cells stably expressing wild-type APP751 increased generation and secretion of amyloid β peptide (Aβ in to the conditioned medium. Interestingly, increased Aβ levels were noticed even at non-toxic concentrations of 2-CDA. Remarkably, chronic treatment of APdE9 mice, a model of Alzheimer's disease with 2-CDA for 60 days increased amyloid plaque burden by more than 1-fold. Increased Aβ generation appears to result from increased turnover of APP as revealed by cycloheximide-chase experiments. Additionally, surface labeling of APP with biotin and immunoprecipitation of surface labeled proteins with anti-biotin antibody also indicated increased APP at the cell surface in 2-CDA treated cells compared to controls. Increased turnover of APP by 2-CDA in turn might be a consequence of decreased protein levels of PIN 1, which is known to regulate cis-trans isomerization and phosphorylation of APP. Most importantly, like many other oncology drugs, 2-CDA administration led to significant delay in acquiring a reward-based learning task in a T maze paradigm. CONCLUSIONS: Taken together, these data provide compelling evidence for the first time that chronic 2-CDA administration can increase amyloidogenic processing of APP leading to robustly increased plaque burden which may be responsible for the observed deficits in learning skills. Thus chronic treatment of mice with 2

  8. Ascertainment of chronic diseases using population health data: a comparison of health administrative data and patient self-report

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    Muggah Elizabeth

    2013-01-01

    Full Text Available Abstract Background Health administrative data is increasingly being used for chronic disease surveillance. This study explored agreement between administrative and survey data for ascertainment of seven key chronic diseases, using individually linked data from a large population of individuals in Ontario, Canada. Methods All adults who completed any one of three cycles of the Canadian Community Health Survey (2001, 2003 or 2005 and agreed to have their responses linked to provincial health administrative data were included. The sample population included 85,549 persons. Previously validated case definitions for myocardial infarction, asthma, diabetes, chronic lung disease, stroke, hypertension and congestive heart failure based on hospital and physician billing codes were used to identify cases in health administrative data and these were compared with self-report of each disease from the survey. Concordance was measured using the Kappa statistic, percent positive and negative agreement and prevalence estimates. Results Agreement using the Kappa statistic was good or very good (kappa range: 0.66-0.80 for diabetes and hypertension, moderate for myocardial infarction and asthma and poor or fair (kappa range: 0.29-0.36 for stroke, congestive heart failure and COPD. Prevalence was higher in health administrative data for all diseases except stroke and myocardial infarction. Health Utilities Index scores were higher for cases identified by health administrative data compared with self-reported data for some chronic diseases (acute myocardial infarction, stroke, heart failure, suggesting that administrative data may pick up less severe cases. Conclusions In the general population, discordance between self-report and administrative data was large for many chronic diseases, particularly disease with low prevalence, and differences were not easily explained by individual and disease characteristics.

  9. Administration

    DEFF Research Database (Denmark)

    Bogen handler om den praksis, vi kalder administration. Vi er i den offentlige sektor i Danmark hos kontorfolkene med deres sagsmapper, computere, telefoner,, lovsamlinger,, retningslinier og regneark. I bogen udfoldes en mangfoldighed af konkrete historier om det administrative arbejde fra...... forskellige områder i den offentlige sektor. Hensigten er at forstå den praksis og faglighed der knytter sig til det administrative arbejde...

  10. Administration of simvastatin after kainic acid-induced status epilepticus restrains chronic temporal lobe epilepsy.

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    Chuncheng Xie

    Full Text Available In this study, we examined the effect of chronic administration of simvastatin immediately after status epilepticus (SE on rat brain with temporal lobe epilepsy (TLE. First, we evaluated cytokines expression at 3 days post KA-lesion in hippocampus and found that simvastatin-treatment suppressed lesion-induced expression of interleukin (IL-1β and tumor necrosis factor-α (TNF-α. Further, we quantified reactive astrocytosis using glial fibrillary acidic protein (GFAP staining and neuron loss using Nissl staining in hippocampus at 4-6 months after KA-lesion. We found that simvastatin suppressed reactive astrocytosis demonstrated by a significant decrease in GFAP-positive cells, and attenuated loss of pyramidal neurons in CA3 and interneurons in dentate hilar (DH. We next assessed aberrant mossy fiber sprouting (MFS that is known to contribute to recurrence of spontaneous seizure in epileptic brain. In contrast to the robust MFS observed in saline-treated animals, the extent of MFS was restrained by simvastatin in epileptic rats. Attenuated MFS was related to decreased neuronal loss in CA3 and DH, which is possibly a mechanism underlying decreased hippocampal susceptibility in animal treated with simvastatin. Electronic encephalography (EEG was recorded during 4 to 6 months after KA-lesion. The frequency of abnormal spikes in rats with simvastatin-treatment decreased significantly compared to the saline group. In summary, simvastatin treatment suppressed cytokines expression and reactive astrocytosis and decreased the frequency of discharges of epileptic brain, which might be due to the inhibition of MFS in DH. Our study suggests that simvastatin administration might be a possible intervention and promising strategy for preventing SE exacerbating to chronic epilepsy.

  11. Effects of acute or chronic administration of substituted benzamides in experimental models of depression in rats.

    Science.gov (United States)

    Drago, F; Arezzi, A; Virzì, A

    2000-12-01

    The effects of substituted benzamides, sulpiride and raclopride on experimental models of depression were studied in male rats after acute or chronic administration in comparison to those of the classical antidepressant, clomipramine. In contrast to clomipramine (50 mg/kg), acute doses of sulpiride or raclopride (1 or 5 mg/kg) failed to change the behavioral response of animals tested in the despair (constrained swim) test or in the model of reserpine-induced changes in the open field behavior. These doses also did not modify the grooming response of rats exposed to a novel environment. Sulpiride or raclopride 10 mg/kg increased the immobility time in the despair test and reduced novelty-induced grooming. The repeated injection for 21 days of sulpiride or raclopride (1 or 5 mg/kg, but not 10 mg/kg) induced a reduction of the immobility period during the constrained swim test similar to that following the chronic treatment with clomipramine 50 mg/kg. This appeared to be a clear-cut reversed dose-response relationship for both substituted benzamides, being the dose potency 1 mg/kg>5 mg/kg>10 mg/kg. Raclopride was more potent than sulpiride in this respect. Furthermore, like clomipramine, sulpiride (1 or 5 mg/kg) and raclopride (1 mg/kg) antagonized reserpine-induced changes in the open field behavior and enhanced novelty-induced grooming. These results indicate that, in contrast to acute injection, repeated administration of small doses of the substituted benzamides, sulpiride or raclopride induce an effect similar to that of the classical antidepressant, clomipramine. The reverse dose-response relationship suggests that these drugs in small doses act on presynaptic dopamine D(2) receptors. This may be consistent with a postsynaptic action of greater doses that exert sedative effects and increase immobility time in the despair test.

  12. Role for M5 muscarinic acetylcholine receptors in cocaine addiction.

    Science.gov (United States)

    Fink-Jensen, Anders; Fedorova, Irina; Wörtwein, Gitta; Woldbye, David P D; Rasmussen, Thøger; Thomsen, Morgane; Bolwig, Tom G; Knitowski, Karen M; McKinzie, David L; Yamada, Masahisa; Wess, Jürgen; Basile, Anthony

    2003-10-01

    Muscarinic cholinergic receptors of the M5 subtype are expressed by dopamine-containing neurons of the ventral tegmentum. These M5 receptors modulate the activity of midbrain dopaminergic neurons, which play an important role in mediating reinforcing properties of abused psychostimulants like cocaine. The potential role of M5 receptors in the reinforcing effects of cocaine was investigated using M5 receptor-deficient mice in a model of acute cocaine self-administration. The M5-deficient mice self-administered cocaine at a significantly lower rate than wild-type controls. In the conditioned place preference procedure, a classic test for evaluating the rewarding properties of drugs, M5-deficient mice spent significantly less time in the cocaine-paired compartment than control mice. Moreover, the severity of the cocaine withdrawal syndrome (withdrawal-associated anxiety measured in the elevated plus-maze) was significantly attenuated in mice lacking the M5 receptor. These results demonstrate that M5 receptors play an important role in mediating both cocaine-associated reinforcement and withdrawal.

  13. Quinine enhances the behavioral stimulant effect of cocaine in mice.

    Science.gov (United States)

    Huertas, Adriana; Wessinger, William D; Kucheryavykh, Yuri V; Sanabria, Priscila; Eaton, Misty J; Skatchkov, Serguei N; Rojas, Legier V; Maldonado-Martínez, Gerónimo; Inyushin, Mikhail Y

    2015-02-01

    The Na(+)-dependent dopamine transporter (DAT) is primarily responsible for regulating free dopamine (DA) concentrations in the brain by participating in the majority of DA uptake; however, other DA transporters may also participate, especially if cocaine or other drugs of abuse compromise DAT. Recently, such cocaine-insensitive low-affinity mono- and poly-amine OCT transporters were described in astrocytes which use DA as a substrate. These transporters are from a different transporter family and while insensitive to cocaine, they are specifically blocked by quinine and some steroids. Quinine is inexpensive and is often found in injected street drugs as an "adulterant". The present study was designed to determine the participation of OCTs in cocaine dependent behavioral and physiological changes in mice. Using FVB mice we showed, that daily single injections of quinine (10 mg/kg, i.p.) co-administered with cocaine (15 mg/kg, i.p.) for 10 days significantly enhanced cocaine-induced locomotor behavioral sensitization. Quinine had no significant effect on the time course of behavioral activation. In astrocytes from the ventral tegmental area of mice, transporter currents of quinine-sensitive monoamine transporters were also augmented after two weeks of cocaine administration. The importance of low-affinity high-capacity transporters for DA clearance is discussed, explaining the known ability of systemically administered DAT inhibitors to anomalously increase DA clearance.

  14. Increase in phorbol ester binding in liver microsomes after chronic administration of phenobarbital

    Energy Technology Data Exchange (ETDEWEB)

    Menez, J.F.; Deitrich, R.A. (Univ. of Colorado, Denver (United States))

    1991-03-15

    The effect of chronic administration of phenobarbital on the binding of phorbol-12,13-dibutyrate (({sup 3}H)PDBu), an activator of protein kinase C (PKC), was examined in rat liver microsomes. A significant increase in the number of binding sites was observed in microsomes of Fisher 344 rats. However, no change appeared in liver cytosol binding of PDBu. Consequently, a translocation process of PKC is unlikely. The increase in ({sup 3}H)PDBu binding in liver microsomes is significant 24 h. after one injection of phenobarbital and reaches its maximum in 2 days. In other strains of rats (ACI and lean Zucker), significant differences were found in the increase of ({sup 3}H)PDBu binding in microsomes. Fisher 344 were the most sensitive, lean Zucker rats, the least sensitive. Those results parallel the pentoxy-resorufin O demethylase activity in the microsomes of the same animals. EC{sub 50} values for inhibition of ({sup 3}H)PDBu binding by pentobarbital were determined in control microsomes from Fisher and Zucker rats. In Fisher rats, ({sup 3}H)PDBu binding in microsomes was found to be more sensitive to the inhibitory effect of pentobarbital than in lean Zucker rats, which suggests that the more microsomes are inhibited in vitro the greater the increase in PKC in microsomes following chronic barbiturate treatment.

  15. Plasma proteomic alterations in non-human primates and humans after chronic alcohol self-administration.

    Science.gov (United States)

    Freeman, Willard M; Vanguilder, Heather D; Guidone, Elizabeth; Krystal, John H; Grant, Kathleen A; Vrana, Kent E

    2011-08-01

    Objective diagnostics of excessive alcohol use are valuable tools in the identification and monitoring of subjects with alcohol use disorders. A number of potential biomarkers of alcohol intake have been proposed, but none have reached widespread clinical usage, often due to limited diagnostic sensitivity and specificity. In order to identify novel potential biomarkers, we performed proteomic biomarker target discovery in plasma samples from non-human primates that chronically self-administer high levels of ethanol. Two-dimensional difference in-gel electrophoresis (2D-DIGE) was used to quantify plasma proteins from within-subject samples collected before exposure to ethanol and after 3 months of excessive ethanol self-administration. Highly abundant plasma proteins were depleted from plasma samples to increase proteomic coverage. Altered plasma levels of serum amyloid A4 (SAA4), retinol-binding protein, inter-alpha inhibitor H4, clusterin, and fibronectin, identified by 2D-DIGE analysis, were confirmed in unmanipulated, whole plasma from these animals by immunoblotting. Examination of these target plasma proteins in human subjects with excessive alcohol consumption (and control subjects) revealed increased levels of SAA4 and clusterin and decreased levels of fibronectin compared to controls. These proteins not only serve as targets for further development as biomarker candidates or components of biomarker panels, but also add to the growing understanding of dysregulated immune function and lipoprotein metabolism with chronic, excessive alcohol consumption.

  16. The lateral habenula is a common target of cocaine and dexamethasone.

    Science.gov (United States)

    Zhang, Chun-Xiao; Zhang, Hong; Xu, Hai-Yan; Li, Ming-Xian; Wang, Shao

    2013-10-25

    The lateral habenular nucleus (LHb) receives projections from areas rich in dopaminergic neurons and sends efferent fibers to these areas, suggesting that the LHb has a role in dopaminergic reward-related activity. The LHb is also implicated in multiple stress reactions, including responses to painful stimuli. However, it is unclear whether the LHb facilitates glucocorticoid/cocaine interactions by serving as a common target of both. In this study we investigated the effect of cocaine and dexamethasone (a synthesized glucocorticoid) on pain-related neurons (pain-excitatory and pain-inhibitory). Cocaine treatment effectively increased the firing rate of 89.7% of pain-excitatory neurons (cocaine-up response) and decreased the firing rate of 81.8% of pain-inhibitory neurons (cocaine-down response) in the LHb, suggesting that LHb neurons respond to cocaine via different mechanisms. Dexamethasone enhanced the firing rate of the cocaine-up neurons, while cocaine-down neurons were not influenced, indicating that both drugs may elicit an electrophysiological response at the same LHb neuron. Effects of either cocaine or dexamethasone alone, or both combined, on FOS expression in the LHb were observed via immunohistochemistry. Single administration of either cocaine or dexamethasone increased the number of FOS-positive neurons in the LHb. Pretreatment with dexamethasone and then cocaine markedly enhanced the number of FOS-positive neurons in the LHb relative to cocaine treatment alone, suggesting that stress and addictive drugs exert a synergistic effect on the LHb. We conclude that the LHb responds to cocaine via more than one mechanism and is a common target of both cocaine and the dexamethasone.

  17. [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.

  18. Effects of acute and chronic administration of venlafaxine and desipramine on extracellular monoamine levels in the mouse prefrontal cortex and striatum.

    Science.gov (United States)

    Higashino, Kosuke; Ago, Yukio; Umehara, Masato; Kita, Yuki; Fujita, Kazumi; Takuma, Kazuhiro; Matsuda, Toshio

    2014-04-15

    Prefrontal catecholamine neurotransmission plays a key role in the therapeutic actions of drugs for attention-deficit/hyperactivity disorder (ADHD). We have recently shown that serotonin/noradrenaline reuptake inhibitors and the noradrenaline reuptake inhibitor desipramine attenuated horizontal hyperactivity in spontaneously hypertensive rats, an animal model of ADHD, and that these drugs are potential pharmacotherapeutics for ADHD. In this study, we used in vivo microdialysis to study the effects of acute and chronic (once daily for 3 weeks) administration of the serotonin/noradrenaline reuptake inhibitor venlafaxine and the noradrenaline reuptake inhibitor desipramine on noradrenaline, dopamine, and serotonin levels, and the expression of the neuronal activity marker c-Fos in the mouse prefrontal cortex and striatum. Both acute and chronic venlafaxine administration increased prefrontal noradrenaline, dopamine, and serotonin levels and striatal noradrenaline and serotonin levels. Both acute and chronic desipramine administration increased prefrontal noradrenaline and dopamine levels and striatal noradrenaline levels, with chronic administration yielding stronger increase. Chronic desipramine did not affect striatal dopamine and serotonin levels. Both acute and chronic venlafaxine administration increased the expression of c-Fos in the prefrontal cortex, whereas chronic, but not acute, desipramine administration increased the expression of c-Fos in the prefrontal cortex. Both acute and chronic venlafaxine administration increased the striatal c-Fos expression to some degree, whereas desipramine administration did not. These results suggest that acute and chronic venlafaxine and chronic desipramine administration maximally activate the prefrontal adrenergic and dopaminergic systems without affecting striatal dopaminergic systems in mice.

  19. Mephedrone (4-methylmethcathinone) and intracranial self-stimulation in C57BL/6J mice: comparison to cocaine.

    Science.gov (United States)

    Robinson, J Elliott; Agoglia, Abigail E; Fish, Eric W; Krouse, Michael C; Malanga, C J

    2012-09-01

    The recreational use of cathinone-derived synthetic stimulants, also known as "bath salts", has increased during the last five years. A commonly abused drug in this class is mephedrone (4-methylmethcathinone or "meow-meow"), which alters mood and produces euphoria in humans. Intracranial self-stimulation (ICSS) measures the behavioral effects of neuroactive compounds on brain reward circuitry. We used ICSS to investigate the ability of mephedrone and cocaine to alter responding for electrical stimulation of the medial forebrain bundle in C57BL/6J mice. Adult male C57BL/6J mice (n=6) implanted with unipolar stimulating electrodes at the level of the lateral hypothalamus responded for varying frequencies of brain stimulation reward (BSR). The frequency that supported half maximal responding (EF50), the BSR threshold (θ(0)), and the maximum response rate were determined before and after intraperitoneal administration of saline, mephedrone (1.0, 3.0, or 10.0 mg/kg), or cocaine (1.0, 3.0, or 10.0 mg/kg). Mephedrone dose-dependently decreased EF50 (max. effect=72.3% of baseline), θ(0) (max. effect=59.6% of baseline), and the maximum response rate (max. effect=67.0% of baseline) beginning 15 min after administration. Beginning immediately after administration, cocaine dose-dependently lowered EF50 (max. effect=66.4% of baseline) and θ(0) (max. effect=60.1% of baseline) but did not affect maximum response rate. These results suggest that mephedrone, like cocaine, potentiates BSR, which may indicate its potential for abuse. Given the public health concern of stimulant abuse, future studies will be necessary to determine the cellular and behavioral effects of acute and chronic mephedrone use.

  20. Antihypertensive effect of auraptene, a monoterpene coumarin from the genus Citrus, upon chronic administration

    Science.gov (United States)

    Razavi, Bibi Marjan; Arasteh, Ebrahim; Imenshahidi, Mohsen; Iranshahi, Mehrdad

    2015-01-01

    Objective(s): Auraptene, a monoterpene coumarin from Citrus species, exhibits cardioprotective effects. In this study, the effects of auraptene administration were investigated on blood pressure of normotensive and desoxycorticosterone acetate (DOCA) salt induced hypertensive rats. Materials and Methods: Five weeks administration of auraptene (2, 4, 8 and 16 mg/kg/day) and nifedipine (0.25, 0.5, 1, 2 and 4 mg/kg/day) in different groups of normotensive and hypertensive rats (at the end of 3 weeks treatment by DOCA salt) was carried out and their effects on mean systolic blood pressure (MSBP) and mean heart rate (MHR) were evaluated using tail cuff method. Results: Our results indicated that chronic administration of auraptene (2, 4, 8 and 16 mg/kg/day) significantly reduced the MSBP in DOCA salt treated rats in a dose and time dependent manner. The percent of decreases in MSBP levels by the highest dose of auraptene (16 mg/kg) at the end of 4 th to 8 th weeks, were 7.00%, 10.78%, 16.07%, 21.28% and 27.54% respectively (P<0.001). Moreover the antihypertensive effect of auraptene was less than nifedipine (ED50 value of nifedipine = 0.7 mg/kg at 8th week and ED50 value of auraptene = 5.64 mg/kg at 8 week). Conclusion: Auraptene considerably reduced MSBP in hypertensive rats, but not in normotensive (normal saline treated) rats. The results of MHR measurement showed that the increase in MHR was not significant in comparison with DOCA treated rats. PMID:25810889

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

    Science.gov (United States)

    Quednow, Boris B.; Hulka, Lea M.; Preller, Katrin H.; Baumgartner, Markus R.; Eisenegger, Christoph; Vonmoos, Matthias

    2017-01-01

    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 correlations

  2. Time-dependent interactions between iboga agents and cocaine.

    Science.gov (United States)

    Maisonneuve, I M; Visker, K E; Mann, G L; Bandarage, U K; Kuehne, M E; Glick, S D

    1997-10-08

    The purpose of this study was to clarify the effects of iboga agents on cocaine-induced hyperactivity. Both inhibition and enhancement of cocaine-induced activity by ibogaine have been reported. In the present study, rats were treated with either ibogaine (40 mg/kg, i.p.), noribogaine (40 mg/kg, i.p.), 18-methoxycoronaridine (40 mg/kg, i.p.), or saline, 1 or 19 h prior to the administration of cocaine (20 mg/kg, i.p.) or saline. Motor activity was monitored thereafter for 3 h. All three iboga agents had acute inhibitory effects and delayed potentiating effects on cocaine-induced hyperactivity. These time-dependent effects, which could not be attributed to the motor activity induced by the iboga agents alone, account for divergent results reported in the literature.

  3. Acute and chronic administration of gold nanoparticles cause DNA damage in the cerebral cortex of adult rats.

    Science.gov (United States)

    Cardoso, Eria; Rezin, Gislaine Tezza; Zanoni, Elton Torres; de Souza Notoya, Frederico; Leffa, Daniela Dimer; Damiani, Adriani Paganini; Daumann, Francine; Rodriguez, Juan Carlos Ortiz; Benavides, Roberto; da Silva, Luciano; Andrade, Vanessa M; da Silva Paula, Marcos Marques

    2014-01-01

    The use of gold nanoparticles is increasing in medicine; however, their toxic effects remain to be elucidated. Studies show that gold nanoparticles can cross the blood-brain barrier, as well as accumulate in the brain. Therefore, this study was undertaken to better understand the effects of gold nanoparticles on rat brains. DNA damage parameters were evaluated in the cerebral cortex of adult rats submitted to acute and chronic administration of gold nanoparticles of two different diameters: 10 and 30nm. During acute administration, adult rats received a single intraperitoneal injection of either gold nanoparticles or saline solution. During chronic administration, adult rats received a daily single injection for 28 days of the same gold nanoparticles or saline solution. Twenty-four hours after either single (acute) or last injection (chronic), the rats were euthanized by decapitation, their brains removed, and the cerebral cortices isolated for evaluation of DNA damage parameters. Our study showed that acute administration of gold nanoparticles in adult rats presented higher levels of damage frequency and damage index in their DNA compared to the control group. It was also observed that gold nanoparticles of 30nm presented higher levels of damage frequency and damage index in the DNA compared to the 10nm ones. When comparing the effects of chronic administration of gold nanoparticles of 10 and 30nm, we observed that occurred significant different index and frequency damage, comparing with control group. However, there is no difference between the 10 and 30nm groups in the levels of DNA damage for both parameters of the Comet assay. Results suggest that gold nanoparticles for both sizes cause DNA damage for chronic as well as acute treatments, although a higher damage was observed for the chronic one.

  4. Reinstatement in a cocaine versus food choice situation: reversal of preference between drug and non-drug rewards.

    Science.gov (United States)

    Tunstall, Brendan J; Kearns, David N

    2014-09-01

    Recent studies show that when given a mutually exclusive choice between cocaine and food, rats almost exclusively choose food. The present experiment investigated potential shifts in preference between levers associated with either food or cocaine that might occur during extinction (food and cocaine no longer available) and during footshock-induced, cocaine-primed and food-primed reinstatement. During self-administration sessions where food and cocaine were simultaneously available, rats demonstrated a stable food preference, choosing food over cocaine on 83% of trials. During extinction when neither reinforcer was available, no preference between levers was evident and responding decreased until rats responded on the previously food- and cocaine-associated levers at equally low rates. Footshock resulted in a non-specific reinstatement of responding upon both levers, while cocaine priming resulted in a significant preference for cocaine seeking over food seeking. This suggests that the mechanism underlying footshock-induced reinstatement is distinct from that of cocaine-primed reinstatement. Food priming engendered a mild, non-specific increase in responding on both levers. Although rats generally prefer food over cocaine when presented with a choice between these primary reinforcers, the present results suggest that in certain situations, cocaine-seeking behavior prevails over food-seeking behavior.

  5. Pathogenesis of nephrogenic diabetes insipidus due to chronic administration of lithium in rats.

    Science.gov (United States)

    Christensen, S; Kusano, E; Yusufi, A N; Murayama, N; Dousa, T P

    1985-06-01

    A polyuric syndrome with nephrogenic diabetes insipidus (NDI) is a frequent consequence of prolonged administration of lithium (Li) salts. Studies in the past, mainly the acute and in vitro experiments, indicated that Li ions can inhibit hydroosmotic effect of [8-arginine]vasopressin (AVP) at the step of cAMP generation in vitro. However, the pathogenesis of the NDI due to chronic oral administration of low therapeutic doses of Li salts is not yet clarified. We conducted a comprehensive study to clarify the mechanism by which Li administered orally for several weeks induces polyuria and NDI in rats. Albino rats consuming a diet which contained Li (60 mmol/kg) for 4 wk developed marked polyuria and polydipsia; at the end of 4 wk the plasma Li was 0.7 +/- 0.09 mM (mean +/- SEM; n = 36). Li-treated rats had a significantly decreased (-33%) tissue osmolality in papilla and greatly reduced cortico-papillary gradient of urea (cortex--43%; medulla--64%; papilla--74%). Plasma urea was significantly (P less than 0.001) lower in Li-treated rats (5.4 +/- 0.2 mM) compared with controls (6.8 +/- 0.3 mM). Medullary collecting tubules (MCT) and papillary collecting ducts (PCD) microdissected from Li-treated animals had higher content of protein than MCT and PCD from the control rats. The cAMP accumulation in response to AVP added in vitro was significantly (delta = -60%) reduced. Also, the cAMP accumulation in MCT and PCD after incubation with forskolin was markedly lower in Li-treated rats. Addition of 0.5 mM 1-methyl,3-isobutyl-xanthine did not restore the cAMP accumulation in response to AVP and forskolin in MCT from Li-treated animals. In collecting tubule segments from polyuric rats with hypothalamic diabetes insipidus (Brattleboro homozygotes) the AVP-dependent cAMP accumulation was not diminished. The activity of adenylate cyclase (AdC) in MCT of Li-treated rats, both the basal and the activity stimulated by AVP, forskolin, or fluoride, was significantly (delta

  6. Behavioural and neurochemical comparison of chronic intermittent cathinone, mephedrone and MDMA administration to the rat.

    Science.gov (United States)

    Shortall, Sinead E; Macerola, Alice E; Swaby, Rabbi T R; Jayson, Rebecca; Korsah, Chantal; Pillidge, Katharine E; Wigmore, Peter M; Ebling, Francis J P; Richard Green, A; Fone, Kevin C F; King, Madeleine V

    2013-09-01

    The synthetic cathinone derivative, mephedrone, is a controlled substance across Europe. Its effects have been compared by users to 3,4-methylenedioxymethamphetamine (MDMA), but little data exist on its pharmacological properties. This study compared the behavioural and neurochemical effects of mephedrone with cathinone and MDMA in rats. Young-adult male Lister hooded rats received i.p. cathinone (1 or 4 mg/kg), mephedrone (1, 4 or 10mg/kg) or MDMA (10mg/kg) on two consecutive days weekly for 3 weeks or as a single acute injection (for neurochemical analysis). Locomotor activity (LMA), novel object discrimination (NOD), conditioned emotional response (CER) and prepulse inhibition of the acoustic startle response (PPI) were measured following intermittent drug administration. Dopamine, 5-hydroxytryptamine (5-HT) and their major metabolites were measured in striatum, frontal cortex and hippocampus by high performance liquid chromatography 7 days after intermittent dosing and 2h after acute injection. Cathinone (1, 4 mg/kg), mephedrone (10mg/kg) and MDMA (10mg/kg) induced hyperactivity following the first and sixth injections and sensitization to cathinone and mephedrone occurred with chronic dosing. All drugs impaired NOD and mephedrone (10mg/kg) reduced freezing in response to contextual re-exposure during the CER retention trial. Acute MDMA reduced hippocampal 5-HT and 5-HIAA but the only significant effect on dopamine, 5-HT and their metabolites following chronic dosing was altered hippocampal 3,4-dihydroxyphenylacetic acid (DOPAC), following mephedrone (4, 10mg/kg) and MDMA. At the doses examined, mephedrone, cathinone, and MDMA induced similar effects on behaviour and failed to induce neurotoxic damage when administered intermittently over 3 weeks.

  7. Ameliorating Adriamycin-Induced Chronic Kidney Disease in Rats by Orally Administrated Cardiotoxin from Naja naja atra Venom

    Directory of Open Access Journals (Sweden)

    Zhi-Hui Ding

    2014-01-01

    Full Text Available Previous studies reported the oral administration of Naja naja atra venom (NNAV reduced adriamycin-induced chronic kidney damage. This study investigated the effects of intragastric administrated cardiotoxin from Naja naja atra venom on chronic kidney disease in rats. Wistar rats were injected with adriamycin (ADR; 6 mg/kg body weight via the tail vein to induce chronic kidney disease. The cardiotoxin was administrated daily by intragastric injection at doses of 45, 90, and 180 μg/kg body weight until the end of the protocol. The rats were placed in metabolic cages for 24 hours to collect urine, for determination of proteinuria, once a week. After 6 weeks, the rats were sacrificed to determine serum profiles relevant to chronic kidney disease, including albumin, total cholesterol, phosphorus, blood urea nitrogen, and serum creatinine. Kidney histology was examined with hematoxylin and eosin, periodic acid-Schiff, and Masson’s trichrome staining. The levels of kidney podocin were analyzed by Western blot analysis and immunofluorescence. We found that cardiotoxin reduced proteinuria and can improve biological parameters in the adriamycin-induced kidney disease model. Cardiotoxin also reduced adriamycin-induced kidney pathology, suggesting that cardiotoxin is an active component of NNAV for ameliorating adriamycin-induced kidney damage and may have a potential therapeutic value on chronic kidney disease.

  8. Ameliorating Adriamycin-Induced Chronic Kidney Disease in Rats by Orally Administrated Cardiotoxin from Naja naja atra Venom.

    Science.gov (United States)

    Ding, Zhi-Hui; Xu, Li-Min; Wang, Shu-Zhi; Kou, Jian-Qun; Xu, Yin-Li; Chen, Cao-Xin; Yu, Hong-Pei; Qin, Zheng-Hong; Xie, Yan

    2014-01-01

    Previous studies reported the oral administration of Naja naja atra venom (NNAV) reduced adriamycin-induced chronic kidney damage. This study investigated the effects of intragastric administrated cardiotoxin from Naja naja atra venom on chronic kidney disease in rats. Wistar rats were injected with adriamycin (ADR; 6 mg/kg body weight) via the tail vein to induce chronic kidney disease. The cardiotoxin was administrated daily by intragastric injection at doses of 45, 90, and 180  μ g/kg body weight until the end of the protocol. The rats were placed in metabolic cages for 24 hours to collect urine, for determination of proteinuria, once a week. After 6 weeks, the rats were sacrificed to determine serum profiles relevant to chronic kidney disease, including albumin, total cholesterol, phosphorus, blood urea nitrogen, and serum creatinine. Kidney histology was examined with hematoxylin and eosin, periodic acid-Schiff, and Masson's trichrome staining. The levels of kidney podocin were analyzed by Western blot analysis and immunofluorescence. We found that cardiotoxin reduced proteinuria and can improve biological parameters in the adriamycin-induced kidney disease model. Cardiotoxin also reduced adriamycin-induced kidney pathology, suggesting that cardiotoxin is an active component of NNAV for ameliorating adriamycin-induced kidney damage and may have a potential therapeutic value on chronic kidney disease.

  9. Postmortem stability of cocaine and cocaethylene in blood and tissues of humans and rabbits.

    Science.gov (United States)

    Moriya, F; Hashimoto, Y

    1996-07-01

    A study was conducted to examine the postmortem stability of cocaine and cocaethylene in rabbit blood and tissues, and to determine whether cocaethylene is produced in decomposed human specimens containing cocaine and endogenous ethanol. Heart blood, liver, brain and femoral muscle taken from rabbits 20 min after oral administration of 20 mg/kg cocaine together with 2 g/kg ethanol were kept at 20-25 degrees C for 5 days. Cocaine and cocaethylene concentrations were in the order brain > liver > muscle > blood, and showed very large intersubject variations at the time of death. Cocaine was degraded rapidly in the blood and liver. However, 12.0 +/- 8.5% and 26.2% +/- 19.4% of the original cocaine was still detectable in the brain and muscle, respectively. Cocaethylene was degraded more slowly than cocaine in all of the specimens. The pH of the blood remained around 7.4 during a 5-day period; all the other specimens showed pH values of 6.2-6.7 on and after the first day postmortem. When 10,000 ng/g cocaine was incubated with decomposed human blood, liver, brain and muscle homogenates containing 0.29-0.60 mg/g endogenous ethanol at 20-25 degrees C and 37 degrees C, no change in cocaine concentration was observed during the study period of 24 h, and no cocaethylene was detected. The pH values of the homogenates were within the range 4.2 to 5.2 at the beginning of the experiment. It was found that: 1) cocaethylene was more stable in postmortem specimens than cocaine; 2) muscle as well as brain was specimen of choice for detecting cocaine and cocaethylene postmortem; 3) cocaine was resistant to decomposition under acidic conditions; and 4) putrefactive bacteria had no ability to produce cocaethylene even in the presence of cocaine and endogenous ethanol.

  10. Mediating effect of dopamine D3 receptors on Jak2 and GABAAα1 expression in mouse brains induced by cocaine

    Institute of Scientific and Technical Information of China (English)

    LIU Nu-yun; ZHANG Lu; ZHANG Lin; WANG Xiao-ning

    2007-01-01

    Background Cocaine addiction may involve complex neuroadaptations, including many changes of genes expression.Dopamine D3 receptors play an important role in cocaine addiction; however, its role in cocaine induced gene expression change is poorly understood. To identify the changes in gene expression induced by repeated cocaine exposure through D3 dopamine receptors, we compared the expression of four molecules: Janus kinase 2 (Jak2), g-aminobutanoic acid receptor subunit alpha 1 (GABAAα1), glutamate receptor AMPA3 alpha 3 (GluR 3) and stromal cell derived factor 1 (SDF1). These four have been implicated in mediating the actions of cocaine in the nucleus accumbens (NAc) and caudoputamen (CPu) in mice after acute and repeated cocaine exposure.Methods For the acute and repeated injections, the mice were divided into four groups: 30 mg/kg cocaine, nafadotride 0.5 mg/kg + cocaine 30 mg/kg, nafadotride 0.5 mg/kg, and saline as the basal group. The expression of Jak2, GABAAα1,GluR 3 and SDF1 were assayed by Western blot, quantitative real-time RT-PCR and immunohistochemistry.Results Twenty-four hours after seven consecutive days of repeated cocaine exposure, the expression of GABAAα1 decreased in cocaine group compared with basal line and further decreased in the cocaine + nafadotride group and remained at basal level in the nafadotride group. Similarly, the Jak2 expression decreased in cocaine group compared with base line. However, the levels of Jak2 increased in cocaine + nafadotride group compared with cocaine group, while remained at basal level in nafadotride group.Conclusions GABAAα1 and Jak2 may be involved in chronic cocaine induced neuroadaptations. D3 dopaminereceptors play an important role in the expression of these genes.

  11. The teratogenicity of cocaine.

    Science.gov (United States)

    Fantel, A G; Macphail, B J

    1982-08-01

    Pregnancy rats and mice received high doses of cocaine hydrochloride by intraperitoneal injection. Despite treatment periods which included most of organogenesis, no increase in congenital abnormalities was observed. Rats showed significant reductions in maternal and fetal weights as well as increased resorption frequencies. Fetal edema was also found. Mice showed only decreased fetal weights with no increase in malformations.

  12. Elimination of alfentanil delivered by infusion is not altered by the chronic administration of atorvastatin.

    LENUS (Irish Health Repository)

    McDonnell, C G

    2012-02-03

    BACKGROUND AND OBJECTIVE: Statins are prescribed for patients with hypercholesterolemia. Atorvastatin is metabolized by cytochrome P4503A4 and inhibits P4503A4 activity in vitro. Alfentanil is a potent opioid used in clinical anaesthetic practice and is also metabolized by P4503A4. This study tested the hypothesis that chronic atorvastatin administration inhibits the metabolism of alfentanil. METHODS: Sixteen patients undergoing elective surgery were studied as matched pairs. One member of each pair was maintained on standard doses of atorvastatin for at least 4 months. Each patient received an alfentanil bolus (80 microg kg(-1)) intravenously (i.v.), followed by an alfentanil infusion (0.67 microg kg(-1) min(-1)) for 90 min. Serial plasma alfentanil concentrations were measured using gas chromatography-nitrogen phosphorous detection. Pharmacokinetic parameters were calculated using two-compartment linear modelling. RESULTS: One patient and the corresponding match were excluded from the analysis. The elimination half-life of alfentanil was similar in the control and atorvastatin groups (98.8 +\\/- 12.4 versus 98.3 +\\/- 11.3 min, respectively). The clearance (Cl), volume of distribution at steady-state (Vdss) and area under the curve (AUC) were similar in the two groups (Cl = 0.20 (+\\/- 0.06) and 0.22 (+\\/- 0.04) L min(-1), Vdss = 0.38 (+\\/- 0.07) and 0.39 (+\\/- 0.07) L kg(-1), AUC = 0.05 (+\\/- 0.02) and 0.04 (+\\/- 0.01) mg min mL(-1)). CONCLUSIONS: Concurrent atorvastatin administration does not alter the pharmacokinetics of alfentanil in patients undergoing elective surgery.

  13. Acute effect of hydralazine administration on pulmonary artery hemodynamics in dogs with chronic heartworm disease.

    Science.gov (United States)

    Atkins, C E; Keene, B W; McGuirk, S M; Sato, T

    1994-02-01

    In an effort to better understand the role of vasodilators in the management of pulmonary hypertension associated with chronic heartworm disease (HWD), pulmonary hemodynamic measurements were obtained from 7 experimentally infected, anesthetized dogs before and after hydralazine administration (mean dose, 1.96 mg/kg of body weight). Five dogs were maintained on room air, while 2 were maintained on 100% oxygen during the hydralazine study. The hemodynamic effect of hydralazine in dogs with HWD was evaluated, using heart rate, cardiac index, mean pulmonary artery pressure, mean arterial pressure, total pulmonary resistance, total systemic resistance, total systemic resistance/total pulmonary resistance, left ventricular dP/dtmax, left ventricular end diastolic pressure, and left and right ventricular double products ([mean arterial pressure x heart rate] and [mean pulmonary artery pressure x heart rate], respectively). Responders were defined as those in which total pulmonary resistance decreased > or = 20% without an increase in mean pulmonary arterial pressure and in which heart rate increase was < or = 10%. Comparison was also made between maximal hemodynamic effect of hydralazine with that after 100% oxygen administration for 15 minutes to previously normoxemic dogs (n = 5). Significance was determined if P < 0.05, using the paired t-test. Hydralazine induced significant reductions in mean pulmonary and systemic arterial pressures and total pulmonary resistance, with no significant change in heart rate, cardiac index, total systemic resistance, left ventricular dP/dtmax, left ventricular end diastolic pressure, or right and left ventricular double products. Four (57%) of the 7 dogs studied were considered responders. Pretreatment cardiac index, mean pulmonary artery pressure, and total pulmonary resistance did not allow differentiation of responders from nonresponders.(ABSTRACT TRUNCATED AT 250 WORDS)

  14. Effects of six months losartan administration on liver fibrosis in chronic hepatitis C patients: A pilot study

    Institute of Scientific and Technical Information of China (English)

    Silvia Sookoian; Maria Alejandra Fernández; Gustavo Casta(n)o

    2005-01-01

    AIM: To evaluate the safety and efficacy of chronic administration of losartan on hepatic fibrosis in chronic hepatitis C patients.METHODS: Fourteen patients with chronic hepatitis C non-responders (n = 10), with contraindications (n = 2)or lack of compliance (n = 2) to interferon plus ribavirin therapy and liver fibrosis were enrolled. Liver and renal function test, clinical evaluation, and liver biopsies were performed at baseline and after losartan administration at a dose of 50 mg/d during the 6 mo. The control group composed of nine patients with the same inclusion criteria and paired liver biopsies (interval 6-14 mo).Histological activity index (HAI) with fibrosis stage was assessed under blind conditions by means of Ishak's score. Subendothelial fibrosis was evaluated by digital image analyses.RESULTS: The changes in the fibrosis stage were significantly different between losartan group (decrease of 0.5±1.3) and controls (increase of 0.89±1.27;P<0.03). In the treated patients, a decrease in fibrosis stage was observed in 7/14 patients vs 1/9 control patients (P<0.04). A decrease in sub-endothelial fibrosis was observed in the losartan group. No differences were found in HAI after losartan administration. Acute and chronic decreases in systolic arterial pressures (P<0.05)were observed after the losartan administration, without changes in mean arterial pressure or renal function.CONCLUSION: Chronic AT-Ⅱ type 1 receptor (AT1R)blockade may reduce liver fibrosis in patients with chronic hepatitis C.

  15. Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus.

    Science.gov (United States)

    Nibuya, M; Nestler, E J; Duman, R S

    1996-04-01

    The present study demonstrates that chronic, but not acute, adminstration of several different classes of antidepressants, including serotonin- and norepinephrine-selective reuptake inhibitors, increases the expression of cAMP response element binding protein (CREB) mRNA in rat hippocampus. In contrast, chronic administration of several nonantidepressant psychotropic drugs did not influence expression of CREB mRNA, demonstrating the pharmacological specificity of this effect. In situ hybridization analysis demonstrates that antidepressant administration increases expression of CREB mRNA in CA1 and CA3 pyramidal and dentate gyrus granule cell layers of the hippocampus. In addition, levels of CRE immunoreactivity and of CRE binding activity were increased by chronic antidepressant administration, which indicates that expression and function of CREB protein are increased along with its mRNA. Chronic administration of the phosphodiesterase (PDE) inhibitors rolipram or papaverine also increased expression of CREB mRNA in hippocampus, demonstrating a role for the cAMP cascade. Moreover, coadministration of rolipram with imipramine resulted in a more rapid induction of CREB than with either treatment alone. Increased expression and function of CREB suggest that specific target genes may be regulated by these treatments. We have found that levels of brain-derived neurotrophic factor (BDNF) and trkB mRNA are also increased by administration of antidepressants or PDE inhibitors. These findings indicate that upregulation of CREB is a common action of chronic antidepressant treatments that may lead to regulation of specific target genes, such as BDNF and trkB, and to the long-term effects of these treatments on brain function.

  16. Cadmium chronic administration to lactating ewes. Reproductive performance, cadmium tissue accumulation and placental transfer

    Energy Technology Data Exchange (ETDEWEB)

    Floris, B.; Bomboi, G.; Sechi, P.; Marongiu, M. L. [Sassari Univ., Sassari (Italy). Dipt. di Biologia Animale; Pirino, S. [Sassari Univ., Sassari (Italy). Ist. di Patologia Generale, Anatomia Patologica e Clinica Ostetrico-chirurgica Veterinaria

    2000-12-01

    20 lactating ewes were allotted to two groups: 10 subjects received orally 100 mg/day of CdCl{sub 2} for 108 consecutive days, and the remaining 10 acted as control. Reproductive performance in ewes and cadmium tissue accumulation, both in ewes and their lambs, were investigated. The results showed that in ewes: 1) the regular cadmium intestinal intake negatively influences all reproductive parameters; 2) cadmium is particularly accumulated in kidney and liver, bur also in mammary gland, although at distinctly lower level; 3) chronic administration does not increase cadmium placental transfer in lactating pregnant subjects. [Italian] 20 pecore in lattazione sono state suddivise in 2 gruppi: 10 soggetti ricevettero per os 100 mg/giorno di CdCl{sub 2} per 108 giorni consecutivi, e i restanti 10 funsero da controllo. Sono stati studiati i parametri riproduttivi delle pecore e l'accumulo di cadmio nei tessuti, sia delle pecore che dei loro agnelli. I risultati hanno mostrato che negli ovini: 1) il regolare assorbimento intestinale di cadmio influenza negativamente tutti i parametri riproduttivi; 2) il cadmio viene accumulato principalmente nei reni e nel fegato, ma anche dalla ghiandola mammaria, sebbene in misura nettamente inferiore; 3) la somministrazione cronica di cadmio nei soggetti gravidi non incrementa il suo passaggio transplacentare.

  17. Chronic food administration of Salvia sclarea oil reduces animals' anxious and dominant behavior.

    Science.gov (United States)

    Gross, Moshe; Nesher, Elimelech; Tikhonov, Tatiana; Raz, Olga; Pinhasov, Albert

    2013-03-01

    Recent studies indicate that an oil extract from Salvia sclarea may provide clinical benefits in various pathological conditions. In comparison to extracts from other Salvia species, S. sclarea oil contains twice as much omega-3 fatty acids, which are involved in eicosanoid synthesis pathways, and has been found to contain significant levels of the psychoactive monoterpane linalool. In the present study, we examined the mood stabilizing and anxiolytic-like effects of chronic food administration of S. sclarea oil extract on behavioral and physiological parameters of mice with prominent dominant and submissive features in behavioral assays used to test mood stabilizing and antidepressant drugs. Experimental animals received oil supplemented food from the age of 4 weeks or from conception via their pregnant dams. Each age group received either S. sclarea oil- or sunflower oil-enriched feed. Dominant animals, whose pregnant mothers received S. sclarea oil-enriched feed from the date of conception, showed a significant reduction of dominant and anxiety-like behavior, in comparison to their sunflower oil-treated counterparts. S. sclarea oil-treated submissive animals exhibited a similar tendency, and showed a significant reduction in blood corticosterone levels. These findings enforce the hypothesis that S. sclarea oil possesses anxiolytic properties.

  18. Chronic arsenic poisoning in the rat: treatment with combined administration of succimers and an antioxidant.

    Science.gov (United States)

    Kannan, Gurusamy M; Flora, Swaran J S

    2004-05-01

    The influence of the coadministration of vitamin C or vitamin E on the efficacy of two thiol chelators, meso-2,3-dimercaptosuccinic acid (DMSA) or monoisoamyl DMSA, in counteracting chronic arsenic toxicity was investigated in rats. Vitamin C and vitamin E were only mildly effective when given alone or in combination with the above chelators in mobilizing arsenic from the target tissues. However, combined administration of vitamin C plus DMSA and vitamin E plus MiADMSA led to a more pronounced depletion of brain arsenic. The supplementation of vitamins was significantly effective in restoring inhibition of blood delta-aminolevulinic acid dehydratase (ALAD) oxidative stress in liver, kidneys, and brain as reflected by reduced levels of thiobarbituric acid reactive substance and oxidized and reduced glutathione levels. The results thus lead us to suggest that coadministration of vitamin E or vitamin C may be useful in the restoration of altered biochemical variables (particularly the effects on heme biosynthesis and oxidative injury) although it has only a limited role in depleting arsenic burden.

  19. Superiority of pulmonary administration of mepenzolate bromide over other routes as treatment for chronic obstructive pulmonary disease.

    Science.gov (United States)

    Tanaka, Ken-Ichiro; Kurotsu, Shota; Asano, Teita; Yamakawa, Naoki; Kobayashi, Daisuke; Yamashita, Yasunobu; Yamazaki, Hiroshi; Ishihara, Tomoaki; Watanabe, Hiroshi; Maruyama, Toru; Suzuki, Hidekazu; Mizushima, Tohru

    2014-03-28

    We recently proposed that mepenzolate bromide (mepenzolate) would be therapeutically effective against chronic obstructive pulmonary disease (COPD) due to its both anti-inflammatory and bronchodilatory activities. In this study, we examined the benefits and adverse effects associated with different routes of mepenzolate administration in mice. Oral administration of mepenzolate caused not only bronchodilation but also decreased the severity of elastase-induced pulmonary emphysema; however, compared with the intratracheal route of administration, about 5000 times higher dose was required to achieve this effect. Intravenously or intrarectally administered mepenzolate also showed these pharmacological effects. The intratracheal route of mepenzolate administration, but not other routes, resulted in protective effects against elastase-induced pulmonary damage and bronchodilation at a much lower dose than that which affected defecation and heart rate. These results suggest that the pulmonary route of mepenzolate administration may be superior to other routes (oral, intravenous or intrarectal) to treat COPD patients.

  20. Role of Corticotropin Releasing Factor 1 Signaling in Cocaine Seeking during Early Extinction in Female and Male Rats.

    Directory of Open Access Journals (Sweden)

    Angie M Cason

    Full Text Available Locus coeruleus norepinephrine (LC-NE and corticotropin releasing factor (CRF neurons are involved in stress responses, including stress's ability to drive drug relapse. Previous animal studies indicate that female rats exhibit greater drug seeking than male rats during initial drug abstinence. Moreover, females are more sensitive to the effect of stress to drive drug seeking than males. Finally, LC-NE neurons are more sensitive to CRF in females compared to males. We hypothesized that increased drug seeking in females on extinction day one (ED1 is due to increased response to the stress of early withdrawal and is dependent upon the increased response of LC in females to CRF. We predicted that LC-NE neurons would exhibit Fos activation on ED1, and that blocking CRF1 signaling would decrease drug seeking on ED1 measured by responding on an active lever previously associated with cocaine self- administration. After chronic cocaine self-administration, female and male rats underwent a test for initial extinction responding by measuring lever pressing in the absence of cocaine. Prior to this Extinction Day 1 (ED1 session, rats were injected with vehicle or the selective CRF1 antagonist (CP to measure effects of CRF antagonism on drug seeking during early abstinence. ED1 increased corticosterone in female rats, in proportion to lever responding in male and female, indicating that ED1 was stressful. Pretreatment with CP decreased cocaine seeking on ED1 more effectively in female compared to male rats. This increase in responding was associated with an increase in activation of LC NE neurons. Together, these findings indicate that stress, and signaling at CRF receptors in LC, may be involved in the increased drug seeking during initial abstinence.

  1. Tips for Teens: The Truth about Cocaine

    Science.gov (United States)

    ... and intense cravings.Cocaine may give users atemporary illusion of power and energy,but it often leaves ... of dollars on cocaine each week. Stay in control. Cocaine impairs your judgment, which may lead to ...

  2. Cerebrovascular adaptations to cocaine-induced transient ischemic attacks in the rodent brain

    Science.gov (United States)

    You, Jiang; Volkow, Nora D.; Park, Kicheon; Zhang, Qiujia; Clare, Kevin; Du, Congwu

    2017-01-01

    Occurrence of transient ischemic attacks (TIA) and cerebral strokes is a recognized risk associated with cocaine abuse. Here, we use a rodent model along with optical imaging to study cocaine-induced TIA and the associated dynamic changes in cerebral blood flow velocity (CBFv) and cerebrovasculature. We show that chronic cocaine exposure in mice resulted in marked cortical hypoperfusion, in significant arterial and venous vasoconstriction, and in a sensitized vascular response to an acute cocaine injection. Starting after 10 days of exposure, an acute cocaine challenge to these mice resulted in a TIA, which presented as hemiparalysis and was associated with an abrupt exacerbation of CBFv. The severity of the TIA correlated with the decreases in cortical CBFv such that the greater the decreases in flow, the longer the TIA duration. The severity of TIA peaked around 17–22 days of cocaine exposure and decreased thereafter in parallel to a reorganization of CBFv from superficial to deep cortical layers, along with an increase in vessel density into these layers. Here, we document for the first time to our knowledge evidence of a TIA in an animal model of chronic cocaine exposure that was associated with profound decreases in CBFv, and we revealed that while the severity of the TIA initially increased with repeated exposures, it subsequently improved in parallel to an increase in the vessel density. This suggests that strategies to accelerate cerebrovascular recovery might be therapeutically beneficial in cocaine abusers.

  3. Oxidative metabolism of cocaine: comparison of brain and liver.

    Science.gov (United States)

    Benuck, M; Reith, M E; Sershen, H; Wiener, H L; Lajtha, A

    1989-01-01

    Norcocaine (NC) and N-hydroxynorcocaine (NHNC), products of the oxidative metabolism of cocaine, were examined in plasma, brain, and liver of mice injected intraperitoneally with cocaine. Plasma levels of NHNC were altered in vivo by inhibiting esterase activity with diazinon and chloral hydrate or activating esterase activity with phenobarbital, and activating the microsomal P-450 system with phenobarbital. Changes in plasma concentrations of NHNC resulted in similar changes in brain, which were often different from those in liver. After intracisternal administration of cocaine to mice, no appreciable amount of NC or NHNC could be detected in brain; the same results were obtained upon intracisternal and intraventricular administration to rats. Microsomal preparations from mouse brain were found to be considerably less active than those from liver in converting NC to NHNC. We conclude that the cerebral oxidative metabolism of cocaine is not appreciable and that most of the NC and NHNC found in the brain after systemic cocaine administration is derived from plasma rather than formed centrally by brain microsomal enzymes.

  4. Pharmacokinetics of cocaine in pregnant and nonpregnant rhesus monkeys.

    Science.gov (United States)

    Duhart, H M; Fogle, C M; Gillam, M P; Bailey, J R; Slikker, W; Paule, M G

    1993-01-01

    To determine pharmacokinetic parameters for cocaine in rhesus monkey plasma, samples were taken over several hours after i.m. administration of cocaine plus a tritiated cocaine tracer. Cocaine and its metabolites, benzoylecgonine and norcocaine, were isolated via HPLC and quantitated using liquid scintillation spectrometry. Pregnant subjects were dosed with cocaine at 0.3 (n = 3) or 1.0 (n = 3) mg/kg, whereas nonpregnant female subjects were dosed with 1.0 mg/kg (n = 3). For the pregnant subjects, pharmacokinetic studies were conducted on about gestational day 125 and areas under the concentration versus time curve (AUCs, ng/mL x h) were 64 +/- 26 (+/- SEM) and 143 +/- 12; half-lives (t1/2s, h) were 1.9 +/- 0.6 and 1.1 +/- 0.1 after 0.3 and 1.0 mg/kg i.m., respectively. For nonpregnant subjects dosed acutely with 1.0 mg/kg, the AUC was 262 +/- 63 and the t1/2 was 1.4 +/- 0.3. There appear to be few differences in the pharmacokinetic parameters of cocaine and benzoylecgonine between pregnant and nonpregnant monkeys in this study.

  5. Novel C-1 Substituted Cocaine Analogs Unlike Cocaine or Benztropine

    OpenAIRE

    Reith, Maarten E. A.; Ali, Solav; Hashim, Audrey; Sheikh, Imran S.; Theddu, Naresh; Gaddiraju, Narendra V.; Mehrotra, Suneet; Schmitt, Kyle C.; Murray, Thomas F.; Sershen, Henry; Unterwald, Ellen M.; Davis, Franklin A.

    2012-01-01

    Despite a wealth of information on cocaine-like compounds, there is no information on cocaine analogs with substitutions at C-1. Here, we report on (R)-(−)-cocaine analogs with various C-1 substituents: methyl (2), ethyl (3), n-propyl (4), n-pentyl (5), and phenyl (6). Analog 2 was equipotent to cocaine as an inhibitor of the dopamine transporter (DAT), whereas 3 and 6 were 3- and 10-fold more potent, respectively. None of the analogs, however, stimulated mouse locomotor activity, in contrast...

  6. mGlu5 Receptors and Relapse to Cocaine-Seeking: The Role of Receptor Trafficking in Postrelapse Extinction Learning Deficits

    Directory of Open Access Journals (Sweden)

    Lori A. Knackstedt

    2016-01-01

    Full Text Available We have previously demonstrated that MTEP, an allosteric antagonist of mGlu5, infused into the nucleus accumbens attenuates relapse after abstinence from cocaine self-administration. MTEP infused into the dorsolateral striatum (dlSTR does not alter relapse but has long-lasting effects on subsequent extinction learning. Here we tested whether systemic MTEP would prevent relapse after abstinence or alter extinction learning. We also investigated the mechanism of action by which intra-dlSTR MTEP on test day alters extinction on subsequent days. Animals self-administered cocaine for 12 days followed by abstinence for 20-21 days. MTEP (0.5–5 mg/kg IP was administered prior to placement into the operant chamber for a context-primed relapse test. A separate group of animals received intra-dlSTR MTEP prior to the relapse test and were sacrificed day later. Systemic administration of MTEP attenuated abstinent-relapse without significantly affecting extinction learning. Surface biotinylation analysis of protein expression in the dlSTR revealed that, in cocaine animals, intra-dlSTR MTEP administration decreased mGlu5 surface expression and prevented changes in Arc and GluA1/GluA2 observed in their vehicle counterparts. Thus, blockade of mGlu5 receptors may be utilized in future treatment strategies for relapse prevention in humans, although the effects of chronic blockade on extinction learning should be further evaluated.

  7. Readmission patterns in patients with chronic obstructive pulmonary disease, chronic heart failure and diabetes mellitus: an administrative dataset analysis.

    Science.gov (United States)

    Brand, C; Sundararajan, V; Jones, C; Hutchinson, A; Campbell, D

    2005-05-01

    Comprehensive disease management programmes for chronic disease aim to improve patient outcomes and reduce health-care utilization. Readmission rates are often used as an outcome measure of effectiveness. This study aimed to document readmission rates, and risk for early and late readmission, for patients discharged from the Royal Melbourne Hospital with a disease diagnosis of chronic heart failure (CHF), chronic obstructive pulmonary disease (COPD) or diabetes mellitus compared to those with other general medical conditions. Eighty five (8.6%) of patients were readmitted within 28 days and 183 (20.8%) were readmitted between 29 and 180 days. No risk factors for early readmission were identified. Patients with a primary disease diagnosis of CHF and COPD are at increased risk of late readmissions (29-180 days).

  8. Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice

    Directory of Open Access Journals (Sweden)

    Koo Edward H

    2007-07-01

    Full Text Available Abstract Background Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs is associated with a reduced incidence of Alzheimer's disease (AD. We and others have shown that certain NSAIDs reduce secretion of Aβ42 in cell culture and animal models, and that the effect of NSAIDs on Aβ42 is independent of the inhibition of cyclooxygenase by these compounds. Since Aβ42 is hypothesized to be the initiating pathologic molecule in AD, the ability of these compounds to lower Aβ42 selectively may be associated with their protective effect. We have previously identified R-flurbiprofen (tarenflurbil as a selective Aβ42 lowering agent with greatly reduced cyclooxygenase activity that shows promise for testing this hypothesis. In this study we report the effect of chronic R-flurbiprofen treatment on cognition and Aβ loads in Tg2576 APP mice. Results A four-month preventative treatment regimen with R-flurbiprofen (10 mg/kg/day was administered to young Tg2576 mice prior to robust plaque or Aβ pathology. This treatment regimen improved spatial learning as assessed by the Morris water maze, indicated by an increased spatial bias during the third probe trial and an increased utilization of a place strategy to solve the water maze. These results are consistent with an improvement in hippocampal- and medial temporal lobe-dependent memory function. A modest, though not statistically significant, reduction in formic acid-soluble levels of Aβ was also observed. To determine if R-flurbiprofen could reverse cognitive deficits in Tg2576 mice where plaque pathology was already robust, a two-week therapeutic treatment was given to older Tg2576 mice with the same dose of R-flurbiprofen. This approach resulted in a significant decrease in Aβ plaque burden but no significant improvement in spatial learning. Conclusion We have found that chronic administration of R-flurbiprofen is able to attenuate spatial learning deficits if given prior to plaque deposition

  9. Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice

    Science.gov (United States)

    Kukar, Thomas; Prescott, Sonya; Eriksen, Jason L; Holloway, Vallie; Murphy, M Paul; Koo, Edward H; Golde, Todd E; Nicolle, Michelle M

    2007-01-01

    Background Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of Alzheimer's disease (AD). We and others have shown that certain NSAIDs reduce secretion of Aβ42 in cell culture and animal models, and that the effect of NSAIDs on Aβ42 is independent of the inhibition of cyclooxygenase by these compounds. Since Aβ42 is hypothesized to be the initiating pathologic molecule in AD, the ability of these compounds to lower Aβ42 selectively may be associated with their protective effect. We have previously identified R-flurbiprofen (tarenflurbil) as a selective Aβ42 lowering agent with greatly reduced cyclooxygenase activity that shows promise for testing this hypothesis. In this study we report the effect of chronic R-flurbiprofen treatment on cognition and Aβ loads in Tg2576 APP mice. Results A four-month preventative treatment regimen with R-flurbiprofen (10 mg/kg/day) was administered to young Tg2576 mice prior to robust plaque or Aβ pathology. This treatment regimen improved spatial learning as assessed by the Morris water maze, indicated by an increased spatial bias during the third probe trial and an increased utilization of a place strategy to solve the water maze. These results are consistent with an improvement in hippocampal- and medial temporal lobe-dependent memory function. A modest, though not statistically significant, reduction in formic acid-soluble levels of Aβ was also observed. To determine if R-flurbiprofen could reverse cognitive deficits in Tg2576 mice where plaque pathology was already robust, a two-week therapeutic treatment was given to older Tg2576 mice with the same dose of R-flurbiprofen. This approach resulted in a significant decrease in Aβ plaque burden but no significant improvement in spatial learning. Conclusion We have found that chronic administration of R-flurbiprofen is able to attenuate spatial learning deficits if given prior to plaque deposition in Tg2576 mice. Given its

  10. Anxiolytic profile of fluoxetine as monitored following repeated administration in animal rat model of chronic mild stress

    Directory of Open Access Journals (Sweden)

    Muhammad Farhan

    2016-09-01

    Full Text Available Background: Fluoxetine, a selective serotonin re-uptake inhibitor (SSRI, has been proposed to be more effective as an antidepressive drug as compared to other SSRIs. After chronic SSRI administration, the increase in synaptic levels of 5-HT leads to desensitization of somatodentritic 5-HT autoreceptors in the raphe nuclei. Chronic stress may alter behavioral, neurochemical and physiological responses to drug challenges and novel stressors. Methods: Twenty four male rats were used in this study. Animals of CMS group were exposed to CMS. Animals of stressed and unstressed group were administrated with fluoxetine at dose of 1.0 mg/kg s well as 5.0 mg/kg repeatedly for 07 days 1 h before exposed to CMS. The objective of the present study was to evaluate that repeated treatment with fluoxetine could attenuate CMS-induced behavioral deficits. Results: Treatment with fluoxetine attenuated CMS-induced behavioral deficits. Fluoxetine administration induced hypophagia in unstressed as well as CMS rats. Acute and repeated administration of fluoxetine increased motor activity in familiar environment but only repeated administration increased exploratory activity in open field. Anxiolytic effects of fluoxetine were greater in unstressed rats. These anxiolytic effects were produced as result of repeated administration not on acute administration of fluoxetine at 1.0 mg/kg as well as 5.0 mg/kg. Conclusion: The present study demonstrated that CMS exposure resulted into behavioral deficits and produced depressive-like symptoms. Fluoxetine, an SSRI, administration attenuated behavioral deficits induced by CMS. Anxiolytic effects of repeated fluoxetine administration were greater in unstressed than CMS animals.

  11. Chronic administration of atorvastatin could partially ameliorate erectile function in streptozotocin-induced diabetic rats

    Science.gov (United States)

    Park, Juhyun; Kwon, Oh Seong; Cho, Sung Yong; Paick, Jae-Seung; Kim, Soo Woong

    2017-01-01

    The efficacy of statins is related to the ‘common soil’ hypothesis, which proposes oxidative stress and inflammation as main pathophysiologic processes in the disease group of diabetes and endothelial dysfunction. This study evaluated the recovery of erectile function after administration of chronic statin alone in streptozotocin (STZ)-induced diabetes mellitus (DM) rats, focusing on the anti-oxidative effects and consequentially recuperated endothelial function. A total of 45 male Sprague-Dawley rats (8 weeks old) were divided into three groups (n = 15 each): an age-matched normal control group (Control group), an uncontrolled DM group (DM group), and a statin-treated group (Statin group). The rats in the DM and Statin group received an injection of STZ (60 mg/kg). Beginning 10 weeks after the establishment of DM, the Statin group received daily treatment with atorvastatin (10 mg/kg) via oral gavage for four weeks. After 14 weeks, the results of the experiment were evaluated. The ratios of intracavernosal pressure (ICP) to mean arterial pressure (MAP) were recorded with cavernosometry (20 Hz, 3 V, 0.2 msec for 30 seconds) before and after the intravenous administration of udenafil (1 mg/kg). Expression of alpha-smooth muscle actin (α-SMA) was evaluated using cavernosal tissue. In addition, changes in RhoA translocation ratio and myosin phosphatase target subunit 1 (MYPT1) phosphorylation were evaluated with western blot. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were also analyzed as measurements of oxidative stress levels. The ICP/MAP and area under the curve (AUC)/MAP ratios of the Statin group were obviously superior to the DM group, but were not comparable to the Control group (PStatin group than in the DM group (P = 0.015), and was comparable to the Control group. In contrast, MDA levels were not considerably different among the groups (P = 0.217). The RhoA translocation ratio was not significantly different among the groups (P = 0

  12. Chronic nandrolone administration induces dysfunction of the reward pathway in rats.

    Science.gov (United States)

    Zotti, Margherita; Tucci, Paolo; Colaianna, Marilena; Morgese, Maria Grazia; Mhillaj, Emanuela; Schiavone, Stefania; Scaccianoce, Sergio; Cuomo, Vincenzo; Trabace, Luigia

    2014-01-01

    Data in animal models and surveys in humans have revealed psychiatric complications of long-term anabolic androgenic steroid abuse. However, the neurobiochemical mechanisms behind the observed behavioral changes are poorly understood. The aim of the present study was to investigate the effects of nandrolone decanoate on emotional behavior and neurochemical brain alterations in gonadally intact male rats. The behavioral reactivity to the elevated plus maze and the social interaction test was used to assess anxiety-related symptoms, and the sucrose preference test was used to evaluate anhedonia. Dopaminergic, serotonergic and noradrenergic transmissions were also evaluated in selected brain areas. The chronic administration of nandrolone, at 5 mg kg(-1) injected daily for 4 weeks, induced the loss of sweet taste preference, a sign of anhedonia and dysfunction of the reward pathway. The behavioral outcomes were accompanied by reductions in the dopamine, serotonin and noradrenaline contents in the nucleus accumbens. Alterations in the time spent in the open arms and in the social interaction test were not found, suggesting that nandrolone did not induce an anxiogenic profile. No differences were revealed between the experimental groups in the amygdala in terms of the neurotransmitters measured. Our data suggest that nandrolone-treated rats have a depressive, but not anxiogenic-like, profile, accompanied by brain region-dependent changes in dopaminergic, serotonergic and noradrenergic neurotransmission. As anabolic androgenic steroid dependence is plausibly the major form of worldwide substance dependence that remains largely unexplored, it should be highlighted that our data could contribute to a better understanding of the altered rewards induced by nandrolone treatment and to the development of appropriate treatments.

  13. Olanzapine induced biochemical and histopathological changes after its chronic administration in rats

    Directory of Open Access Journals (Sweden)

    Rehmat Shah

    2016-11-01

    Full Text Available Objective: Olanzapine is a second generation antipsychotic acting mainly as a dopamine D2 and serotonine 5-HT2 receptors antagonist prescribed in the treatment of schizophrenia and various other psychiatric illnesses. Even though olanzapine is widely used in psychiatry, its effects on the architecture of pancreas, liver and kidneys are little known. The histology of pancreas especially has never been studied. For these reasons, the current study was designed to elucidate the toxic effects of chronic administration of olanzapine on pancreas, liver and kidneys and the enzymes released by these tissues in an escalating dose manner. Methods: Fourteen male rats were divided into two groups equally, the olanzapine group and the controls. Olanzapine was administered in a dose of 5 mg/kg/d for the first eight weeks, 10 mg/kg/d for next four weeks and 15 mg/kg/d through the last two week period of 14 weeks experiment. The controls received acidified saline only. Both the groups received restricted diet (20 g/12 h. The body weight and level of random blood sugar (RBS were measured on a weekly basis. The levels of lipase, amylase, alanine transaminase (ALT and aspartate transaminase (AST were determined terminally. At the end of the experiment, the tissues were dissected out for histopathological evaluation. Results: Significant loss in body weight, change in the level of random blood sugar (∗∗P  0.05. The pancreas has shown derangement of beta cells and fibrotic growth. A mild to moderate focal increase in glomerular cellularity, cellular proliferation and glomerular capsules with negligible basement membranes were observed in the kidneys. No changes were observed in the architecture of the liver. Conclusion: The findings of this study indicated that the incidence of adverse effects associated with olanzapine could be prevented/alleviated/delayed by allowing restricted diet.

  14. Effects of monoamine releasers with varying selectivity for releasing dopamine/norepinephrine versus serotonin on choice between cocaine and food in rhesus monkeys.

    Science.gov (United States)

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

    2011-12-01

    Monoamine releasers constitute one class of candidate medications for the treatment of cocaine abuse, and concurrent cocaine-versus-food choice procedures are potentially valuable as experimental tools to evaluate the efficacy and safety of candidate medications. This study assessed the choice between cocaine and food by rhesus monkeys during treatment with five monoamine releasers that varied in selectivity to promote the release of dopamine and norepinephrine versus serotonin (5HT) [m-fluoroamphetamine, (+)-phenmetrazine, (+)-methamphetamine, napthylisopropylamine and (±)-fenfluramine]. Rhesus monkeys (n=8) responded under a concurrent-choice schedule of food delivery (1-g pellets, fixed ratio 100 schedule) and cocaine injections (0-0.1 mg/kg/injection, fixed ratio 10 schedule). Cocaine choice dose-effect curves were determined daily during continuous 7-day treatment with saline or with each test compound dose. During saline treatment, cocaine maintained a dose-dependent increase in cocaine choice, and the highest cocaine doses (0.032-0.1 mg/kg/injection) maintained almost exclusive cocaine choice. Efficacy of monoamine releasers to decrease cocaine choice corresponded to their pharmacological selectivity to release dopamine and norepinephrine versus 5HT. None of the releasers reduced cocaine choice or promoted reallocation of responding to food choice to the same extent as when saline was substituted for cocaine. These results extend the range of conditions across which dopamine and norepinephrine-selective releasers have been shown to reduce cocaine self-administration.

  15. Pneumorachis after cocaine sniffing

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    S. Challita

    2014-01-01

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

  16. 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

    Muscarinic cholinergic receptors modulate dopaminergic function in brain pathways thought to mediate cocaine's abuse-related effects. Here, we sought to confirm and extend in the mouse species findings that nonselective muscarinic receptor antagonists can enhance cocaine's discriminative stimulus....... More importantly, we tested the hypothesis that muscarinic receptor agonists with varied receptor subtype selectivity can blunt cocaine's discriminative stimulus and reinforcing effects; we hypothesized a critical role for the M(1) and/or M(4) receptor subtypes in this modulation. Mice were trained...... to discriminate cocaine from saline, or to self-administer intravenous cocaine chronically. The nonselective muscarinic antagonists scopolamine and methylscopolamine, the nonselective muscarinic agonists oxotremorine and pilocarpine, the M(1)/M(4)-preferring agonist xanomeline, the putative M(1)-selective agonist...

  17. Extensive Necrotic Purpura in Levamisole-Adulterated Cocaine Abuse - A Case Report.

    Science.gov (United States)

    Le Garff, Erwan; Tournel, Gilles; Becquart, Coralie; Cottencin, Olivier; Dupin, Nicolas; Delaporte, Emmanuel; Hedouin, Valéry

    2016-11-01

    Levamisole, which is used as an adulterated compound of cocaine, is currently being seen year after year in cocaine intoxication. For a few cases in the last decade, necrotic purpura and neutropenia after levamisole/cocaine intoxication have been described in the medical community. Herein, we present an original case of levamisole intoxication of a 40-year-old woman who smoked heroin and cocaine few during a month. She rapidly presented an extensive necrotic purpura of the nose, cheeks and extremities (lower and upper), and immunologic reactions (positive anti-MPO and anti-HNE). Levamisole was detected on hairs with ultra-high performance liquid chromatography and tandem mass spectrometry. The case reports also a probable cocaine supplier deceit, which bring pure drug for hospital investigation after the intoxication of his client. The intoxicated woman had survived with several skin and chronic pain complications. That case recalls the knowledge about levamisole with a short review of the forensic literature.

  18. Role of Tet1 and 5-hydroxymethylcytosine in cocaine action.

    Science.gov (United States)

    Feng, Jian; Shao, Ningyi; Szulwach, Keith E; Vialou, Vincent; Huynh, Jimmy; Zhong, Chun; Le, Thuc; Ferguson, Deveroux; Cahill, Michael E; Li, Yujing; Koo, Ja Wook; Ribeiro, Efrain; Labonte, Benoit; Laitman, Benjamin M; Estey, David; Stockman, Victoria; Kennedy, Pamela; Couroussé, Thomas; Mensah, Isaac; Turecki, Gustavo; Faull, Kym F; Ming, Guo-li; Song, Hongjun; Fan, Guoping; Casaccia, Patrizia; Shen, Li; Jin, Peng; Nestler, Eric J

    2015-04-01

    Ten-eleven translocation (TET) enzymes mediate the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which is enriched in brain, and its ultimate DNA demethylation. However, the influence of TET and 5hmC on gene transcription in brain remains elusive. We found that ten-eleven translocation protein 1 (TET1) was downregulated in mouse nucleus accumbens (NAc), a key brain reward structure, by repeated cocaine administration, which enhanced behavioral responses to cocaine. We then identified 5hmC induction in putative enhancers and coding regions of genes that have pivotal roles in drug addiction. Such induction of 5hmC, which occurred similarly following TET1 knockdown alone, correlated with increased expression of these genes as well as with their alternative splicing in response to cocaine administration. In addition, 5hmC alterations at certain loci persisted for at least 1 month after cocaine exposure. Together, these reveal a previously unknown epigenetic mechanism of cocaine action and provide new insight into how 5hmC regulates transcription in brain in vivo.

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

    NARCIS (Netherlands)

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

    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

  20. Cocaine and benzoylecgonine oral fluid on-site screening and confirmation.

    Science.gov (United States)

    Ellefsen, Kayla N; Concheiro, Marta; Pirard, Sandrine; Gorelick, David A; Huestis, Marilyn A

    2016-01-01

    Accurate on-site devices to screen for drug intake are critical for establishing whether an individual is driving under the influence of drugs (DUID); however, on-site oral fluid (OF) cocaine device performance is variable. We evaluated the performance of a newly developed benzoylecgonine (BE) test-strip for the Draeger® DrugTest 5000 device (20 µg/L cut-off) with equivalent cross reactivity for cocaine and BE. Ten cocaine users provided OF, collected with the Draeger cassette and Oral-Eze® and StatSure Saliva Sampler(TM) devices, up to 69 h following 25 mg intravenous cocaine administration. All screening results were confirmed by a validated two-dimensional-gas chromatography-mass spectrometry (2D-GC-MS) method for cocaine and/or BE. Cocaine test-strip median Tlast for screening only results was 6.5 h, and 6.5 h with Oral-Eze® and 4 h for StatSure OF confirmation for cocaine and/or BE at 1, 8, and 10 µg/L; sensitivity, specificity, and efficiency ranged from 85.5 to 100% and 83.3 to 100% for cocaine only confirmation at 8 and 10 µg/L. For the BE test-strip, median Tlast was 12.5 h for screening only and confirmation for cocaine and/or BE at all three cut-offs; sensitivity, specificity, and efficiency ranged from 85.5 to 97.5% and 78.4 to 97.4% with cocaine and/or BE confirmation at 8 and 10 µg/L cut-offs, respectively. The Draeger cocaine test-strip with cocaine only confirmation offers a useful option for monitoring the acute intoxication phase of DUID; additionally the BE test-strip with cocaine and/or BE confirmation increases the length of detection of cocaine intake for workplace drug testing, drug court, parole, pain management, drug treatment programs and both the acute cocaine intoxication and cocaine crash/fatigue phase of DUID. Copyright © 2016 John Wiley & Sons, Ltd.

  1. 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

  2. Cocaine dependence and thalamic functional connectivity: a multivariate pattern analysis

    Directory of Open Access Journals (Sweden)

    Sheng Zhang

    2016-01-01

    Full Text Available Cocaine dependence is associated with deficits in cognitive control. Previous studies demonstrated that chronic cocaine use affects the activity and functional connectivity of the thalamus, a subcortical structure critical for cognitive functioning. However, the thalamus contains nuclei heterogeneous in functions, and it is not known how thalamic subregions contribute to cognitive dysfunctions in cocaine dependence. To address this issue, we used multivariate pattern analysis (MVPA to examine how functional connectivity of the thalamus distinguishes 100 cocaine-dependent participants (CD from 100 demographically matched healthy control individuals (HC. We characterized six task-related networks with independent component analysis of fMRI data of a stop signal task and employed MVPA to distinguish CD from HC on the basis of voxel-wise thalamic connectivity to the six independent components. In an unbiased model of distinct training and testing data, the analysis correctly classified 72% of subjects with leave-one-out cross-validation (p < 0.001, superior to comparison brain regions with similar voxel counts (p < 0.004, two-sample t test. Thalamic voxels that form the basis of classification aggregate in distinct subclusters, suggesting that connectivities of thalamic subnuclei distinguish CD from HC. Further, linear regressions provided suggestive evidence for a correlation of the thalamic connectivities with clinical variables and performance measures on the stop signal task. Together, these findings support thalamic circuit dysfunction in cognitive control as an important neural marker of cocaine dependence.

  3. Mitochondrial dysfunction and lipid peroxidation in rat frontal cortex by chronic NMDA administration can be partially prevented by lithium treatment.

    Science.gov (United States)

    Kim, Helena K; Isaacs-Trepanier, Cameron; Elmi, Nika; Rapoport, Stanley I; Andreazza, Ana C

    2016-05-01

    Chronic N-methyl-d-aspartate (NMDA) administration to rats may be a model to investigate excitotoxicity mediated by glutamatergic hyperactivity, and lithium has been reported to be neuroprotective. We hypothesized that glutamatergic hyperactivity in chronic NMDA injected rats would cause mitochondrial dysfunction and lipid peroxidation in the brain, and that chronic lithium treatment would ameliorate some of these NMDA-induced alterations. Rats treated with lithium for 6 weeks were injected i.p. 25 mg/kg NMDA on a daily basis for the last 21 days of lithium treatment. Brain was removed and frontal cortex was analyzed. Chronic NMDA decreased brain levels of mitochondrial complex I and III, and increased levels of the lipid oxidation products, 8-isoprostane and 4-hydroxynonenal, compared with non-NMDA injected rats. Lithium treatment prevented the NMDA-induced increments in 8-isoprostane and 4-hydroxynonenal. Our findings suggest that increased chronic activation of NMDA receptors can induce alterations in electron transport chain complexes I and III and in lipid peroxidation in brain. The NMDA-induced changes may contribute to glutamate-mediated excitotoxicity, which plays a role in brain diseases such as bipolar disorder. Lithium treatment prevented changes in 8-isoprostane and 4-hydroxynonenal, which may contribute to lithium's reported neuroprotective effect and efficacy in bipolar disorder.

  4. 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.

  5. The characterization of neuroenergetic effects of chronic L-tyrosine administration in young rats: evidence for striatal susceptibility.

    Science.gov (United States)

    Ferreira, Gabriela K; Carvalho-Silva, Milena; Gomes, Lara M; Scaini, Giselli; Teixeira, Leticia J; Mota, Isabella T; Schuck, Patrícia F; Ferreira, Gustavo C; Streck, Emilio L

    2015-02-01

    Tyrosinemia type II is an inborn error of metabolism caused by a deficiency in hepatic cytosolic aminotransferase. Affected patients usually present a variable degree of mental retardation, which may be related to the level of plasma tyrosine. In the present study we evaluated effect of chronic administration of L-tyrosine on the activities of citrate synthase, malate dehydrogenase, succinate dehydrogenase and complexes I, II, II-III and IV in cerebral cortex, hippocampus and striatum of rats in development. Chronic administration consisted of L-tyrosine (500 mg/kg) or saline injections 12 h apart for 24 days in Wistar rats (7 days old); rats were killed 12 h after last injection. Our results demonstrated that L-tyrosine inhibited the activity of citrate synthase in the hippocampus and striatum, malate dehydrogenase activity was increased in striatum and succinate dehydrogenase, complexes I and II-III activities were inhibited in striatum. However, complex IV activity was increased in hippocampus and inhibited in striatum. By these findings, we suggest that repeated administrations of L-tyrosine cause alterations in energy metabolism, which may be similar to the acute administration in brain of infant rats. Taking together the present findings and evidence from the literature, we hypothesize that energy metabolism impairment could be considered an important pathophysiological mechanism underlying the brain damage observed in patients with tyrosinemia type II.

  6. Cocaine activates Rac1 to control structural and behavioral plasticity in caudate putamen.

    Science.gov (United States)

    Li, Juan; Zhang, Lei; Chen, Zhenzhong; Xie, Minjuan; Huang, Lu; Xue, Jinhua; Liu, Yutong; Liu, Nuyun; Guo, Fukun; Zheng, Yi; Kong, Jiming; Zhang, Lin; Zhang, Lu

    2015-03-01

    Repeated exposure to cocaine was previously found to cause sensitized behavioral responses and structural remodeling on medium spiny neurons of the nucleus accumbens (NAc) and caudate putamen (CPu). Rac1 has emerged as a key integrator of environmental cues that regulates dendritic cytoskeletons. In this study, we investigated the role of Rac1 in cocaine-induced dendritic and behavioral plasticity in the CPu. We found that Rac1 activation was reduced in the NAc but increased in the CPu following repeated cocaine treatment. Inhibition of Rac1 activity by a Rac1-specific inhibitor NSC23766, overexpression of a dominant negative mutant of Rac1 (T17N-Rac1) or local knockout of Rac1 attenuated the cocaine-induced increase in dendrites and spine density in the CPu, whereas overexpression of a constitutively active Rac1 exert the opposite effect. Moreover, NSC23766 reversed the increased number of asymmetric spine synapses in the CPu following chronic cocaine exposure. Downregulation of Rac1 activity likewise attenuates behavioral reward responses to cocaine exposure, with activation of Rac1 producing the opposite effect. Thus, Rac1 signaling is differentially regulated in the NAc and CPu after repeated cocaine treatment, and induction of Rac1 activation in the CPu is important for cocaine exposure-induced dendritic remodeling and behavioral plasticity.

  7. 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

  8. Effects of chronic lithium administration on renal acid excretion in humans and rats

    OpenAIRE

    Weiner, I. David; Leader, John P.; Bedford, Jennifer J.; Verlander, Jill W.; Ellis, Gaye; Kalita, Priyakshi; Vos, Frederiek; de Jong, Sylvia; Walker, Robert J.

    2014-01-01

    Abstract Lithium therapy's most common side effects affecting the kidney are nephrogenic diabetes insipidus (NDI) and chronic kidney disease. Lithium may also induce a distal renal tubular acidosis. This study investigated the effect of chronic lithium exposure on renal acid–base homeostasis, with emphasis on ammonia and citrate excretion. We compared 11 individuals on long‐term lithium therapy with six healthy individuals. Under basal conditions, lithium‐treated individuals excreted signific...

  9. Enhancement of behavioral sensitization, anxiety-like behavior, and hippocampal and frontal cortical CREB levels following cocaine abstinence in mice exposed to cocaine during adolescence.

    Directory of Open Access Journals (Sweden)

    Maria Cristina Valzachi

    Full Text Available Adolescence has been linked to greater risk-taking and novelty-seeking behavior and a higher prevalence of drug abuse and risk of relapse. Decreases in cyclic adenosine monophosphate response element binding protein (CREB and phosphorylated CREB (pCREB have been reported after repeated cocaine administration in animal models. We compared the behavioral effects of cocaine and abstinence in adolescent and adult mice and investigated possible age-related differences in CREB and pCREB levels. Adolescent and adult male Swiss mice received one daily injection of saline or cocaine (10 mg/kg, i.p. for 8 days. On day 9, the mice received a saline injection to evaluate possible environmental conditioning. After 9 days of withdrawal, the mice were tested in the elevated plus maze to evaluate anxiety-like behavior. Twelve days after the last saline/cocaine injection, the mice received a challenge injection of either cocaine or saline, and locomotor activity was assessed. One hour after the last injection, the brains were extracted, and CREB and pCREB levels were evaluated using Western blot in the prefrontal cortex (PFC and hippocampus. The cocaine-pretreated mice during adolescence exhibited a greater magnitude of the expression of behavioral sensitization and greater cocaine withdrawal-induced anxiety-like behavior compared with the control group. Significant increases in CREB levels in the PFC and hippocampus and pCREB in the hippocampus were observed in cocaine-abstinent animals compared with the animals treated with cocaine in adulthood. Interestingly, significant negative correlations were observed between cocaine sensitization and CREB levels in both regions. These results suggest that the behavioral and neurochemical consequences of psychoactive substances in a still-developing nervous system can be more severe than in an already mature nervous system.

  10. Lesions of the oral mucosa in cocaine users who apply the drug topically.

    Science.gov (United States)

    Gandara-Rey, J M; Diniz-Freitas, M; Gandara-Vila, P; Blanco-Carrion, A; Garcia-Garcia, A

    2002-01-01

    The use and abuse of cocaine is increasingly frequent in many countries, and the associated problems are increasingly evident. The effects of cocaine in the oral cavity vary depending on the form used and the route of self-administration. In the present study we describe the lesions observed in four patients with a history of topical self-application of cocaine to the oral and/or nasal mucosa, with the aim of relieving pain produced by cocaine-induced cluster headache. In three of the four patients this practice has led to erythematous lesions, while the remaining patient showed gingival recession and bone sequestration. These lesions can probably be attributed to the vasoconstrictor activity of cocaine, and to its caustic effects on the mucosa.

  11. Effects of six weeks of chronic ethanol administration on the behavioral outcome of rats after lateral fluid percussion brain injury.

    Science.gov (United States)

    Zhang, L; Maki, A; Dhillon, H S; Barron, S; Clerici, W J; Hicks, R; Kraemer, P J; Butcher, J; Prasad, R M

    1999-03-01

    This study examined the effects of 6 weeks of chronic ethanol administration on the behavioral outcome in rats after lateral fluid percussion (FP) brain injury. Rats were given either an ethanol liquid diet (ethanol diet-groups) or a pair-fed isocaloric sucrose control diet (control diet groups) for 6 weeks. After 6 weeks, the ethanol diet was discontinued for the ethanol diet rats and they were then given the control sucrose diet for 2 days. During those 2 days, the rats were trained to perform a beam-walking task and subjected to either lateral FP brain injury of low to moderate severity (1.8 atm) or to sham operation. In both the control diet and the ethanol diet groups, lateral FP brain injury caused beam-walking impairment on days 1 and 2 and spatial learning disability on days 7 and 8 after brain injury. There were no significant differences in beam-walking performance and spatial learning disability between brain injured animals from the control and ethanol diet groups. However, a trend towards greater behavioral deficits was observed in brain injured animals in the ethanol diet group. Histologic analysis of both diet groups after behavioral assessment revealed comparable ipsilateral cortical damage and observable CA3 neuronal loss in the ipsilateral hippocampus. These results only suggest that chronic ethanol administration, longer than six weeks of administration, may worsen behavioral outcome following lateral FP brain injury. For more significant behavioral and/or morphological change to occur, we would suggest that the duration of chronic ethanol administration must be increased.

  12. Reinforcer interactions under concurrent schedules of food, water, and intravenous cocaine.

    Science.gov (United States)

    Dworkin, S.I.; Mirkis, S.; Smith, J.E.

    1990-01-01

    Rats housed in three-lever, operant-conditioning chambers were trained under a concurrent, chained fixed-ratio 1, fixed-ratio 9 schedule (conc chain FR1 FR9) of food and water deliveries. After stable patterns of food and water intake were observed, the rats were prepared with intravenous catheters and a drug self-administration option was added to the schedule. Cocaine infusions (0.33 mg/infusion) were available for only 6 h (09.00 h-15.00 h), while access to food and water was available for 24 h. Addition of the cocaine option produced a minimal decrease in food and water intake and a considerable disruption ruption of food and water intake patterns. Changes in the cocaine dose (0.08-0.84 mg/infusion) did not alter responding on the levers resulting in either food or water deliveries. Cocaine self-administration, however, showed an inverted "U" shaped function as the dose of cocaine was increased. Drug extinction probes resulted in a significant increase in responding on the levers resulting in food and water deliveries and substantial decreases on the lever previously resulting in cocaine infusions. Twenty-four hour food extinction probes decreased responding on the levers resulting in food and water deliveries and produced a modest decrease in the self-administration of cocaine.

  13. Norcocaine and cocaethylene distribution patterns in hair samples from light, moderate, and heavy cocaine users

    Science.gov (United States)

    Rossi, Riccardo; Aroni, Kyriaki; Gili, Alessio; Bacci, Mauro; Pascali, Vincenzo; Fucci, Nadia

    2015-01-01

    Even though hair analysis often seems to be the best choice for retrospective monitoring of cocaine intake, differentiating between incorporated cocaine and external contamination is widely debated. In this study we report results obtained in 90 hair samples from addicts. All samples were analyzed for cocaine, benzoylecgonine, norcocaine, cocaethylene, and tropococaine by gas chromatography‐mass spectrometry (GC‐MS) techniques coupled with direct immersion solid‐phase micro‐extraction. Cocaine concentrations were stratified into three classes of usage: light (0.5–3 ng/mg), moderate (3.1–10 ng/mg) and heavy (10.1–40 ng/mg). The Substance Abuse and Mental Health Services Administration cut‐off criteria for establishing active cocaine use were applied to the results. For all samples criteria were cocaine levels above 0.5 ng/mg (ranging from 1.63 to 39.29 ng/mg, mean 9.49 ng/mg), benzoylecgonine concentrations ≥ 0.05 ng/mg (ranging from 0.19 to 5.77 ng/mg, mean 1.40), and benzoylecgonine to cocaine % ratio ≥5% (from 6.43 to 26.09%). Norcocaine was present in 58.9% of samples (concentration range: 0.22–3.14 ng/mg) and was strongly predictive only of heavy cocaine use (sensitivity 100% for cocaine concentrations above 9.58 ng/mg). Twenty hair samples from moderate and heavy users tested positive for cocaethylene (concentration range: 0.22–1.98 ng/mg, mean 0.73 ng/mg). This study on hair samples with no chance of false positive cases highlights the very limited applications of testing minor cocaine metabolites for definitive proof of active cocaine consumption. © 2015 The Authors. Drug Testing and Analysis Published by John Wiley & Sons, Ltd. PMID:26621770

  14. Necrotizing and crescentic glomerulonephritis with membranous nephropathy in a patient exposed to levamisole-adulterated cocaine.

    Science.gov (United States)

    Carrara, Camillo; Emili, Stefano; Lin, Mercury; Alpers, Charles E

    2016-04-01

    Levamisole is an antihelminthic agent widely used as an adulterant of illicit cocaine recently implicated as a cause of antineutrophil cytoplasmic antibody (ANCA)-associated microscopic polyangiitis in cocaine abusers. An isolated case of membranous nephropathy (MN) associated with levamisole exposure has also been reported. We report the first case, to our knowledge, of a patient with both microscopic polyangiitis manifest as a pauci-immune necrotizing and crescentic glomerulonephritis and concurrent MN in the setting of chronic cocaine abuse and presumed levamisole exposure, raising the hypothesis that levamisole was the causative agent in the development of this rare dual glomerulopathy.

  15. Changes in ensemble activity of hippocampus CA1 neurons induced by chronic morphine administration in freely behaving mice.

    Science.gov (United States)

    Liu, F; Jiang, H; Zhong, W; Wu, X; Luo, J

    2010-12-15

    The hippocampus plays an important role in the formation of new memories and spatial navigation. Recently, growing evidence supports the view that it is also involved in addiction to opiates and other drugs. Theoretical and experimental studies suggest that hippocampal neural-network oscillations at specific frequencies and unit firing patterns reflect information of learning and memory encoding. Here, using multichannel recordings from the hippocampal CA1 area in behaving mice, we investigated the phase correlations between the theta (4-10 Hz) and gamma (40-100 Hz) oscillations, and the timing of spikes modulated by these oscillations. Local field potentials and single unit recordings in the CA1 area of mice receiving chronic morphine treatment revealed that the power of the theta rhythm was strongly increased; at the same time, the theta frequency during different behavioral states shifted markedly, and the characteristic coupling of theta and gamma oscillations was altered. Surprisingly, though the gamma oscillation frequency changed, the power of gamma lacking theta did not. Moreover, the timing of pyramidal cell spikes relative to the theta rhythm and the timing of interneuron spikes relative to the gamma rhythm changed during chronic morphine administration. Furthermore, these responses were impaired by a selective D1/D5 receptor antagonist intra-hippocampus injection. These results indicate that chronic morphine administration induced the changes of ensemble activity in the CA1 area, and these changes were dependent on local dopamine receptor activation.

  16. Administration of Lactobacillus helveticus NS8 improves behavioral, cognitive, and biochemical aberrations caused by chronic restraint stress.

    Science.gov (United States)

    Liang, S; Wang, T; Hu, X; Luo, J; Li, W; Wu, X; Duan, Y; Jin, F

    2015-12-03

    Increasing numbers of studies have suggested that the gut microbiota is involved in the pathophysiology of stress-related disorders. Chronic stress can cause behavioral, cognitive, biochemical, and gut microbiota aberrations. Gut bacteria can communicate with the host through the microbiota-gut-brain axis (which mainly includes the immune, neuroendocrine, and neural pathways) to influence brain and behavior. It is hypothesized that administration of probiotics can improve chronic-stress-induced depression. In order to examine this hypothesis, the chronic restraint stress depression model was established in this study. Adult specific pathogen free (SPF) Sprague-Dawley rats were subjected to 21 days of restraint stress followed by behavioral testing (including the sucrose preference test (SPT), elevated-plus maze test, open-field test (OFT), object recognition test (ORT), and object placement test (OPT)) and biochemical analysis. Supplemental Lactobacillus helveticus NS8 was provided every day during stress until the end of experiment, and selective serotonin reuptake inhibitor (SSRI) citalopram (CIT) served as a positive control. Results showed that L. helveticus NS8 improved chronic restraint stress-induced behavioral (anxiety and depression) and cognitive dysfunction, showing an effect similar to and better than that of CIT. L. helveticus NS8 also resulted in lower plasma corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels, higher plasma interleukin-10 (IL-10) levels, restored hippocampal serotonin (5-HT) and norepinephrine (NE) levels, and more hippocampal brain-derived neurotrophic factor (BDNF) mRNA expression than in chronic stress rats. Taken together, these results indicate an anti-depressant effect of L. helveticus NS8 in rats subjected to chronic restraint stress depression and that this effect could be due to the microbiota-gut-brain axis. They also suggest the therapeutic potential of L. helveticus NS8 in stress-related and possibly other

  17. Gene by Disease Interaction on Orbitofrontal Gray Matter in Cocaine Addiction

    Energy Technology Data Exchange (ETDEWEB)

    Alia-Klein, N.; Alia-Klein, N.; Parvaz, M.A.; Woicik, P.A.; Konova, A.; Maloney, T.; Shumay, E.; Wang, R.; Telang, F.; Biegon, A.; Wang, G.-J.; Fowler, J.S.; Tomasi, D.; Volkow, N.D.; Goldstein, R.Z.

    2010-12-05

    Chronic cocaine use has been associated with structural deficits in brain regions having dopamine receptive neurons. However, the concomitant use of other drugs and common genetic variability in monoamine regulation present additional structural variability. We therefore examined variations in gray matter volume (GMV) as a function of lifetime drug use and the monoamine oxidase A (MAOA) genotype in cocaine use disorders (CUD) and healthy controls.

  18. Molecular mechanism for a gateway drug: epigenetic changes initiated by nicotine prime gene expression by cocaine.

    Science.gov (United States)

    Levine, Amir; Huang, Yanyou; Drisaldi, Bettina; Griffin, Edmund A; Pollak, Daniela D; Xu, Shiqin; Yin, Deqi; Schaffran, Christine; Kandel, Denise B; Kandel, Eric R

    2011-11-02

    In human populations, cigarettes and alcohol generally serve as gateway drugs, which people use first before progressing to marijuana, cocaine, or other illicit substances. To understand the biological basis of the gateway sequence of drug use, we developed an animal model in mice and used it to study the effects of nicotine on subsequent responses to cocaine. We found that pretreatment of mice with nicotine increased the response to cocaine, as assessed by addiction-related behaviors and synaptic plasticity in the striatum, a brain region critical for addiction-related reward. Locomotor sensitization was increased by 98%, conditioned place preference was increased by 78%, and cocaine-induced reduction in long-term potentiation (LTP) was enhanced by 24%. The responses to cocaine were altered only when nicotine was administered first, and nicotine and cocaine were then administered concurrently. Reversing the order of drug administration was ineffective; cocaine had no effect on nicotine-induced behaviors and synaptic plasticity. Nicotine primed the response to cocaine by enhancing its ability to induce transcriptional activation of the FosB gene through inhibition of histone deacetylase, which caused global histone acetylation in the striatum. We tested this conclusion further and found that a histone deacetylase inhibitor simulated the actions of nicotine by priming the response to cocaine and enhancing FosB gene expression and LTP depression in the nucleus accumbens. Conversely, in a genetic mouse model characterized by reduced histone acetylation, the effects of cocaine on LTP were diminished. We achieved a similar effect by infusing a low dose of theophylline, an activator of histone deacetylase, into the nucleus accumbens. These results from mice prompted an analysis of epidemiological data, which indicated that most cocaine users initiate cocaine use after the onset of smoking and while actively still smoking, and that initiating cocaine use after smoking

  19. Acute withdrawal from repeated cocaine treatment enhances latent inhibition of a conditioned fear response.

    Science.gov (United States)

    Murphy, C A; Heidbreder, C; Feldon, J

    2001-02-01

    Psychostimulant-induced locomotor sensitization and disrupted latent inhibition (LI) of a classically conditioned association are two paradigms that have been widely studied as animal behavioural models of psychosis. In this study we assessed the effects of withdrawal from the repeated intermittent administration of cocaine on LI of a conditioned fear response. Animals which were either preexposed (PE) to a tone conditioned stimulus (CS) or naive to the tone (i.e. non-preexposed: NPE) subsequently experienced 10 pairings of the tone CS with footshock. Afterwards, both groups received five daily injections of cocaine (20 mg/kg, i.p.) or saline. After 3 days of withdrawal from drug treatment, animals were tested for conditioned freezing to the context of the footshock chamber, and 1 day later, for conditioned freezing to the tone CS. Cocaine-sensitized animals exhibited markedly enhanced LI compared to saline-treated animals, due to the fact that NPE-cocaine animals spent more time freezing during the tone CS than NPE-saline animals, whereas PE-cocaine animals showed a tendency toward reduced freezing compared to the saline groups. While these results suggest the presence of increased anxiety in cocaine-withdrawn NPE animals, the absence of this effect in cocaine-withdrawn PE rats indicates that cocaine withdrawal also influences the retrieval of previously learned information.

  20. 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

  1. SERUM PROTEIN CHANGES IN RABBITS AFTER CHRONIC ADMINISTRATION OF LEAD AND CADMIUM

    Directory of Open Access Journals (Sweden)

    Hristo HRISTEV

    2008-07-01

    Full Text Available The infl uence of lead (5mg/kg b.w and cadmium (2mg/kg b.w after chronic treatment of the rabbits on serum protein is investigated. Signifi cantly raised content of the cholesterol, ASAT and ALAT; hypo-albuminemia and hyperbetaglobulinemia of the background of one hypoproteinemia and low A/G coeffi cient are established. On basis of obtained result can to show degree of liver parenchyma damage and as trial for used the hyperbeta-globulinemia (at chronic treatment with cadmium is stronger markedly as indicator for delimitation of enteral from parenteral toxication, at that is noted hypergamma-globulinemia.

  2. Spectral confocal imaging of fluorescently tagged nicotinic receptors in knock-in mice with chronic nicotine administration.

    Science.gov (United States)

    Renda, Anthony; Nashmi, Raad

    2012-02-10

    Ligand-gated ion channels in the central nervous system (CNS) are implicated in numerous conditions with serious medical and social consequences. For instance, addiction to nicotine via tobacco smoking is a leading cause of premature death worldwide (World Health Organization) and is likely caused by an alteration of ion channel distribution in the brain. Chronic nicotine exposure in both rodents and humans results in increased numbers of nicotinic acetylcholine receptors (nAChRs) in brain tissue. Similarly, alterations in the glutamatergic GluN1 or GluA1 channels have been implicated in triggering sensitization to other addictive drugs such as cocaine, amphetamines and opiates. Consequently, the ability to map and quantify distribution and expression patterns of specific ion channels is critically important to understanding the mechanisms of addiction. The study of brain region-specific effects of individual drugs was advanced by the advent of techniques such as radioactive ligands. However, the low spatial resolution of radioactive ligand binding prevents the ability to quantify ligand-gated ion channels in specific subtypes of neurons. Genetically encoded fluorescent reporters, such as green fluorescent protein (GFP) and its many color variants, have revolutionized the field of biology. By genetically tagging a fluorescent reporter to an endogenous protein one can visualize proteins in vivo. One advantage of fluorescently tagging proteins with a probe is the elimination of antibody use, which have issues of nonspecificity and accessibility to the target protein. We have used this strategy to fluorescently label nAChRs, which enabled the study of receptor assembly using Förster Resonance Energy Transfer (FRET) in transfected cultured cells. More recently, we have used the knock-in approach to engineer mice with yellow fluorescent protein tagged α4 nAChR subunits (α4YFP), enabling precise quantification of the receptor ex vivo at submicrometer resolution in CNS

  3. COMPARATIVE EVALUATION OF BARBERIS ARISTATA EXTRACT AS SYSTEMIC ADMINISTRATION AND LOCAL APPLICATION IN MANAGEMENT OF CHRONIC PHARYNGITIS

    Directory of Open Access Journals (Sweden)

    Bhardwaj Atul

    2013-02-01

    Full Text Available Pharynx is a cross road between respiratory tract and alimentary canal and is a frequent site of inflammatory pathologies. Chronic pharyngitis is not a life threatening disorder but surely an incapacitating malady by virtue of its recalcitrant behaviour, frequent antibiotic consumption and compromised social output and quality of life and hence can not be nominated as innocuous disease by any stretch of imagination per se. Berberis aristata DC. (Family - Berberidaceae or Daru Haridra in Ayurveda is historically and time tested drug used primarily in inflammatory disorders. The usage of Berberis aristata is well documented in non healing wounds, infective disorders of the eye, hepatobiliary stimulation, chronic inflammatory mucosal disorders and skin diseases. Berberine which is chief phytochemical active constituent of Barberis aristata as has got proven action as an anti inflammatory, anti hyperplastic, immunomodulation, enhancement of delayed T cell mediated activity, anti oxidant, anti pyretic, analgesic and cytoprotective actions. Present randomized, single blind, prospective, unicenteral experimental clinical trial intends to compare to effectiveness of Barberis aristata extract as systemic administration and local application (oral rinse by ramifying clinically diagnosed 120 chronic pharyngitis patients into two trial groups. Paired ‘t’ test was used to evaluate the individual effectiveness of the trial drugs and also to compare the outcome of the two trial drugs administration as an inter group comparison. Statistical analysis conspicuously reflected the superior outcome in favour of systemic usage of Barberis aristata extract than that of oral rinse and the difference may be attributed to the fact that constant salivation had restricted the contact time of the drug on inflamed mucosa to a few minutes only and flushing is the end result of the locally applied drug invariably, but this incapacitation is bypassed by making the drug

  4. Effects of chronic delta-9-tetrahydrocannabinol (THC) administration on neurotransmitter concentrations and receptor binding in the rat brain.

    Science.gov (United States)

    Ali, S F; Newport, G D; Scallet, A C; Gee, K W; Paule, M G; Brown, R M; Slikker, W

    1989-01-01

    THC is the major psychoactive constituent of marijuana and is also known as an hallucinogenic compound. Numerous reports have shown that large doses of THC produce significant alterations in various neurotransmitter systems. The present study was designed to determine whether chronic exposure to THC produces significant alterations in selected neurotransmitter systems (dopamine, serotonin, acetylcholine, GABAergic, benzodiazepine, and opiate) in the rat brain. In Experiment 1, male Sprague-Dawley rats were gavaged with vehicle, 10 or 20 mg THC/kg body weight daily, 5 days/week for 90 days. Animals were killed either 24 hours or two months after the last dose. Brains were dissected into different regions for neurochemical analyses. Two months after the cessation of chronic administration, there was a significant decrease in GABA receptor binding in the hippocampus of animals in the high dose group. However, no other significant changes were found in neurotransmitter receptor binding characteristics in the hippocampus or in neurotransmitter concentrations in the caudate nucleus, hypothalamus or septum after chronic THC administration. In an attempt to replicate the GABA receptor binding changes and also to determine the [35S]TBPS binding in hippocampus, we designed Experiment 2. In this experiment, we dosed the animals by gavage with 0, 5, 10 or 20 mg THC/kg daily, 5 days/week or with 20 mg THC/kg Monday through Thursday and 60 mg/kg on Friday for 90 days. Results from this experiment failed to replicate the dose-dependent effect of THC on GABA receptor binding in hippocampus. Modulation of [35S]TBPS binding by GABA or 3 alpha-OH-DHP or inhibition by cold TBPS in frontal cortex did not show any significant dose-related effects. Results from these experiments suggest that chronic exposure to THC does not produce significant alterations in catecholamine or indoleamine neurotransmitter systems or in opiate or GABA receptor systems in the rat brain.

  5. Adolescent but not adult ethanol binge drinking modulates cocaine withdrawal symptoms in mice

    Science.gov (United States)

    Aguilar, Maria A.; Giménez-Gómez, Pablo; Miñarro, José; Rodríguez-Arias, Marta

    2017-01-01

    Background Ethanol (EtOH) binge drinking is an increasingly common behavior among teenagers that induces long-lasting neurobehavioral alterations in adulthood. An early history of EtOH abuse during adolescence is highly correlated with cocaine addiction in adulthood. Abstinence of cocaine abuse can cause psychiatric symptoms, such as anxiety, psychosis, depression, and cognitive impairments. This study assessed the consequences of adolescent exposure to EtOH on the behavioral alterations promoted by cocaine withdrawal in adulthood. Methods We pretreated juvenile (34–47 days old) or adult (68–81 days old) mice with EtOH (1.25 g/kg) following a binge-drinking pattern. Then, after a three-week period without drug delivery, they were subjected to a chronic cocaine treatment in adulthood and tested under cocaine withdrawal by the ensuing paradigms: open field, elevated plus maze, prepulse inhibition, tail suspension test, and object recognition. Another set of mice were treated with the same EtOH binge-drinking procedure during adolescence and were tested immediately afterwards under the same behavioral paradigms. Results Adolescent EtOH pretreatment undermined the anxiogenic effects observed after cocaine abstinence, reduced prepulse inhibition, and increased immobility scores in the tail suspension test following cocaine withdrawal. Moreover, the memory deficits evoked by these substances when given separately were enhanced in cocaine-withdrawn mice exposed to EtOH during adolescence. EtOH binge drinking during adolescence also induced anxiety, depressive symptoms, and memory impairments when measured immediately afterwards. In contrast, neither EtOH nor cocaine alone or in combination altered any of these behaviors when given in adulthood. Conclusions EtOH binge drinking induces short- and long-term behavioral alterations and modulates cocaine withdrawal symptoms when given in adolescent mice. PMID:28291777

  6. Determination of cocaine and benzoylecgonine in guinea pig's hair after a single dose administration by LC-MS/MS%LC-MS/MS法测定豚鼠毛发中可卡因及其代谢物苯甲酰爱康宁

    Institute of Scientific and Technical Information of China (English)

    孙其然; 向平; 严慧; 沈敏

    2008-01-01

    A sensitive LC-MS/MS method to determine cocaine and its major metabolite benzoylecgonine in guinea pig's hair has been established. About 20 mg of decontaminated hair sample was hydrolyzed with 0.1 mol·L-1 HCl at 50 ℃ overnight, in the presence of cocaine-d3 and benzoylecgonine-d8 used as internal standards, and then extracted with dichlormethane. The analysis was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Positive electrospray ionization (ESI+) and multiple reactions monitoring (MRM) mode were used. The limit of detection (LOD) for cocaine and benzoylecgonine was 1 pg·mg-1. The calibration curves of extracted standards were linear over the range from 5 pg·mg-1 to 250 pg·mg-1 (r2≥0.999 7). The method was validated and applied to the analysis of guinea pig's hair after a single dose administration of cocaine hydrochloride. Cocaine and benzoylecgonine were not only detected, but also quantified in guinea pigs hair.%本实验旨在建立豚鼠毛发中可卡因及其代谢物苯甲酰爱康宁的液相色谱-串联质谱分析方法,并考察单次给药后豚鼠毛发中可卡因和苯甲酰爱康宁的质量浓度.毛发洗涤、晾干后剪成1~2 mm小段,取20 mg,加入0.1 mol·L-1 HCl 1 mL和内标溶液(50 ng·mL-1 d3-可卡因和d8-苯甲酰爱康宁) 20 μL,50 ℃水浴中酸水解过夜;调pH为中性,用二氯甲烷液液提取,移取有机相于60 ℃水浴下挥干,用甲醇100 μL复溶,进样5 μL.目标化合物用Allure PFP丙基柱分离,以甲醇-20 mmol·L-1乙酸铵(0.1%甲酸)(80∶ 20)为流动相.质谱采用电喷雾电离-正离子模式(ESI+),多反应监测模式(MRM).动物实验:豚鼠8只分两组,分别以10和0.4 mg·kg-1的剂量腹腔注射盐酸可卡因水溶液一次,在给药后d 7和d 14分色剃取毛发进行检测.结果显示,毛发中可卡因和苯甲酰爱康宁的最低检出限均为1 pg·mg-1,在5~250 pg·mg-1线性良好(r2≥0.999 7).在给药后d 7收集的豚鼠毛发中同

  7. Increased late sodium current contributes to the electrophysiological effects of chronic, but not acute, dofetilide administration

    NARCIS (Netherlands)

    Qiu, Xiaoliang S.; Chauveau, Samuel; Anyukhovsky, Evgeny P.; Rahim, Tania; Jiang, Ya Ping; Harleton, Erin; Feinmark, Steven J.; Lin, Richard Z.; Coronel, Ruben; Janse, Michiel J.; Opthof, Tobias; Rosen, Tove S.; Cohen, Ira S.; Rosen, Michael R.

    2016-01-01

    Background - Drugs are screened for delayed rectifier potassium current (I Kr) blockade to predict long QT syndrome prolongation and arrhythmogenesis. However, single-cell studies have shown that chronic (hours) exposure to some I Kr blockers (eg, dofetilide) prolongs repolarization additionally by

  8. Cocaine depresses GABAA current of hippocampal neurons.

    Science.gov (United States)

    Ye, J H; Liu, P L; Wu, W H; McArdle, J J

    1997-10-01

    Although blockade of dopamine re-uptake and the resulting elevation of excitatory agonists is commonly thought the primary mechanism of cocaine-induced seizures, it is possible that other neurotransmitters such as gamma-aminobutyric acid (GABA) are involved. To examine this possibility, the effects of cocaine on the whole cell GABA current (IGABA) of freshly isolated rat hippocampal neurons were investigated with the patch-clamp technique. Preincubation or acute application of cocaine reversibly suppressed IGABA. The IC50 was 127 microM when cocaine was applied before the application of GABA. The concentration-response relations of cocaine in various GABA concentrations revealed that cocaine inhibited IGABA non-competitively. This effect of cocaine appeared to be independent of voltage. The present study suggests that the GABA receptor/channel complex is also a target for cocaine's action. The suppression of IGABA may contribute to cocaine-induced seizures.

  9. N-Methyl-3,4-methylenedioxyamphetamine-induced hepatotoxicity in rats: Oxidative stress after acute and chronic administration

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    Ninković Milica

    2004-01-01

    Full Text Available Background. The underlying mechanisms of N-Methyl-3,4-methylenedioxyamphetamine-MDMA-induced hepatotoxicity are still unknown. The aim of this study was to evaluate hepatic oxido-reductive status in the rats liver after the single and repeated administration of MDMA. Methods. MDMA was dissolved in distilled water and administered in the doses of 5 mg, 10 mg, 20 mg, and 40 mg/kg. The animals from the acute experiment were treated per os with the single dose of the appropriate solution, through the orogastric tube. The animals from the chronic experiment were treated per os, with the doses of 5, 10, or 20 mg/kg of MDMA every day during 14 days. The control groups were treated with water only. Eight hours after the last dose, the animals were sacrificed, dissected their livers were rapidly removed, frozen and stored at -70°C until the moment of analysis. The parameters of oxidative stress in the crude mitochondrial fractions of the livers were analyzed. Results. Superoxide dismutase (SOD activity increased in the livers of the animals that were treated with single doses of MDMA. Chronically treated animals showed the increased SOD activity only after the highest dose (20 mg/kg. The content of reduced glutathione decreased in both groups, but the depletion was much more expressed after the single administration. Lipid peroxidation index increased in dose-dependent manner in both groups, being much higher after the single administration. Conclusion. The increased index of lipid peroxidation and the decreased reduced glutathione levels suggested that MDMA application induced the state of oxidative stress in the liver. These changes were much more expressed after the single administration of MDMA.

  10. Long-term L-Carnitine Administration reduces Erythropoietin Resistance in Chronic Hemodialysis Patients with Thalassemia Minor

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    Biagio R. Di Iorio

    2007-01-01

    Full Text Available Background and Aim: Both thalassemia and carnitine deficiency represent independent causes of erythropoietin resistance, and thus anemia, in uremic patients. We evaluated the unknown long-term effects of L-carnitine administration in β-thalassemic on chronic hemodialysis.Methods: We studied twelve subjects (M = 8; F = 4 affected by β-thalassemia minor (β-thal; HbA2 level = 6.6 ± 0.6% and forty non-thalassemic subjects (M = 24; F = 16 as controls (C, on chronic hemodialysis treatment. Patients and controls were at target hemoglobin levels (11–12g/dl prior to the study and underwent to i.v. L-carnitine administration for a one year period-time.Results: Groups were comparable for age, gender, serum levels of hemoglobin (Hb, iron, ferritine, PTH and aluminum, transferrin saturation, and dialysis modalities. During the study both groups showed signifi cant Hb increase and erythropoietin (EPO decrease; as a difference, such changes emerged at the 3rd month in C but at the 8th month in β-thal. At start, during the dialysis session the erythrocyte MCV reduced in C but not in β-thal (65.3 ± 3.2 to 65.5 ± 3.2 fl ; NS; along carnitine administration period, however, MCV during dialysis decreased also in β-thal, starting since the 9th month of treatment.Conclusion: This study provides evidence of the lowering of EPO resistance in β-thalassemia patients on hemodialysis due to long-term carnitine administration. Thus, prolonged carnitine supplementation should be suggested to patients on dialysis affected by β-thalassemia with poorly responsive anemia, or requiring large doses of erythropoietin.

  11. Chronic administration of a microencapsulated probiotic enhances the bioavailability of orange juice flavanones in humans.

    Science.gov (United States)

    Pereira-Caro, Gema; Oliver, Christine M; Weerakkody, Rangika; Singh, Tanoj; Conlon, Michael; Borges, Gina; Sanguansri, Luz; Lockett, Trevor; Roberts, Susan A; Crozier, Alan; Augustin, Mary Ann

    2015-07-01

    Orange juice (OJ) flavanones are bioactive polyphenols that are absorbed principally in the large intestine. Ingestion of probiotics has been associated with favorable changes in the colonic microflora. The present study examined the acute and chronic effects of orally administered Bifidobacterium longum R0175 on the colonic microflora and bioavailability of OJ flavanones in healthy volunteers. In an acute study volunteers drank OJ with and without the microencapsulated probiotic, whereas the chronic effects were examined when OJ was consumed after daily supplementation with the probiotic over 4 weeks. Bioavailability, assessed by 0-24h urinary excretion, was similar when OJ was consumed with and without acute probiotic intake. Hesperetin-O-glucuronides, naringenin-O-glucuronides, and hesperetin-3'-O-sulfate were the main urinary flavanone metabolites. The overall urinary excretion of these metabolites after OJ ingestion and acute probiotic intake corresponded to 22% of intake, whereas excretion of key colon-derived phenolic and aromatic acids was equivalent to 21% of the ingested OJ (poly)phenols. Acute OJ consumption after chronic probiotic intake over 4 weeks resulted in the excretion of 27% of flavanone intake, and excretion of selected phenolic acids also increased significantly to 43% of (poly)phenol intake, corresponding to an overall bioavailability of 70%. Neither the probiotic bacterial profiles of stools nor the stool moisture, weight, pH, or levels of short-chain fatty acids and phenols differed significantly between treatments. These findings highlight the positive effect of chronic, but not acute, intake of microencapsulated B. longum R0175 on the bioavailability of OJ flavanones.

  12. Topical Administration of Pirfenidone Increases Healing of Chronic Diabetic Foot Ulcers: A Randomized Crossover Study

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    Marcela Janka-Zires

    2016-01-01

    Full Text Available Only 30 percent of chronic diabetic foot ulcers heal after 20 weeks of standard treatment. Pirfenidone is a drug with biological, anti-inflammatory, and antifibrotic effects. The aim of this study was to evaluate the effect of topical pirfenidone added to conventional treatment in noninfected chronic diabetic foot ulcers. This was a randomized crossover study. Group 1 received topical pirfenidone plus conventional treatment for 8 weeks; after this period, they were switched to receive conventional treatment only for 8 more weeks. In group 2, the order of the treatments was the opposite. The end points were complete ulcer healing and size reduction. Final data were obtained from 35 ulcers in 24 patients. Fifty-two percent of ulcers treated with pirfenidone healed before 8 weeks versus 14.3% treated with conventional treatment only (P=0.025. Between 8 and 16 weeks, 30.8% ulcers that received pirfenidone healed versus 0% with conventional treatment (P=0.081. By week 8, the reduction in ulcer size was 100% [73–100] with pirfenidone versus 57.5% with conventional treatment [28.9–74] (P=0.011. By week 16, the reduction was 93% [42.7–100] with pirfenidone and 21.8% [8–77.5] with conventional treatment (P=0.050. The addition of topical pirfenidone to conventional treatment significantly improves the healing of chronic diabetic noninfected foot ulcers.

  13. Topical Administration of Pirfenidone Increases Healing of Chronic Diabetic Foot Ulcers: A Randomized Crossover Study

    Science.gov (United States)

    Janka-Zires, Marcela; Uribe-Wiechers, Ana Cecilia; Juárez-Comboni, Sonia Citlali; López-Gutiérrez, Joel; Escobar-Jiménez, Jarod Jazek; Gómez-Pérez, Francisco J.

    2016-01-01

    Only 30 percent of chronic diabetic foot ulcers heal after 20 weeks of standard treatment. Pirfenidone is a drug with biological, anti-inflammatory, and antifibrotic effects. The aim of this study was to evaluate the effect of topical pirfenidone added to conventional treatment in noninfected chronic diabetic foot ulcers. This was a randomized crossover study. Group 1 received topical pirfenidone plus conventional treatment for 8 weeks; after this period, they were switched to receive conventional treatment only for 8 more weeks. In group 2, the order of the treatments was the opposite. The end points were complete ulcer healing and size reduction. Final data were obtained from 35 ulcers in 24 patients. Fifty-two percent of ulcers treated with pirfenidone healed before 8 weeks versus 14.3% treated with conventional treatment only (P = 0.025). Between 8 and 16 weeks, 30.8% ulcers that received pirfenidone healed versus 0% with conventional treatment (P = 0.081). By week 8, the reduction in ulcer size was 100% [73–100] with pirfenidone versus 57.5% with conventional treatment [28.9–74] (P = 0.011). By week 16, the reduction was 93% [42.7–100] with pirfenidone and 21.8% [8–77.5] with conventional treatment (P = 0.050). The addition of topical pirfenidone to conventional treatment significantly improves the healing of chronic diabetic noninfected foot ulcers. PMID:27478849

  14. Effects of chronic lithium administration on renal acid excretion in humans and rats.

    Science.gov (United States)

    Weiner, I David; Leader, John P; Bedford, Jennifer J; Verlander, Jill W; Ellis, Gaye; Kalita, Priyakshi; Vos, Frederiek; de Jong, Sylvia; Walker, Robert J

    2014-12-01

    Lithium therapy's most common side effects affecting the kidney are nephrogenic diabetes insipidus (NDI) and chronic kidney disease. Lithium may also induce a distal renal tubular acidosis. This study investigated the effect of chronic lithium exposure on renal acid-base homeostasis, with emphasis on ammonia and citrate excretion. We compared 11 individuals on long-term lithium therapy with six healthy individuals. Under basal conditions, lithium-treated individuals excreted significantly more urinary ammonia than did control subjects. Following an acute acid load, urinary ammonia excretion increased approximately twofold above basal rates in both lithium-treated and control humans. There were no significant differences between lithium-treated and control subjects in urinary pH or urinary citrate excretion. To elucidate possible mechanisms, rats were randomized to diets containing lithium or regular diet for 6 months. Similar to humans, basal ammonia excretion was significantly higher in lithium-treated rats; in addition, urinary citrate excretion was also significantly greater. There were no differences in urinary pH. Expression of the critical ammonia transporter, Rhesus C Glycoprotein (Rhcg), was substantially greater in lithium-treated rats than in control rats. We conclude that chronic lithium exposure increases renal ammonia excretion through mechanisms independent of urinary pH and likely to involve increased collecting duct ammonia secretion via the ammonia transporter, Rhcg.

  15. A silent synapse-based mechanism for cocaine-induced locomotor sensitization.

    Science.gov (United States)

    Brown, Travis E; Lee, Brian R; Mu, Ping; Ferguson, Deveroux; Dietz, David; Ohnishi, Yoshinori N; Lin, Ying; Suska, Anna; Ishikawa, Masago; Huang, Yanhua H; Shen, Haowei; Kalivas, Peter W; Sorg, Barbara A; Zukin, R Suzanne; Nestler, Eric J; Dong, Yan; Schlüter, Oliver M

    2011-06-01

    Locomotor sensitization is a common and robust behavioral alteration in rodents whereby following exposure to abused drugs such as cocaine, the animal becomes significantly more hyperactive in response to an acute drug challenge. Here, we further analyzed the role of cocaine-induced silent synapses in the nucleus accumbens (NAc) shell and their contribution to the development of locomotor sensitization. Using a combination of viral vector-mediated genetic manipulations, biochemistry, and electrophysiology in a locomotor sensitization paradigm with repeated, daily, noncontingent cocaine (15 mg/kg) injections, we show that dominant-negative cAMP-element binding protein (CREB) prevents cocaine-induced generation of silent synapses of young (30 d old) rats, whereas constitutively active CREB is sufficient to increase the number of NR2B-containing NMDA receptors (NMDARs) at synapses and to generate silent synapses. We further show that occupancy of CREB at the NR2B promoter increases and is causally related to the increase in synaptic NR2B levels. Blockade of NR2B-containing NMDARs by administration of the NR2B-selective antagonist Ro256981 directly into the NAc, under conditions that inhibit cocaine-induced silent synapses, prevents the development of cocaine-elicited locomotor sensitization. Our data are consistent with a cellular cascade whereby cocaine-induced activation of CREB promotes CREB-dependent transcription of NR2B and synaptic incorporation of NR2B-containing NMDARs, which generates new silent synapses within the NAc. We propose that cocaine-induced activation of CREB and generation of new silent synapses may serve as key cellular events mediating cocaine-induced locomotor sensitization. These findings provide a novel cellular mechanism that may contribute to cocaine-induced behavioral alterations.

  16. 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.

  17. Levamisole tainted cocaine causing severe neutropenia in Alberta and British Columbia

    Science.gov (United States)

    2009-01-01

    Background Five cases of severe neutropenia (neutrophil counts < 0.5 per 109 cells/L) associated with exposure to cocaine and levamisole, an antihelimithic agent no longer available in Canada, were identified in Alberta in 2008. Alberta and British Columbia (BC) public health officials issued an advisory and urged health care professionals to report cases to public health. This paper presents the findings of the public health investigations. Methods Cases were identified prospectively through reporting by clinicians and a retrospective review of laboratory and medical examiners data from January 1, 2006 to March 31, 2009. Cases were categorized as confirmed, probable or suspect. Only the confirmed and probable cases are included in this paper. Results We compare cases of severe neutropenia associated with tainted cocaine (NATC) identified in Alberta and BC between January 1, 2008 to March 31, 2009. Of the 42 NATC cases: 23(55%) were from Alberta; 19(45%) were from British Columbia; 57% of these cases reported crack cocaine use (93% of those who identified type of cocaine used); 7% reported using cocaine powder; and the main route of cocaine administration was from smoking (72%). Fifty percent of the NATC cases had multiple episodes of neutropenia associated with cocaine use. Cases typically presented with bacterial/fungal infections and fever. One Alberta NATC case produced anti-neutrophil antibodies, and four were positive for anti-neutrophil cytoplasmic antibody (ANCA). Analysis of two crack pipes and one drug sample obtained from NATC cases confirmed the presence of both cocaine and levamisole. A further 18 cases were identified through the retrospective review of laboratory and medical examiner data in Alberta Interpretation Our findings support a link between neutropenia and levamisole tainted cocaine; particularly from smoking the crack form of cocaine. Some patients may be genetically predisposed to develop levamisole-related neutropenia. Awareness of the

  18. Levamisole tainted cocaine causing severe neutropenia in Alberta and British Columbia

    Directory of Open Access Journals (Sweden)

    Fan Shihe

    2009-11-01

    Full Text Available Abstract Background Five cases of severe neutropenia (neutrophil counts 9 cells/L associated with exposure to cocaine and levamisole, an antihelimithic agent no longer available in Canada, were identified in Alberta in 2008. Alberta and British Columbia (BC public health officials issued an advisory and urged health care professionals to report cases to public health. This paper presents the findings of the public health investigations. Methods Cases were identified prospectively through reporting by clinicians and a retrospective review of laboratory and medical examiners data from January 1, 2006 to March 31, 2009. Cases were categorized as confirmed, probable or suspect. Only the confirmed and probable cases are included in this paper. Results We compare cases of severe neutropenia associated with tainted cocaine (NATC identified in Alberta and BC between January 1, 2008 to March 31, 2009. Of the 42 NATC cases: 23(55% were from Alberta; 19(45% were from British Columbia; 57% of these cases reported crack cocaine use (93% of those who identified type of cocaine used; 7% reported using cocaine powder; and the main route of cocaine administration was from smoking (72%. Fifty percent of the NATC cases had multiple episodes of neutropenia associated with cocaine use. Cases typically presented with bacterial/fungal infections and fever. One Alberta NATC case produced anti-neutrophil antibodies, and four were positive for anti-neutrophil cytoplasmic antibody (ANCA. Analysis of two crack pipes and one drug sample obtained from NATC cases confirmed the presence of both cocaine and levamisole. A further 18 cases were identified through the retrospective review of laboratory and medical examiner data in Alberta Interpretation Our findings support a link between neutropenia and levamisole tainted cocaine; particularly from smoking the crack form of cocaine. Some patients may be genetically predisposed to develop levamisole-related neutropenia. Awareness

  19. 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.

  20. Effect of chronic administration of forskolin on glycemia and oxidative stress in rats with and without experimental diabetes.

    Science.gov (United States)

    Ríos-Silva, Mónica; Trujillo, Xóchitl; Trujillo-Hernández, Benjamín; Sánchez-Pastor, Enrique; Urzúa, Zorayda; Mancilla, Evelyn; Huerta, Miguel

    2014-01-01

    Forskolin is a diterpene derived from the plant Coleus forskohlii. Forskolin activates adenylate cyclase, which increases intracellular cAMP levels. The antioxidant and antiinflammatory action of forskolin is due to inhibition of macrophage activation with a subsequent reduction in thromboxane B2 and superoxide levels. These characteristics have made forskolin an effective medication for heart disease, hypertension, diabetes, and asthma. Here, we evaluated the effects of chronic forskolin administration on blood glucose and oxidative stress in 19 male Wistar rats with streptozotocin-induced diabetes compared to 8 healthy male Wistar rats. Rats were treated with forskolin, delivered daily for 8 weeks. Glucose was assessed by measuring fasting blood glucose in diabetic rats and with an oral glucose tolerance test (OGTT) in healthy rats. Oxidative stress was assessed by measuring 8-hydroxydeoxyguanosine (8‑OHdG) in 24-h urine samples. In diabetic rats, without forskolin, fasting blood glucose was significantly higher at the end than at the beginning of the experiment (8 weeks). In both healthy and diabetic rats, forskolin treatment lowered the fasting glucose at the end of the experiment but no effect was found on oral glucose tolerance. The 8-OHdG levels tended to be less elevated in forskolin-treated than in untreated group. Our results showed that chronic administration of forskolin decreased fasting blood glucose levels; however, the reductions of 8-OHdG were not statistically significant.

  1. Chronic dietary administration of valproic acid protects neurons of the rat nucleus basalis magnocellularis from ibotenic acid neurotoxicity.

    Science.gov (United States)

    Eleuteri, Simona; Monti, Barbara; Brignani, Sara; Contestabile, Antonio

    2009-02-01

    Valproic acid (VPA) has been used for many years as a drug of choice for epilepsy and mood disorders. Recently, evidence has been proposed for a wide spectrum of actions of this drug, including antitumoral and neuroprotective properties. Valproic acid-mediated neuroprotection in vivo has been so far demonstrated in a limited number of experimental models. In this study, we have tested the neuroprotective potential of chronic (4 + 1 weeks) dietary administration of VPA on degeneration of cholinergic and GABAergic neurons of the rat nucleus basalis magnocellularis (NBM), injected with the excitotoxin, ibotenic acid (IBO), an animal models that is relevant for Alzheimer's disease-like neurodegeneration. We show that VPA treatment significantly protects both cholinergic and GABAergic neurons present in the injected area from the excitotoxic insult. A significant level of neuroprotection, in particular, is exerted towards the cholinergic neurons of the NBM projecting to the cortex, as demonstrated by the substantially higher levels of cholinergic markers maintained in the target cortical area of VPA-treated rats after IBO injection in the NBM. We further show that chronic VPA administration results in increased acetylation of histone H3 in brain, consistent with the histone deacetylase inhibitory action of VPA and putatively linked to a neuroprotective action of the drug mediated at the epigenetic level.

  2. Chronic Administration of High Doses of Nandrolone Decanoate on the Pituitary-Gonadal Axis in Male Rats

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    Shahraki

    2015-09-01

    Full Text Available Background Anabolic-androgenic steroids (AAS are abused by athletes. Objectives The present study was designed to evaluate chronic administration of high doses of nandrolone decanoate (ND on the pituitary-gonadal axis and hematological parameters in normal male rats. Materials and Methods Thirty Wistar-Albino male rats were divided assigned to control (C, placebo (P and test (T groups (n = 10. Group T received 15 mg/kg intramuscular (IM ND for eight weeks. Group P received the same volume of peanut oil, but group C did not receive any agent during the trial period. At the end, animals were anesthetized, killed and blood samples collected from cervical vessels. Serum follicle stimulating hormone (FSH and luteinizing hormone (LH levels were determined by sensitive rat gonadotropins kit, using ELISA methods. Serum testosterone and hematological parameters were measured by ordinary laboratory methods. Obtained data was analyzed using SPSS 17 by ANOVA and Tukey statistical tests. Results were expressed as Mean ± SD. Statistical difference considered significantly by P < 0.05. Results Serum testosterone, LH, FSH, weight gain, food and water intake in group T were significantly decreased compared to other groups (P < 0.05. In addition erythrocyte, leucocytes, hemoglobin and hematocrit in group T were significantly increased compared to those of other groups (P < 0.05. Conclusions Chronic administration of high doses of ND can alter serum FSH, LH and testosterone and hematological parameters in male rats.

  3. Chronic morphine administration induces over-expression of aldolase C with reduction of CREB phosphorylation in the mouse hippocampus.

    Science.gov (United States)

    Yang, Hai-Yu; Pu, Xiao-Ping

    2009-05-01

    In recent studies, alterations in the activity and expression of metabolic enzymes, such as those involved in glycolysis, have been detected in morphine-dependent patients and animals. Increasing evidence demonstrates that the hippocampus is an important brain region associated with morphine dependence, but the molecular events occurring in the hippocampus following chronic exposure to morphine are poorly understood. Aldolase C is the brain-specific isoform of fructose-1, 6-bisphosphate aldolase which is a glycolytic enzyme catalyzing reactions in the glycolytic, gluconeogenic, and fructose metabolic pathways. Using Western blot and immunofluorescence assays, we found the expression of aldolase C was markedly increased in the mouse hippocampus following chronic morphine treatment. Naloxone pretreatment before morphine administration suppressed withdrawal jumping, weight loss, and overexpression of aldolase C. CREB is a transcription factor regulated through phosphorylation on Ser133, which is known to play a key role in the mechanism of morphine dependence. When detecting the expression of phosphorylated CREB (p-CREB) in the mouse hippocampus using Western blot and immunohistochemistry, we found CREB phosphorylation was clearly decreased following chronic morphine treatment. Interestingly, laser-confocal microscopy showed that overexpression of aldolase C in mouse hippocampal neurons was concomitant with the decreased immunoreactivity of p-CREB. The results suggest potential links between the morphine-induced alteration of aldolase C and the regulation of CREB phosphorylation, a possible mechanism of morphine dependence.

  4. Chronic administration of U50,488H fails to produce hypothalamo-pituitary-adrenal axis tolerance in neonatal rats.

    Science.gov (United States)

    Ignar, D M; Windh, R T; Kuhn, C M

    1992-02-01

    The present study investigated the effect of chronic administration of a kappa opioid receptor agonist on the function of kappa and mu opioid, serotonergic and cholinergic regulation of secretion from the hypothalamo-pituitary-adrenal axis in neonatal rats. After chronic treatment with saline or U50,488H (trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]- benzeneacetamide methane sulfonate), a kappa opioid receptor agonist and subsequent pharmacological challenge, corticosterone (CS) in serum was determined. Kappa tolerance did not develop in pups treated on postnatal days 5-9 with increasing doses of U50,488H (0.5-2.5 mg/kg). When the rats were treated with the same chronic regimen of U50,488H at different stages of development from birth through weaning, only weanling rats became tolerant to U50,488H. In the absence of measurable kappa tolerance, the responses of corticosterone in serum to morphine, quipazine, a serotonin receptor agonist and physostigmine, an inhibitor of acetylcholinesterase, were attenuated in neonatal rats, treated with U50,488H. These studies suggest that kappa tolerance is more difficult to induce in developing rats than in adults and that regulation of the function of the hypothalamo-pituitary-adrenal axis by other neurotransmitter systems is altered by treatment with kappa opioid receptor agonists, even in the apparent absence of tolerance.

  5. Repeated cocaine exposure increases fast-spiking interneuron excitability in the rat medial prefrontal cortex.

    Science.gov (United States)

    Campanac, Emilie; Hoffman, Dax A

    2013-06-01

    The medial prefrontal cortex plays a key role in cocaine addiction. However, how chronic cocaine exposure affects cortical networks remains unclear. Most studies have focused on layer 5 pyramidal neurons (the circuit output), while the response of local GABAergic interneurons to cocaine remains poorly understood. Here, we recorded from fast-spiking interneurons (FS-IN) after repeated cocaine exposure and found altered membrane excitability. After cocaine withdrawal, FS-IN showed an increase in the number of spikes evoked by positive current injection, increased input resistance, and decreased hyperpolarization-activated current. We also observed a reduction in miniature excitatory postsynaptic currents, whereas miniature inhibitory postsynaptic current activity was unaffected. We show that, in animals with cocaine history, dopamine receptor D(2) activation is less effective in increasing FS-IN intrinsic excitability. Interestingly, these alterations are only observed 1 wk or more after the last cocaine exposure. This suggests that the dampening of D(2)-receptor-mediated response may be a compensatory mechanism to rein down the excitability of FS-IN.

  6. Effects of chronic delta-9-tetrahydrocannabinol (THC) administration on neurotransmitter concentrations and receptor binding in the rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Ali, S.F.; Newport, G.D.; Scallet, A.C.; Gee, K.W.; Paule, M.G.; Brown, R.M.; Slikker, W. Jr. (National Center for Toxicological Research, Jefferson, Arkansas (USA))

    THC is the major psychoactive constituent of marijuana and is also known as an hallucinogenic compound. Numerous reports have shown that large doses of THC produce significant alterations in various neurotransmitter systems. The present study was designed to determine whether chronic exposure to THC produces significant alterations in selected neurotransmitter systems (dopamine, serotonin, acetylcholine, GABAergic, benzodiazepine, and opiate) in the rat brain. In Experiment 1, male Sprague-Dawley rats were gavaged with vehicle, 10 or 20 mg THC/kg body weight daily, 5 days/week for 90 days. Animals were killed either 24 hours or two months after the last dose. Brains were dissected into different regions for neurochemical analyses. Two months after the cessation of chronic administration, there was a significant decrease in GABA receptor binding in the hippocampus of animals in the high dose group. However, no other significant changes were found in neurotransmitter receptor binding characteristics in the hippocampus or in neurotransmitter concentrations in the caudate nucleus, hypothalamus or septum after chronic THC administration. In an attempt to replicate the GABA receptor binding changes and also to determine the (35S)TBPS binding in hippocampus, we designed Experiment 2. In this experiment, we dosed the animals by gavage with 0, 5, 10 or 20 mg THC/kg daily, 5 days/week or with 20 mg THC/kg Monday through Thursday and 60 mg/kg on Friday for 90 days. Results from this experiment failed to replicate the dose-dependent effect of THC on GABA receptor binding in hippocampus. Modulation of (35S)TBPS binding by GABA or 3 alpha-OH-DHP or inhibition by cold TBPS in frontal cortex did not show any significant dose-related effects.

  7. Long-term experience with implanted intrathecal drug administration systems for failed back syndrome and chronic mechanical low back pain

    Directory of Open Access Journals (Sweden)

    Treharne GJ

    2002-06-01

    Full Text Available Abstract Background Continuous intrathecal drug delivery has been shown in open studies to improve pain and quality of life in those with intractable back pain who have had spinal surgery. There is limited data on long term effects and and even less for patients with mechanical back pain without prior spinal surgery. Methods We have investigated spinal drug administration systems for patients with failed back syndrome and chronic mechanical low back pain by patient questionnaire study of the efficacy of this therapy and a case notes review. Results 36 patients (97% of 37 approached completed questionnaires, 24 with failed back syndrome and 12 with chronic mechanical low back pain. Recalled pre-treatment levels with current post-treatment levels of pain and a range of quality of life measures (recorded on 11-point numerical rating scales were compared. Pain improved significantly in both groups (Wilcoxan signed ranks test, p 0.005, Wilcoxan signed ranks test with Bonferroni correction. Diamorphine was used in all 37 patients, bupivacaine in 32, clonidine in 27 and baclofen in 3. The mean dose of diamorphine increased for the first 2 years but did not change 2–6 years post implant, averaging 4.5 mg/day. Revision surgery was required in 24% of cases, but reduced to 12% in the later years of our experience. Conclusions We conclude that spinal drug administration systems appear to be of benefit in alleviating pain in the failed back syndrome and chronic mechanical low back pain but need to be examined prospectively.

  8. Effects of chronic administration of tamsulosin and tadalafil, alone or in combination, in rats with bladder outlet obstruction induced by chronic nitric oxide deficiency

    Directory of Open Access Journals (Sweden)

    Rommel Prata Regadas

    2014-08-01

    Full Text Available Purpose The aim of this study was to define if tadalafil causes detrusor muscle impairment and to observe the effect of combination of tadalafil with tamsulosin on the lower urinary tract of rats with bladder outlet obstruction (BOO induced by chronic nitric oxide deficiency. Materials and Methods Thirty-one male rats were randomized to following groups: 1 - control; 2 - L-Nitroarginine methyl ester (L-NAME; 3 - Tamsulosin + L-NAME, 4 Tadalafil+L-NAME; and 5 - Tamsulosin + Tadalafil + L-NAME. At the end of the treatment period (30 days, all animals were submitted to urodynamic study. Results The administration of L-NAME increased the number of non-voiding contractions (NVC (1.04 ± 0.22, volume threshold (VT (1.86 ± 0.35, and micturition cycle (MC (1.34 ± 0.11 compared with control (0.52 ± 0.06, 0.62 ± 0.06, and 0.67 ± 0.30, respectively. The administration of tamsulosin reduced the number of NVC (0.57 ± 0.42 and VT (0.76 ± 0.24 compared with L-NAME group. Co-treatment with tadalafil decreased the number of VT (0.85 ± 0.53 and MC (0.76 ± 0.22 compared with L-NAME group. The combination of tamsulosin with tadalafil improved the number of NVC (0.56 ± 0.18, VT (0.97 ± 0.52 and MC (0.68 ± 0.30 compared with L-NAME group. Conclusion In rats with BOO induced by chronic nitric oxide deficiency, tadalafil did not cause impairment in detrusor muscle and seems to have an addictive effect to tamsulosin because the combination decreased non voiding contractions as well the number of micturition cycles.

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

    LENUS (Irish Health Repository)

    McGovern, E

    2015-03-01

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

  10. Stress Alters the Discriminative Stimulus and Response Rate Effects of Cocaine Differentially in Lewis and Fischer Inbred Rats

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    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.

  11. Development of a novel algorithm to determine adherence to chronic pain treatment guidelines using administrative claims

    Science.gov (United States)

    Margolis, Jay M; Princic, Nicole; Smith, David M; Abraham, Lucy; Cappelleri, Joseph C; Shah, Sonali N; Park, Peter W

    2017-01-01

    Objective To develop a claims-based algorithm for identifying patients who are adherent versus nonadherent to published guidelines for chronic pain management. Methods Using medical and pharmacy health care claims from the MarketScan® Commercial and Medicare Supplemental Databases, patients were selected during July 1, 2010, to June 30, 2012, with the following chronic pain conditions: osteoarthritis (OA), gout (GT), painful diabetic peripheral neuropathy (pDPN), post-herpetic neuralgia (PHN), and fibromyalgia (FM). Patients newly diagnosed with 12 months of continuous medical and pharmacy benefits both before and after initial diagnosis (index date) were categorized as adherent, nonadherent, or unsure according to the guidelines-based algorithm using disease-specific pain medication classes grouped as first-line, later-line, or not recommended. Descriptive and multivariate analyses compared patient outcomes with algorithm-derived categorization endpoints. Results A total of 441,465 OA patients, 76,361 GT patients, 10,645 pDPN, 4,010 PHN patients, and 150,321 FM patients were included in the development of the algorithm. Patients found adherent to guidelines included 51.1% for OA, 25% for GT, 59.5% for pDPN, 54.9% for PHN, and 33.5% for FM. The majority (~90%) of patients adherent to the guidelines initiated therapy with prescriptions for first-line pain medications written for a minimum of 30 days. Patients found nonadherent to guidelines included 30.7% for OA, 6.8% for GT, 34.9% for pDPN, 23.1% for PHN, and 34.7% for FM. Conclusion This novel algorithm used real-world pharmacotherapy treatment patterns to evaluate adherence to pain management guidelines in five chronic pain conditions. Findings suggest that one-third to one-half of patients are managed according to guidelines. This method may have valuable applications for health care payers and providers analyzing treatment guideline adherence. PMID:28223842

  12. Development of a novel algorithm to determine adherence to chronic pain treatment guidelines using administrative claims

    Directory of Open Access Journals (Sweden)

    Margolis JM

    2017-02-01

    Full Text Available Jay M Margolis,1 Nicole Princic,2 David M Smith,2 Lucy Abraham,3 Joseph C Cappelleri,4 Sonali N Shah,5 Peter W Park5 1Truven Health Analytics, Bethesda, MD, 2Truven Health Analytics, Cambridge, MA, USA; 3Pfizer Ltd, Tadworth, UK; 4Pfizer Inc, Groton, CT, 5Pfizer Inc, New York, NY, USA Objective: To develop a claims-based algorithm for identifying patients who are adherent versus nonadherent to published guidelines for chronic pain management. Methods: Using medical and pharmacy health care claims from the MarketScan® Commercial and Medicare Supplemental Databases, patients were selected during July 1, 2010, to June 30, 2012, with the following chronic pain conditions: osteoarthritis (OA, gout (GT, painful diabetic peripheral neuropathy (pDPN, post-herpetic neuralgia (PHN, and fibromyalgia (FM. Patients newly diagnosed with 12 months of continuous medical and pharmacy benefits both before and after initial diagnosis (index date were categorized as adherent, nonadherent, or unsure according to the guidelines-based algorithm using disease-specific pain medication classes grouped as first-line, later-line, or not recommended. Descriptive and multivariate analyses compared patient outcomes with algorithm-derived categorization endpoints. Results: A total of 441,465 OA patients, 76,361 GT patients, 10,645 pDPN, 4,010 PHN patients, and 150,321 FM patients were included in the development of the algorithm. Patients found adherent to guidelines included 51.1% for OA, 25% for GT, 59.5% for pDPN, 54.9% for PHN, and 33.5% for FM. The majority (~90% of patients adherent to the guidelines initiated therapy with prescriptions for first-line pain medications written for a minimum of 30 days. Patients found nonadherent to guidelines included 30.7% for OA, 6.8% for GT, 34.9% for pDPN, 23.1% for PHN, and 34.7% for FM. Conclusion: This novel algorithm used real-world pharmacotherapy treatment patterns to evaluate adherence to pain management guidelines in five

  13. Requirement for the POZ/BTB protein NAC1 in acute but not chronic psychomotor stimulant response.

    Science.gov (United States)

    Mackler, Scott; Pacchioni, Alejandra; Degnan, Ryan; Homan, Ying; Conti, Alana C; Kalivas, Peter; Blendy, Julie A

    2008-02-11

    NAC1 is a novel member of the POZ/BTB (Pox virus and Zinc finger/Bric-a-bracTramtrack Broad complex) but varies from other proteins of this class in that it lacks the characteristic DNA-binding motif, suggesting a novel role. We have employed constitutive gene deletion to elucidate the role of NAC1 in vivo. Nac1 mutant mice are viable with no obvious developmental or physiological impairments. Previous studies suggest a role for NAC1 in cocaine-mediated behaviors. Therefore, we evaluated a variety of behaviors associated with psychomotor stimulant effects in Nac1 mutant mice. Acute locomotor activating effects of cocaine or amphetamine are absent in Nac1 mutant mice, however longer exposure to these psychomotor stimulants result in the development of behavioral sensitization. Acute rewarding properties of cocaine and amphetamine are also blunted in mutant mice, yet repeated exposure resulted in conditioned place preference similar to that observed in wild-type mice. Lastly, increases in extracellular dopamine in the nucleus accumbens, which accompany acute cocaine administration, are blunted in mutant mice, but following chronic cocaine extracellular dopamine levels are increased to the same extent as in wild-type mice. Together these data indicate involvement of NAC1 in the acute behavioral and neurochemical responses to psychomotor stimulants.

  14. The neurogenic phase of angiotensin II-salt hypertension is prevented by chronic intracerebroventricular administration of benzamil.

    Science.gov (United States)

    Osborn, John W; Olson, Dalay M; Guzman, Pilar; Toney, Glenn M; Fink, Gregory D

    2014-02-01

    Hypertension induced by chronic administration of angiotensin II (AngII) is exacerbated by high-salt intake. Previous studies have demonstrated that this salt-sensitive component is due to increased activity of the sympathetic nervous system, suggesting an interaction of plasma AngII with sodium-sensitive regions of the brain. This study tested the hypothesis that the salt-sensitive component of AngII-induced hypertension would be prevented by intracerebroventricular (ICV) administration of the sodium channel/transporter blocker benzamil. Male Sprague Dawley rats were instrumented to measure mean arterial pressure (MAP) by radio telemetry and for ICV administration of benzamil or vehicle and placed in metabolic cages for measurement of sodium and water intake and excretion. In rats consuming a high-salt diet (2.0% NaCl) and treated with ICV vehicle, administration of AngII (150 ng/kg/min, sc) for 13 days increased MAP by ~30 mmHg. ICV administration of benzamil (16 nmol/day) had no effect during the first 5 days of AngII, but returned MAP to control levels by Day 13. There were minimal or no differences between ICV vehicle or benzamil groups in regards to sodium and water balance. A lower dose of ICV benzamil administered ICV at 8 nmol/day had no effect on the MAP response to AngII in rats on a high-salt diet. Finally, in contrast to rats on a high-salt diet, AngII had negligible effects on MAP in rats consuming a low-salt diet (0.1% NaCl) and there were no differences in any variable between ICV benzamil (16 nmol/day) and ICV vehicle-treated groups. We conclude that the salt-sensitive component of AngII-induced hypertension is dependent on benzamil blockable sodium channels or transporters in the brain.

  15. Adverse effects of levamisole in cocaine users: a review and risk assessment.

    Science.gov (United States)

    Brunt, Tibor Markus; van den Berg, Jorrit; Pennings, Ed; Venhuis, Bastiaan

    2017-03-17

    The immunomodulatory adjuvant and antihelminth levamisole is increasingly used as an adulterant in cocaine worldwide. An accumulating body of clinical and toxicological literature has appeared since 2010 describing neutropenia, agranulocytosis, leukoencephalopathy and vasculitis in cases associated with levamisole-adulterated cocaine. Mostly, neutropenia and agranulocytosis were reported, characterized by a decimation of neutrophils. A large proportion of cases also involved vasculopathy, characterized by pronounced black and purple skin purpura with cutaneous necrosis. Females are more susceptible for both agranulocytosis and vasculitis. Another complication reported with levamisole-adulterated cocaine is leukoencephalopathy, a disabling and potentially fatal neurological disorder caused by cerebral demyelination. In this review, all adverse effects associated with therapeutic levamisole and levamisole-adulterated cocaine are described. In addition, this review provides an update of the pharmacology of levamisole, its metabolism, including toxic metabolites and metabolites that are relevant for levamisole's addition to cocaine. Special emphasis is put on the immunopathology and the dose-effect relationship of chronic levamisole exposure. Finally, a risk assessment is provided based on the current level of levamisole adulteration in street cocaine, the dose range calculated per gram and the pattern of chronic exposure in heavy or dependent users.

  16. Chronic administration of anticonvulsants but not antidepressants impairs bone strength: clinical implications.

    Science.gov (United States)

    Gold, P W; Pavlatou, M G; Michelson, D; Mouro, C M; Kling, M A; Wong, M-L; Licinio, J; Goldstein, S A

    2015-06-02

    Major depression and bipolar disorder are associated with decreased bone mineral density (BMD). Antidepressants such as imipramine (IMIP) and specific serotonin reuptake inhibitors (SSRIs) have been implicated in reduced BMD and/or fracture in older depressed patients. Moreover, anticonvulsants such as valproate (VAL) and carbamazepine (CBZ) are also known to increase fracture rates. Although BMD is a predictor of susceptibility to fracture, bone strength is a more sensitive predictor. We measured mechanical and geometrical properties of bone in 68 male Sprague Dawley rats on IMIP, fluoxetine (FLX), VAL, CBZ, CBZ vehicle and saline (SAL), given intraperitoneally daily for 8 weeks. Distinct regions were tested to failure by four-point bending, whereas load displacement was used to determine stiffness. The left femurs were scanned in a MicroCT system to calculate mid-diaphyseal moments of inertia. None of these parameters were affected by antidepressants. However, VAL resulted in a significant decrease in stiffness and a reduction in yield, and CBZ induced a decrease in stiffness. Only CBZ induced alterations in mechanical properties that were accompanied by significant geometrical changes. These data reveal that chronic antidepressant treatment does not reduce bone strength, in contrast to chronic anticonvulsant treatment. Thus, decreased BMD and increased fracture rates in older patients on antidepressants are more likely to represent factors intrinsic to depression that weaken bone rather than antidepressants per se. Patients with affective illness on anticonvulsants may be at particularly high risk for fracture, especially as they grow older, as bone strength falls progressively with age.

  17. Chronic antidepressant administration alleviates frontal and hippocampal BDNF deficits in CUMS rat.

    Science.gov (United States)

    Zhang, Yang; Gu, Fenghua; Chen, Jia; Dong, Wenxin

    2010-12-17

    Stress activates the hypothalamo-pituitary-adrenal (HPA) axis, regulates the expression of brain-derived neurotrophic factor (BDNF) in the brain, and mediates mood. Antidepressants alleviate stress and up-regulate BDNF gene expression. In this study, we investigated the effect of chronic unpredictable mild stress (CUMS) and the different kinds of antidepressant treatments on the HPA axis and the BDNF expression in the rat brain. Adult Wistar male rats were exposed to a six-week CUMS procedure and received different antidepressant treatments including venlafaxine, mirtazapine, and fluoxetine. Immunohistochemistry and real-time PCR were used to measure BDNF expression levels in the rat brain, and ELISAs were used to investigate the plasma corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels. CUMS significantly decreased the BDNF protein level in the DG, CA1, and CA3 of the hippocampus and increased plasma CORT level. Chronic antidepressant treatments all significantly increased BDNF protein levels in the hippocampus and the pre-frontal cortex. In addition, venlafaxine and mirtazapine inhibited the increase of plasma CORT level. These results suggested that an increase in the BDNF level in the brain could be a pivotal mechanism of various antidepressants to exert their therapeutic effects.

  18. The Administration and Effect of Sodium Nitroprusside in the Treatment of Chronic Congestive Heart Failure

    Institute of Scientific and Technical Information of China (English)

    Sun Ming; Wang Wenmeng; Wu Qiong

    2000-01-01

    To prove the effectiveness and safety of sodium nitroprusside (SNP) in the treatment of chronic congestive heart failure, 58 patients with heart failure and normal renal and hepatic function were selected and divided into 3 groups and treated differently. Group A was treated with routine vasodilators; Group B was treaeted intermittently with SNP (12.5 -75mg/24hrs);Group C was treated continuously with SNP (continuous infusion of 100-300mg/24hrs) Positively inotropie agents and diuretic agents were used in each group.The results showed that the highly effective rates of the three groups were 46.9% (15/32), 90.5% (19/21)and 100% (12/12) respectively. The effective rates were 81.3% (26/32), 100% (21/21), 100%(12/12) respectively. The highly effective rates of group B and C were much higher than that of group A (P<0.005, P< 0.005) . The reduction of blood pressure of group B and C was greater than that of group A ( P < 0. 025) . Among the patients we studied, no body had severe side effects. We concluded that the use of SNP in the treatment of chronic congestive heart failure is safe, with better effect than routine treatment,and continous infusion of SNP is the best choice.

  19. Mesenchymal Stem Cell Administration in Patients with Chronic Obstructive Pulmonary Disease: State of the Science

    Science.gov (United States)

    Cheng, Shih-Lung

    2017-01-01

    Patients with chronic obstructive pulmonary disease (COPD) have chronic, irreversible airway inflammation; currently, there is no effective or curative treatment and the main goals of COPD management are to mitigate symptoms and improve patients' quality of life. Stem cell based therapy offers a promising therapeutic approach that has shown potential in diverse degenerative lung diseases. Preclinical studies have demonstrated encouraging outcomes of mesenchymal stem/stromal cells (MSCs) therapy for lung disorders including emphysema, bronchopulmonary dysplasia, fibrosis, and acute respiratory distress syndrome. This review summarizes available data on 15 studies currently registered by the ClinicalTrials.gov repository, which used different stem cell therapy protocols for COPD; these included bone marrow mononuclear cells (BMMCs), bone marrow-derived MSCs, adipose-derived stem/stromal cells (ADSCs), and adipose-derived MSCs. Published results of three trials indicate that administering BMMCs or MSCs in the setting of degenerative lung disease is safe and may improve patients' condition and quality of life; however, larger-scale studies are needed to evaluate efficacy. Results of another completed trial (NCT01872624) are not yet published, and eleven other studies are ongoing; these include MSCs therapy in emphysema, several studies of ADSCs in COPD, another in idiopathic pulmonary fibrosis, and plerixafor mobilization of CD117 stem cells to peripheral blood.

  20. Orexin administration to mice that underwent chronic stress produces bimodal effects on emotion-related behaviors.

    Science.gov (United States)

    Chung, Hye-Seung; Kim, Jae-Gon; Kim, Jae-Won; Kim, Hyung-Wook; Yoon, Bong-June

    2014-11-01

    Orexin plays diverse roles in regulating behaviors, such as sleep and wake, reward processing, arousal, and stress and anxiety. The orexin system may accomplish these multiple tasks through its complex innervations throughout the brain. The emerging evidence indicates a role of orexin in emotional behaviors; however, most of the previous studies have investigated the function of orexin in naïve animals. Here, we examined a functional role of orexin in mice that had been exposed to repeated stress. Chronic social defeat stress produced differential social interaction behaviors in mice (susceptible versus resilient) and these two groups of mice displayed different levels of prepro-orexin in the hypothalamus. Exogenously added orexin A to the brain induced an antidepressant-like effect in only the susceptible mice but not in the resilient mice. In contrast, orexin A and orexin B infused together produced an anxiogenic effect in only the resilient mice and not in the susceptible mice. Furthermore, we found that the antidepressant-like effect of orexin A is mediated by the bed nucleus of the stria terminalis (BNST) after exposure to chronic restraint stress. These findings reveal a bimodal effect of the orexin system in regulating emotional behavior that depends on stress susceptibility.

  1. Combined administration of iron and monoisoamyl-DMSA in the treatment of chronic arsenic intoxication in mice.

    Science.gov (United States)

    Modi, M; Flora, S J S

    2007-11-01

    Co-administration of iron in combination with monoisoamyl dimercaptosuccinic acid (MiADMSA) against chronic arsenic poisoning in mice was studied. Mice preexposed to arsenic (25 ppm in drinking water for 6 months) mice were treated with MiADMSA (50 mg/kg, intraperitoneally) either alone or in combination with iron (75 or 150 mg/kg, orally) once daily for 5 days. Arsenic exposure led to a significant depletion of blood delta-aminolevulinic acid dehydratase (ALAD) activity, hematocrit, and white blood cell (WBC) counts accompanied by small decline in blood hemoglobin level. Hepatic reduced glutathione (GSH) level, catalase and superoxide dismutase (SOD) activities showed a significant decrease while, oxidized glutathione (GSSG) and thiobarbituric acid-reactive substances (TBARS) levels increased on arsenic exposure, indicating arsenic-induced hepatic oxidative stress. Liver aspartate and alanine transaminases (AST and ALT) activities also decreased significantly on arsenic exposure. Kidney GSH, GSSG, catalase level and SOD activities remained unchanged, while, TBARS level increased significantly following arsenic exposure. Brain GSH, glutathione peroxidase (GPx), and SOD activities decreased, accompanied by a significant elevation of TBARS level after chronic arsenic exposure. Treatment with MiADMSA was marginally effective in reducing ALAD activity, while administration of iron was ineffective when given alone. Iron when co-administered with MiADMSA restored blood ALAD activity. Administration of iron alone had no beneficial effects on hepatic oxidative stress, while in combination with MiADMSA it produced significant decline in hepatic TBARS level compared to the individual effect of MiADMSA. Renal biochemical variables were insensitive to any of the treatments. Combined administration of iron with MiADMSA also had no additional beneficial effect over the individual protective effect of MiADMSA on brain oxidative stress. Interestingly, combined administration of

  2. Delayed nootropic effects of arginine vasopressin after early postnatal chronic administration to albino rat pups.

    Science.gov (United States)

    Kim, P A; Voskresenskaya, O G; Kamensky, A A

    2009-06-01

    Intranasal administration of arginine vasopressin (10 microg/kg) to albino rat pups had a strong nootropic effect during training with positive and negative reinforcement. This effect was different in animals of various age groups: training with positive reinforcement was improved in "adolescent" rats and pubertal animals, while during training with negative reinforcement, the nootropic effect of the peptide was more prolonged and persisted also in adult animals.

  3. Modeling of pharmacokinetics of cocaine in human reveals the feasibility for development of enzyme therapies for drugs of abuse.

    Directory of Open Access Journals (Sweden)

    Fang Zheng

    Full Text Available A promising strategy for drug abuse treatment is to accelerate the drug metabolism by administration of a drug-metabolizing enzyme. The question is how effectively an enzyme can actually prevent the drug from entering brain and producing physiological effects. In the present study, we have developed a pharmacokinetic model through a combined use of in vitro kinetic parameters and positron emission tomography data in human to examine the effects of a cocaine-metabolizing enzyme in plasma on the time course of cocaine in plasma and brain of human. Without an exogenous enzyme, cocaine half-lives in both brain and plasma are almost linearly dependent on the initial cocaine concentration in plasma. The threshold concentration of cocaine in brain required to produce physiological effects has been estimated to be 0.22±0.07 µM, and the threshold area under the cocaine concentration versus time curve (AUC value in brain (denoted by AUC2(∞ required to produce physiological effects has been estimated to be 7.9±2.7 µM·min. It has been demonstrated that administration of a cocaine hydrolase/esterase (CocH/CocE can considerably decrease the cocaine half-lives in both brain and plasma, the peak cocaine concentration in brain, and the AUC2(∞. The estimated maximum cocaine plasma concentration which a given concentration of drug-metabolizing enzyme can effectively prevent from entering brain and producing physiological effects can be used to guide future preclinical/clinical studies on cocaine-metabolizing enzymes. Understanding of drug-metabolizing enzymes is key to the science of pharmacokinetics. The general insights into the effects of a drug-metabolizing enzyme on drug kinetics in human should be valuable also in future development of enzyme therapies for other drugs of abuse.

  4. Competing neurobehavioral decision systems theory of cocaine addiction: From mechanisms to therapeutic opportunities.

    Science.gov (United States)

    Bickel, Warren K; Snider, Sarah E; Quisenberry, Amanda J; Stein, Jeffrey S; Hanlon, Colleen A

    2016-01-01

    Cocaine dependence is a difficult-to-treat, chronically relapsing disorder. Multiple scientific disciplines provide distinct perspectives on this disorder; however, connections between disciplines are rare. The competing neurobehavioral decision systems (CNDS) theory posits that choice results from the interaction between two decision systems (impulsive and executive) and that regulatory imbalance between systems can induce pathology, including addiction. Using this view, we integrate a diverse set of observations on cocaine dependence, including bias for immediacy, neural activity and structure, developmental time course, behavioral comorbidities, and the relationship between cocaine dependence and socioeconomic status. From the CNDS perspective, we discuss established and emerging behavioral, pharmacological, and neurological treatments and identify possible targets for future treatments. The ability of the CNDS theory to integrate diverse findings highlights its utility for understanding cocaine dependence and supports that dysregulation between the decision systems contributes to addiction.

  5. Levamisole-Contaminated Cocaine: An Emergent Cause of Vasculitis and Skin Necrosis

    Science.gov (United States)

    Mobarakai, Neville

    2014-01-01

    The prevalence of cocaine adulterated with levamisole-induced vasculitis is increasing and physicians should be aware of this unique entity. There have been many reports of cutaneous vasculitis syndrome caused by cocaine which is contaminated with levamisole. Levamisole was used as an antihelminth drug and later was rescinded from use in humans due to adverse effects. Through this paper, we will report a 39-year-old crack cocaine user who presented with purpuric rash and skin necrosis of his ear lobes. Levamisole-induced vasculitis syndrome was suspected. A urine toxicology screen was positive for cocaine, opiates, and marijuana. Blood work revealed positive titres of ANA and p-ANCA, as well as anti-cardiolipin antibody. Biopsy taken from the left ear showed focal acute inflammation, chronic inflammation with thrombus formation, and extravasated blood cells. Treatment was primarily supportive with wound care. PMID:24778656

  6. Levamisole-Contaminated Cocaine: An Emergent Cause of Vasculitis and Skin Necrosis

    Directory of Open Access Journals (Sweden)

    Osama Souied

    2014-01-01

    Full Text Available The prevalence of cocaine adulterated with levamisole-induced vasculitis is increasing and physicians should be aware of this unique entity. There have been many reports of cutaneous vasculitis syndrome caused by cocaine which is contaminated with levamisole. Levamisole was used as an antihelminth drug and later was rescinded from use in humans due to adverse effects. Through this paper, we will report a 39-year-old crack cocaine user who presented with purpuric rash and skin necrosis of his ear lobes. Levamisole-induced vasculitis syndrome was suspected. A urine toxicology screen was positive for cocaine, opiates, and marijuana. Blood work revealed positive titres of ANA and p-ANCA, as well as anti-cardiolipin antibody. Biopsy taken from the left ear showed focal acute inflammation, chronic inflammation with thrombus formation, and extravasated blood cells. Treatment was primarily supportive with wound care.

  7. Citalopram enhances cocaine's subjective effects in rats

    OpenAIRE

    Soto, Paul L.; Hiranita, Takato; Katz, Jonathan L.

    2009-01-01

    Serotonin-selective reuptake inhibitors (SSRIs) have been shown to enhance the locomotor stimulatory, discriminative-stimulus, and convulsive effects of cocaine in rodents. A pharmacokinetic mechanism for the interaction is supported by increases in the brain levels of cocaine by fluoxetine treatment. Furthermore, the locomotor-stimulant effects of cocaine in rodents are enhanced by fluoxetine and fluvoxamine, SSRIs known to inhibit cocaine-metabolizing cytochrome P450 enzymes, whereas citalo...

  8. Pharmacological and genetic manipulation of kappa opioid receptors: effects on cocaine- and pentylenetetrazol-induced convulsions and seizure kindling.

    Science.gov (United States)

    Kaminski, Rafal M; Witkin, Jeffrey M; Shippenberg, Toni S

    2007-03-01

    The present study used pharmacological and gene ablation techniques to examine the involvement of kappa opioid receptors (KOPr) in modulating the convulsant effects of two mechanistically different drugs: cocaine and pentylenetetrazol (PTZ; GABA-A receptor antagonist) in mice. Systemic administration of the selective KOPr-1 agonist, U69593 (0.16-0.6mg/kg; s.c.), failed to modify cocaine-evoked convulsions or cocaine kindling. Similarly, no alteration in responsiveness to cocaine was observed in wild-type mice that received the selective KOPr-1 antagonist, nor-binaltorphimine (nor-BNI; 5mg/kg) or in mice lacking the gene encoding KOPr-1. In contrast to cocaine, U69593 attenuated the seizures induced by acute or repeated PTZ administration. Nor-BNI decreased the threshold for PTZ-evoked seizures and increased seizure incidence during the initial induction of kindling relative to controls. Decreased thresholds for PTZ-induced seizures were also observed in KOPr-1 knock out mice. Together, these data demonstrate an involvement of endogenous KOPr systems in modulating vulnerability to the convulsant effects of PTZ but not cocaine. Furthermore, they demonstrate that KOPr-1 activation protects against acute and kindled seizures induced by this convulsant. Finally, the results of our study suggest that KOPr-1 antagonists will not have therapeutic utility against cocaine-induced seizures, while they may prove beneficial in attenuating several actions of cocaine that have been linked to its abuse.

  9. Short term administration of glucocorticoids in patients with protracted and chronic gout arthritis. Part III – frequency of adverse events

    Directory of Open Access Journals (Sweden)

    A A Fedorova

    2009-01-01

    Full Text Available Objective. To assess frequency of adverse events during short term administration of gluco- corticoid (GC in protracted and chronic gout arthritis. Material and methods. 59 pts with tophaceous gout (crystal-verified diagnosis and arthritis of three and more joints lasting more than a months in spite of treatment with sufficient doses of nonsteroidal anti-inflammatory drugs were included. Median age of pts was 56 [48;63], median disease duration – 15,2 years [7,4;20], median swollen joint count at the examination – 8 [5;11]. The patients were randomized into 2 groups. Methylprednisolone (MP 500 mg/day iv during 2 days and placebo im once was administered in one of them, betamethasone (BM 7 mg im once and placebo iv twice – in the other. Clinical evaluation of inflamed joints was performed every day. Standard laboratory examination and ECG were done before drug administration, at 3rd, 7th, and 14th day of follow up. Immunoreactive insulin level was evaluated before drug administration and at day 14. Blood pressure (BP was measured every day. Results. After first GC administration BP elevated in 28 (47% pts. In pts not having appropriate BP values BP elevated in 73% of cases. Pts with appropriate BP values showed less frequent BP elevation – 38% (p=0,02. In 8 (13% pts at day 3 after GC administration ECG signs of myocardial blood supply deterioration were revealed. Glucose level elevated in 10 (17% pts and after the second BM administration – in 5 (8% pts. Cholesterol level did not significantly change after 14 days of follow up but in 28 (47% pts it increased in comparison with baseline. Trigliceride level significantly decreased at day 14 from 149 [106; 187] to 108 [66,5; 172] mg/dl (p=0,02. 26 (44% pts had face hyperemia, 4 (7% –42 palpitation and 2 (3,4% – bitter taste. Conclusion. Administration of short course of GC in pts with gout requires monitoring of possible adverse events. Antihypertensive therapy providing appropriate BP

  10. 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.

  11. Cross-sensitization between testosterone and cocaine in adolescent and adult rats.

    Science.gov (United States)

    Engi, Sheila A; Cruz, Fabio C; Crestani, Carlos C; Planeta, Cleopatra S

    2015-11-01

    Cocaine and anabolic-androgenic steroids are substances commonly co-abused. The use of anabolic steroids and cocaine has increased among adolescents. However, few studies investigated the consequences of the interaction between anabolic-androgenic steroids in animals' model of adolescence. We examined the effects of acute and repeated testosterone administration on cocaine-induced locomotor activity in adult and adolescent rats. Rats received ten once-daily subcutaneous (s.c.) injections of testosterone (10mg/kg) or vehicle. Three days after the last testosterone or vehicle injections rats received an intraperitoneal (i.p.) challenge injection of either saline or cocaine (10mg/kg). A different subset of rats was treated with a single injection of testosterone (10mg/kg) or vehicle and three days later was challenged with cocaine (10mg/kg, i.p.) or saline. Immediately after cocaine or saline injections the locomotor activity was recorded during forty minutes. Our results demonstrated that repeated testosterone induced locomotor sensitization to cocaine in adolescent but not adult rats.

  12. Reduced attentional scope in cocaine polydrug users

    NARCIS (Netherlands)

    Colzato, L.S.; van den Wildenberg, W.P.M.; Hommel, B.

    2009-01-01

    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. Coc

  13. The emergency care of cocaine intoxications.

    NARCIS (Netherlands)

    Vroegop, M.P.; Franssen, E.J.; Voort, P.H. van der; Berg, T.N. van den; Langeweg, R.J.; Kramers, C.

    2009-01-01

    Cocaine is frequently used, especially among adolescents and by men between the age of 25 and 44. Many of them are able to use cocaine in normal day-to-day life, without any problems. Reduced prices of cocaine and other recreational drugs such as MDMA (ecstasy) and gamma hydroxybutyrate (GHB) has le

  14. Effects of acute and chronic administration of MK-801 on c-Fos protein expression in mice brain regions implicated in schizophrenia and antagonistic action of clozapine

    Institute of Scientific and Technical Information of China (English)

    ZUO Dai-ying; CAO Yue; ZHANG Lan; WANG Hai-feng; WU Ying-liang

    2008-01-01

    Objective To investigate the effects of acute and chronic administration of the non-competitive NMDA receptor antagonists MK-801 on c-Fos protein expression in different brain regions of mice and antagonistic action of clozapine. Methods Immunohistochemistry was used to detect the expression of c-Fos protein. Results MK-801 (0.6 mg·kg-1) acute administration produced a significant increase in the expression of c-Fos protein in the layers Ⅲ-Ⅳ of posterior cingulate and retrosplenial (PC/RS) cortex, which was consistent with the previous reports. Moreover, we presented a new finding that MK-801 (0.6 mg·kg-1) chronic administration for 8 days produced a significant increase of c-Fos protein expression in the PC/RS cortex, prefrontal cortex (PFC) and hypothalamus of mice. Among that, c-Fos protein expression in the PC/ RS cortex of mice was most significant. Compared acute administration with chronic administration, we found that MK-801 chronic administration significantly increased the expression of c-Fos protein in the PC/ RS cortex, PFC and hypothalamus. Furthermore, pretreatment of mice with clozapine significantly decreased the expression of c-Fos protein induced by MK-801 acute and chronic administration. Conclusions Marked expression of c-Fos protein induced by MK-801 is associated with neurotransmitters' change noted in our previous studies, and c-Fos protein, the marker of neuronal activation, might play an important role in the chronic pathophysiological process of schizophrenic model induced by NMDA receptor antagonist.

  15. Electrophysiological characteristics of paraventricular thalamic (PVT) neurons in response to cocaine and cocaine- and amphetamine-regulated transcript (CART).

    Science.gov (United States)

    Yeoh, Jiann Wei; James, Morgan H; Graham, Brett A; Dayas, Christopher V

    2014-01-01

    Recent work has established that the paraventricular thalamus (PVT) is a central node in the brain reward-seeking pathway. This role is mediated in part through projections from hypothalamic peptide transmitter systems such as cocaine- and amphetamine-regulated transcript (CART). Consistent with this proposition, we previously found that inactivation of the PVT or infusions of CART into the PVT suppressed drug-seeking behavior in an animal model of contingent cocaine self-administration. Despite this work, few studies have assessed how the basic physiological properties of PVT neurons are influenced by exposure to drugs such as cocaine. Further, our previous work did not assess how infusions of CART, which we found to decrease cocaine-seeking, altered the activity of PVT neurons. In the current study we address these issues by recording from anterior PVT (aPVT) neurons in acutely prepared brain slices from cocaine-treated (15 mg/ml, n = 8) and saline-treated (control) animals (n = 8). The excitability of aPVT neurons was assessed by injecting a series of depolarizing and hyperpolarizing current steps and characterizing the resulting action potential (AP) discharge properties. This analysis indicated that the majority of aPVT neurons exhibit tonic firing (TF), and initial bursting (IB) consistent with previous studies. However, we also identified PVT neurons that exhibited delayed firing (DF), single spiking (SS) and reluctant firing (RF) patterns. Interestingly, cocaine exposure significantly increased the proportion of aPVT neurons that exhibited TF. We then investigated the effects of CART on excitatory synaptic inputs to aPVT neurons. Application of CART significantly suppressed excitatory synaptic drive to PVT neurons in both cocaine-treated and control recordings. This finding is consistent with our previous behavioral data, which showed that CART signaling in the PVT negatively regulates drug-seeking behavior. Together, these studies suggest that cocaine

  16. Electrophysiological characteristics of paraventricular thalamic (PVT) neurons in response to cocaine and cocaine- and amphetamine-regulated transcript (CART)

    Science.gov (United States)

    Yeoh, Jiann Wei; James, Morgan H.; Graham, Brett A.; Dayas, Christopher V.

    2014-01-01

    Recent work has established that the paraventricular thalamus (PVT) is a central node in the brain reward-seeking pathway. This role is mediated in part through projections from hypothalamic peptide transmitter systems such as cocaine- and amphetamine-regulated transcript (CART). Consistent with this proposition, we previously found that inactivation of the PVT or infusions of CART into the PVT suppressed drug-seeking behavior in an animal model of contingent cocaine self-administration. Despite this work, few studies have assessed how the basic physiological properties of PVT neurons are influenced by exposure to drugs such as cocaine. Further, our previous work did not assess how infusions of CART, which we found to decrease cocaine-seeking, altered the activity of PVT neurons. In the current study we address these issues by recording from anterior PVT (aPVT) neurons in acutely prepared brain slices from cocaine-treated (15 mg/ml, n = 8) and saline-treated (control) animals (n = 8). The excitability of aPVT neurons was assessed by injecting a series of depolarizing and hyperpolarizing current steps and characterizing the resulting action potential (AP) discharge properties. This analysis indicated that the majority of aPVT neurons exhibit tonic firing (TF), and initial bursting (IB) consistent with previous studies. However, we also identified PVT neurons that exhibited delayed firing (DF), single spiking (SS) and reluctant firing (RF) patterns. Interestingly, cocaine exposure significantly increased the proportion of aPVT neurons that exhibited TF. We then investigated the effects of CART on excitatory synaptic inputs to aPVT neurons. Application of CART significantly suppressed excitatory synaptic drive to PVT neurons in both cocaine-treated and control recordings. This finding is consistent with our previous behavioral data, which showed that CART signaling in the PVT negatively regulates drug-seeking behavior. Together, these studies suggest that cocaine

  17. Long-term Administration of Angiotension-Converting Enzyme Inhibitor Improves the Outcome of Chronic Heart Failure in Senile Patients

    Institute of Scientific and Technical Information of China (English)

    陈学林; 张劲农; 柯琴梅; 张银环; 刘承云

    2002-01-01

    Summary: One hundred and sixteen senile patients (older than 65 years) with chronic heart failure (CHF) were analyzed retrospectively in order to verify if old patients with CHF would benefit from long-term (one year) angiotension-converting enzyme inhibitor (ACEI) treatment. The frequency of drugs (including ACEI, digitalis and diuretic) used was stratified into four degrees accordingly. Development of the CHF was scored with regard to relapse rate and severity of this disease. Stepwise regression analysis was applied to explore the relationship between the scored outcome of CHF and the frequency of individual drug administra tion. A significant relationship of the scored outcome of CHF to the frequency of ACEI usage but not to digitalis nor to diuretics was found (partial coefficient of the correlation r=0. 42, P=0. 002). It was concluded that the longterm administration of ACEI improves the outcome of CHF in senile patients.

  18. Self-administration and interviewer-administration of the German Chronic Respiratory Questionnaire: instrument development and assessment of validity and reliability in two randomised studies

    Directory of Open Access Journals (Sweden)

    Lichtenschopf Alfred

    2004-01-01

    Full Text Available Abstract Background Assessment of health-related quality of life (HRQL is important in patients with chronic obstructive pulmonary disease (COPD. Despite the high prevalence of COPD in Germany, Switzerland and Austria there is no validated disease-specific instrument available. The objective of this study was to translate the Chronic Respiratory Questionnaire (CRQ, one of the most widely used respiratory HRQL questionnaires, into German, develop an interviewer- and self-administered version including both standardised and individualised dyspnoea questions, and validate these versions in two randomised studies. Methods We recruited three groups of patients with COPD in Switzerland, Germany and Austria. The 44 patients of the first group completed the CRQ during pilot testing to adapt the CRQ to German-speaking patients. We then recruited 80 patients participating in pulmonary rehabilitation programs to assess internal consistency reliability and cross-sectional validity of the CRQ. The third group consisted of 38 patients with stable COPD without an intervention to assess test-retest reliability. To compare the interviewer- and self-administered versions, we randomised patients in groups 2 and 3 to the interviewer- or self-administered CRQ. Patients completed both the standardised and individualised dyspnoea questions. Results For both administration formats and all domains, we found good internal consistency reliability (Crohnbach's alpha between 0.73 and 0.89. Cross-sectional validity tended to be better for the standardised compared to the individualised dyspnoea questions and cross-sectional validity was slightly better for the self-administered format. Test-retest reliability was good for both the interviewer-administered CRQ (intraclass correlation coefficients for different domains between 0.81 and 0.95 and the self-administered format (intraclass correlation coefficients between 0.78 and 0.86. Lower within-person variability was

  19. Effect of Ocimum sanctum, ascorbic acid, and verapamil on macrophage function and oxidative stress in mice exposed to cocaine

    Directory of Open Access Journals (Sweden)

    Bhattacharya S

    2009-01-01

    Full Text Available Objective: To investigate the effect of Ocimum sanctum, ascorbic acid, and verapamil on macrophage function and oxidative stress in experimental animals exposed to cocaine. Materials and Methods: Mice were used in this study and were divided randomly into different groups of six animals each. They were either treated with intraperitoneal injection of saline or cocaine hydrochloride or an oral feeding of oil of Ocimum sanctum, ascorbic acid or verapamil, or both (ascorbic acid and verapamil, and were evaluated for a respiratory burst of macrophages, superoxide and nitric oxide (NO production, estimation of TNF-a in the serum and supernatant of cultured macrophages, estimation of lipid peroxidation (malondialdehyde- MDA in the serum, and superoxide dismutase activity in the erythrocytes. Results: Unstimulated respiratory burst as well as superoxide production was enhanced on treatment with cocaine and all the three drugs were found to attenuate this enhancement. The bactericidal capacity of macrophages decreased significantly on chronic cocaine exposure, as it was associated with decreased respiratory burst and superoxide production. There was a significant decrease in NO production by macrophages on chronic cocaine exposure and all the test drugs were found to restore nitrite formation to a normal level. There was an increase in the malonylodialdehyde (MDA level and decrease in the superoxide dismutase level on chronic cocaine exposure, and all the three drugs effectively decreased the MDA level and increased superoxide dismutase level. There was an increase in serum TNF-α on chronic cocaine exposure, which was decreased significantly by ascorbic acid and verapamil. Conclusion: O. sanctum, ascorbic acid, and verapamil were equally effective in improving the macrophage function and reducing oxidative stress. These findings suggested that O. sanctum, ascorbic acid, and verapamil attenuated acute and chronic cocaine-mediated effects.

  20. Evaluation of skeletal and cardiac muscle function after chronic administration of thymosin beta-4 in the dystrophin deficient mouse.

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    Christopher F Spurney

    Full Text Available Thymosin beta-4 (Tbeta4 is a ubiquitous protein with many properties relating to cell proliferation and differentiation that promotes wound healing and modulates inflammatory mediators. We studied the effects of chronic administration of Tbeta4 on the skeletal and cardiac muscle of dystrophin deficient mdx mice, the mouse model of Duchenne muscular dystrophy. Female wild type (C57BL10/ScSnJ and mdx mice, 8-10 weeks old, were treated with 150 microg of Tbeta4 twice a week for 6 months. To promote muscle pathology, mice were exercised for 30 minutes twice a week. Skeletal and cardiac muscle function were assessed via grip strength and high frequency echocardiography. Localization of Tbeta4 and amount of fibrosis were quantified using immunohistochemistry and Gomori's tri-chrome staining, respectively. Mdx mice treated with Tbeta4 showed a significant increase in skeletal muscle regenerating fibers compared to untreated mdx mice. Tbeta4 stained exclusively in the regenerating fibers of mdx mice. Although untreated mdx mice had significantly decreased skeletal muscle strength compared to untreated wild type, there were no significant improvements in mdx mice after treatment. Systolic cardiac function, measured as percent shortening fraction, was decreased in untreated mdx mice compared to untreated wild type and there was no significant difference after treatment in mdx mice. Skeletal and cardiac muscle fibrosis were also significantly increased in untreated mdx mice compared to wild type, but there was no significant improvement in treated mdx mice. In exercised dystrophin deficient mice, chronic administration of Tbeta4 increased the number of regenerating fibers in skeletal muscle and could have a potential role in treatment of skeletal muscle disease in Duchenne muscular dystrophy.

  1. Effects of Chronic Oral Administration of Natural Honey on Ischemia/Reperfusion-induced Arrhythmias in Isolated Rat Heart

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    Moslem Najafi

    2011-01-01

    Full Text Available Objective(sIn this study, effects of chronic administration of oral natural honey against ischemia/reperfusion (I/R-induced cardiac arrhythmias were investigated in isolated rat heart. Materials and MethodsMale Wistar rats were divided into four groups (n= 10-14 rats in each group and fed with natural honey (1%, 2% and 4% dissolved in the drinking water for 45 days except for the control group. After anesthesia, the rats’ hearts were isolated quickly, mounted on a Langendorff apparatus and perfused with a modified Krebs-Henseleit solution during stabilization, 30 min regional ischemia followed by 30 min reperfusion. The ECGs were recorded throughout the experiments to analyze cardiac arrhythmias based on the Lambeth conventions. ResultsIn the ischemic phase, honey (1% significantly reduced (P<0.05 the number and duration of ventricular tachycardia (VT. Honey (1% and 2% also significantly decreased number of ventricular ectopic beats (VEBs. In addition, incidence and duration of reversible ventricular fibrillation (Rev VF were lowered by honey 2% (P<0.05. During reperfusion time, VT incidence was 73% in the control group, however natural honey (1% decreased it to 22% (P<0.05. Honey also produced significant reduction in the incidences of total VF, Rev VF, duration and number of VT. ConclusionFor the first time, the results of present study demonstrated protective effects of chronic oral honey administration against I/R-induced arrhythmias in isolated rat heart. Antioxidant activity, the existence of energy sources such as glucose and fructose and improvement of some hemodynamic functions might be responsible for these effects.

  2. Effects of chronic doxepin and amitriptyline administration in naïve mice and in neuropathic pain mice model.

    Science.gov (United States)

    Mika, J; Jurga, A M; Starnowska, J; Wasylewski, M; Rojewska, E; Makuch, W; Kwiatkowski, K; Malek, N; Przewlocka, B

    2015-05-21

    Neuropathic pain is a severe clinical problem, often appearing as a co-symptom of many diseases or manifesting as a result of damage to the nervous system. Many drugs and agents are currently used for the treatment of neuropathic pain, such as tricyclic antidepressants (TCAs). The aims of this paper were to test the effects of two classic TCAs, doxepin and amitriptyline, in naïve animals and in a model of neuropathic pain and to determine the role of cytokine activation in the effects of these drugs. All experiments were carried out with Albino-Swiss mice using behavioral tests (von Frey test and the cold plate test) and biochemical analyses (qRT-PCR and Western blot). In the mice subjected to chronic constriction injury (CCI), doxepin and amitriptyline attenuated the symptoms of neuropathic pain and diminished the CCI-induced increase in the levels of spinal interleukin (IL)-6 and -1β mRNA, but not the protein levels of these cytokines, measured on day 12. Unexpectedly, chronic administration of doxepin or amitriptyline for 12 days produced allodynia and hyperalgesia in naïve mice. The treatment with these drugs did not influence the spinal levels of IL-1β and IL-6 mRNA, however, the protein levels of these pronociceptive factors were increased. The administration of ondansetron (5-HT3 receptor antagonist) significantly weakened the allodynia and hyperalgesia induced by both antidepressants in naïve mice; in contrast, yohimbine (α2-adrenergic receptors antagonist) did not influence these effects. Allodynia and hyperalgesia induced in naïve animals by amitriptyline and doxepin may be associated with an increase in the levels of pronociceptive cytokines resulting from 5-HT3-induced hypersensitivity. Our results provide new and important information about the possible side effects of antidepressants. Further investigation of these mechanisms may help to guide decisions about the use of classic TCAs for therapy.

  3. Alternative Splicing of AMPA subunits in Prefrontal Cortical Fields of Cynomolgus Monkeys following Chronic Ethanol Self-Administration

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    Glen eAcosta

    2012-01-01

    Full Text Available Functional impairment of the orbital and medial prefrontal cortex underlies deficits in executive control that characterize addictive disorders, including alcohol addiction. Previous studies indicate that alcohol alters glutamate neurotransmission and one substrate of these effects may be through the reconfiguration of the subunits constituting ionotropic glutamate receptor (iGluR complexes. Glutamatergic transmission is integral to cortico-cortical and cortico-subcortical communication and alcohol-induced changes in the abundance of the receptor subunits and/or their splice variants may result in critical functional impairments of prefrontal cortex in alcohol dependence. To this end, the effects of chronic ethanol self-administration on glutamate receptor ionotropic AMPA (GRIA subunit variant and kainate (GRIK subunit mRNA expression were studied in the orbitofrontal cortex (OFC, dorsolateral prefrontal cortex (DLPFC and anterior cingulate cortex (ACC of male cynomolgus monkeys. In DLPFC, total AMPA splice variant expression and total kainate receptor subunit expression were significantly decreased in alcohol drinking monkeys. Expression levels of GRIA3 flip and flop and GRIA4 flop mRNAs in this region were positively correlated with daily ethanol intake and blood ethanol concentrations averaged over the six months prior to necropsy. In OFC, AMPA subunit splice variant expression was reduced in the alcohol treated group. GRIA2 flop mRNA levels in this region were positively correlated with daily ethanol intake and blood ethanol concentrations averaged over the six months prior to necropsy. Results from these studies provide further evidence of transcriptional regulation of iGluR subunits in the primate brain following chronic alcohol self-administration. Additional studies examining the cellular localization of such effects in the framework of primate prefrontal cortical circuitry are warranted.

  4. Voluntary exercise does not ameliorate spatial learning and memory deficits induced by chronic administration of nandrolone decanoate in rats.

    Science.gov (United States)

    Tanehkar, Fatemeh; Rashidy-Pour, Ali; Vafaei, Abbas Ali; Sameni, Hamid Reza; Haghighi, Saeed; Miladi-Gorji, Hossien; Motamedi, Fereshteh; Akhavan, Maziar Mohammad; Bavarsad, Kowsar

    2013-01-01

    Chronic exposure to the anabolic androgenic steroids (AAS) nandrolone decanoate (ND) in supra-physiological doses is associated with learning and memory impairments. Given the well-known beneficial effects of voluntary exercise on cognitive functions, we examined whether voluntary exercise would improve the cognitive deficits induced by chronic administration of ND. We also investigated the effects of ND and voluntary exercise on hippocampal BDNF levels. The rats were randomly distributed into 4 experimental groups: the vehicle-sedentary group, the ND-sedentary group, the vehicle-exercise group, and the ND-exercise group. The vehicle-exercise and the ND-exercise groups were allowed to freely exercise in a running wheel for 15 days. The vehicle-sedentary and the ND-sedentary groups were kept sedentary for the same period. Vehicle or ND injections were started 14 days prior to the voluntary exercise and continued throughout the 15 days of voluntary exercise. After the 15-day period, the rats were trained and tested on a water maze spatial task using four trials per day for 5 consecutive days followed by a probe trial two days later. Exercise significantly improved performance during both the training and retention of the water maze task, and enhanced hippocampal BDNF. ND impaired spatial learning and memory, and this effect was not rescued by exercise. ND also potentiated the exercise-induced increase in hippocampal BDNF levels. These results seem to indicate that voluntary exercise is unable to improve the disruption of cognitive functions by chronic ND. Moreover, increased levels of BDNF may play a role in ND-induced impairments in learning and memory. The harmful effects of ND and other AAS on learning and memory should be taken into account when athletes decide to use AAS for performance or body image improvement.

  5. Cerebral metabolic responses to meta-chlorophenylpiperazine are reduced during its chronic administration to young and aged rats.

    Science.gov (United States)

    Freo, U; Larson, D M; Soncrant, T T

    1993-01-01

    The effects of the 5-HT agonist meta-chlorophenylpiperazine (MCPP) on regional cerebral metabolic rates for glucose (rCMRglc) were measured in 3- and 24-month-old rats that were not pretreated or were pretreated for 2 weeks with continuous infusion of saline or MCPP. rCMRglc were measured using the quantitative autoradiographic [14C]2-deoxy-D-glucose technique in 71 brain regions at 15 min after acute administration of MCPP 2.5 mg/kg. In the absence of chronic pretreatment, intraperitoneal MCPP 2.5 mg/kg produced widespread rCMRglc reductions (41 brain areas) in 3-month-old rats and more limited rCMRglc decreases (8 brain areas) in 24-month-old rats. After chronic treatment, MCPP failed to reduce rCMRglc in any region of either group of rats. These findings indicate that mechanisms of downregulation of response to MCPP are functional in young and aged rats and suggest that the age-related reduction in rCMRglc responses to acute MCPP in non-pretreated animals may be due to compensation for age-related losses of 5-HT terminals.

  6. Reversing gastric mucosal alterations during ethanol-induced chronic gastritis in rats by oral administration of Opuntia ficus- indica mucilage

    Institute of Scientific and Technical Information of China (English)

    Ricardo Vázquez-Ramírez; Marisela Olguín-Martínez; Carlos Kubli-Garfias; Rolando Hernández-Mu(n)oz

    2006-01-01

    AIM: To study the effect of mucilage obtained from cladodes of Opuntia ficus-indica (Cactaceae) on the healing of ethanol-induced gastritis in rats.METHODS: Chronic gastric mucosa injury was treated with mucilage (5 mg/kg per day) after it was induced by ethanol. Lipid composition, activity of 5'-nucleotidase (a membrane-associated ectoenzyme) and cytosolic activities of lactate and alcohol dehydrogenases in the plasma membrane of gastric mucosa were determined.Histological studies of gastric samples from the experimental groups were included.RESULTS: Ethanol elicited the histological profile of gastritis characterized by loss of the surface epithelium and infiltration of polymorphonuclear leukocytes.Phosphatidylcholine (PC) decreased and cholesterol content increased in plasma membranes of the gastric mucosa. In addition, cytosolic activity increased while the activity of alcohol dehydrogenases decreased. The administration of mucilage promptly corrected these enzymatic changes. In fact, mucilage readily accelerated restoration of the ethanol-induced histological alterations and the disturbances in plasma membranes of gastric mucosa, showing a univocal anti-inflammatory effect.The activity of 5'-nucleotidase correlated with the changes in lipid composition and the fluidity of gastric mucosal plasma membranes.CONCLUSION: The beneficial action of mucilage seems correlated with stabilization of plasma membranes of damaged gastric mucosa. Molecular interactions between mucilage monosaccharides and membrane phospholipids,mainly PC and phosphatidylethanolamine (PE), may be the relevant features responsible for changing activities of membrane-attached proteins during the healing process after chronic gastric mucosal damage.

  7. Alterations of the Host Microbiome Affect Behavioral Responses to Cocaine

    Science.gov (United States)

    Kiraly, Drew D.; Walker, Deena M.; Calipari, Erin S.; Labonte, Benoit; Issler, Orna; Pena, Catherine J.; Ribeiro, Efrain A.; Russo, Scott J.; Nestler, Eric J.

    2016-01-01

    Addiction to cocaine and other psychostimulants represents a major public health crisis. The development and persistence of addictive behaviors comes from a complex interaction of genes and environment - the precise mechanisms of which remain elusive. In recent years a surge of evidence has suggested that the gut microbiome can have tremendous impact on behavioral via the microbiota-gut-brain axis. In this study we characterized the influence of the gut microbiota on cocaine-mediated behaviors. Groups of mice were treated with a prolonged course of non-absorbable antibiotics via the drinking water, which resulted in a substantial reduction of gut bacteria. Animals with reduced gut bacteria showed an enhanced sensitivity to cocaine reward and enhanced sensitivity to the locomotor-sensitizing effects of repeated cocaine administration. These behavioral changes were correlated with adaptations in multiple transcripts encoding important synaptic proteins in the brain’s reward circuitry. This study represents the first evidence that alterations in the gut microbiota affect behavioral response to drugs of abuse. PMID:27752130

  8. Serotonin2C receptors and drug addiction: focus on cocaine.

    Science.gov (United States)

    Devroye, Céline; Filip, Malgorzata; Przegaliński, Edmund; McCreary, Andrew C; Spampinato, Umberto

    2013-10-01

    This review provides an overview of the role of central serotonin2C (5-HT2C) receptors in drug addiction, specifically focusing on their impact on the neurochemical and behavioral effects of cocaine, one of the most worldwide abused drug. First, we described the neurochemical and electrophysiological mechanisms underlying the interaction between 5-HT2C receptors and the mesocorticolimbic dopaminergic network, in keeping with the key role of this system in drug abuse and dependence. Thereafter, we focused on the role of 5-HT2C receptors in the effects of cocaine in various preclinical behavioral models used in drug addiction research, such as locomotor hyperactivity, locomotor sensitization, drug discrimination, and self-administration, to end with an overview of the neurochemical mechanisms underlying the interactions between 5-HT2C receptors, mesocorticolimbic dopamine system, and cocaine. On their whole, the presented data provide compelling preclinical evidence that 5-HT2C receptor agonists may have efficacy in the treatment of cocaine abuse and dependence, thereby underlying the need for additional clinical studies to ascertain whether preclinical data translate to the human.

  9. Advanced cocaine-related necrotising sinusitis presenting with restrictive ophthalmolplegia.

    Science.gov (United States)

    Lascaratos, Gerassimos; McHugh, James; McCarthy, Karon; Bunting, Howard

    2016-06-01

    We report a case of bilateral infero-medial orbital wall destruction, associated with loss of sinonasal architecture. The patient presented with intermittent horizontal diplopia following an acute on chronic infective sinusitis. Eight months previously the patient had developed a midline hard palate fistula for which a palatine prosthesis had been fitted. The broad differential diagnosis is discussed, though in this patient chronic cocaine abuse was identified as the underlying aetiology. Eye movement restriction worsened progressively with bilateral inflammation around the medial and inferior rectus muscles. Attempts to resolve the recurring cycle of sinus infection and inflammation by palatal fistula closure failed despite augmented techniques mobilising flaps from both nasal and palatal sides.

  10. Ginger extract protects rat's kidneys against oxidative damage after chronic ethanol administration.

    Science.gov (United States)

    Shirpoor, Aireza; Rezaei, Farzaneh; Fard, Amin Abdollahzade; Afshari, Ali Taghizadeh; Gharalari, Farzaneh Hosseini; Rasmi, Yousef

    2016-12-01

    Chronic alcohol ingestion is associated with pronounced detrimental effects on the renal system. In the current study, the protective effect of ginger extract on ethanol-induced damage was evaluated through determining 8-OHdG, cystatin C, glomerular filtration rate, and pathological changes such as cell proliferation and fibrosis in rats' kidneys. Male wistar rats were randomly divided into three groups and were treated as follows: (1) control, (2) ethanol and (3) ginger extract treated ethanolic (GETE) groups. After a six weeks period of treatment, the results revealed proliferation of glomerular and tubular cells, fibrosis in glomerular and peritubular and a significant rise in the level of 8-OHdG, cystatin C, plasma urea and creatinine. Moreover, compared to the control group, the ethanol group showed a significant decrease in the urine creatinine and creatinine clearance. In addition, significant amelioration of changes in the structure of kidneys, along with restoration of the biochemical alterations were found in the ginger extract treated ethanolic group, compared to the ethanol group. These findings indicate that ethanol induces kidneys abnormality by oxidative DNA damage and oxidative stress, and that these effects can be alleviated using ginger as an antioxidant and anti-inflammatory agent.

  11. Thymoquinone ameliorates testicular tissue inflammation induced by chronic administration of oral sodium nitrite.

    Science.gov (United States)

    Alyoussef, A; Al-Gayyar, M M H

    2016-06-01

    Although sodium nitrite has been widely used as food preservative, building bases of scientific evidence about nitrite continues to oppose the general safety in human health. Moreover, thymoquinone (TQ) has therapeutic potential as antioxidant, anti-inflammatory, antibacterial and anticancer. Therefore, we investigated the effects of both sodium nitrite and TQ on testicular tissues of rats. Forty adult male Sprague Dawley rats were used. They received either 80 mg kg(-1) sodium nitrite or 50 mg kg(-1) TQ daily for twelve weeks. Serum testosterone was measured. Testis were weighed and the testicular tissue homogenates were used for measurements of tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-4, IL-6, IL10, caspase-3, caspase-8 and caspase-9. Sodium nitrite resulted in significant reduction in serum testosterone concentration and elevation in testis weight and Gonado-Somatic Index. We found significant reduction in testicular tissues levels of IL-4 and IL-10 associated with elevated levels of TNF-α, IL-1β, IL-6, caspase-3, caspase-8 and caspase-9. In conclusion, chronic oral sodium nitrite induced changes in the weight of rat testis accompanied by elevation in the testicular tissue level of oxidative stress markers and inflammatory cytokines. TQ attenuated sodium nitrite-induced testicular tissue damage through blocking oxidative stress, restoration of normal inflammatory cytokines balance and blocking of apoptosis.

  12. Food consumption and weight gain after cessation of chronic amphetamine administration.

    Science.gov (United States)

    Orsini, Caitlin A; Ginton, Guy; Shimp, Kristy G; Avena, Nicole M; Gold, Mark S; Setlow, Barry

    2014-07-01

    Cessation of drug use often coincides with increased food consumption and weight gain in recovering addicts. However, it is not known whether this phenomenon (particularly the weight gain) is uniquely human, or whether it represents a consequence of drug cessation common across species. To address this issue, rats (n = 10/group) were given systemic injections of D-amphetamine (3 mg/kg) or an equal volume of saline vehicle for 9 consecutive days. Beginning 2 days after the final injection, rats were given free access to a highly palatable food mixture (consisting of sugar and butter) along with their standard chow diet, and food consumption and body weight were measured every 48 h for 30 days. Consistent with clinical observations, amphetamine-treated rats showed a greater increase in body weight over the course of the 30 days relative to vehicle-treated rats. Surprisingly, there was no difference in highly palatable food consumption between amphetamine- and vehicle-treated groups, but the amphetamine-treated group consumed significantly more standard chow than the control group. The finding that a history of chronic amphetamine exposure increases food consumption is consistent with previous work in humans showing that withdrawal from drugs of abuse is associated with overeating and weight gain. The current findings may reflect amphetamine-induced sensitization of mechanisms involved in reward motivation, suggesting that weight gain following drug cessation in humans could be due to similar mechanisms.

  13. Effects of chronic administration of valproic acid to epileptic patients on coagulation tests and primary hemostasis.

    Science.gov (United States)

    Zighetti, Maddalena L; Fontana, Gessica; Lussana, Federico; Chiesa, Valentina; Vignoli, Aglaia; Canevini, Maria Paola; Cattaneo, Marco

    2015-05-01

    Valproic acid (VPA) is an antiepileptic drug that has been associated with impaired hemostasis and increased risk for postsurgical bleeding. However, the published reports provide controversial results. We measured parameters of primary hemostasis in VPA-treated patients with epilepsy, focusing on adenosine nucleotide-dependent platelet responses, which play a central role in primary hemostasis. We enrolled 20 cases (epileptic patients receiving treatment with VPA) and 20 controls (12 epileptic patients receiving treatment with drugs different from VPA and 8 healthy subjects). Measurements included prothrombin time (PT), activated partial thromboplastin time (APTT), platelet count, platelet function analyzer (PFA)-100 closure times, plasma von Willebrand factor levels, platelet content of ADP, ATP, and serotonin (all stored in platelet dense granules), and platelet shape change and aggregation induced by ADP and other platelet agonists, including the ATP analog α,β-methylene-ATP. The plasma concentration of VPA was in the therapeutic range in 17 patients and slightly above the upper limit in 3 patients. There were no statistically significant differences in any of the studied parameters in cases versus controls. Our thorough controlled study failed to show that chronic treatment with VPA induces significant abnormalities of coagulation and primary hemostasis. Therefore, VPA, when present in the circulation in the therapeutic range, does not impair hemostasis.

  14. Acute and chronic administration of immunomodulators induces anorexia in Zucker rats.

    Science.gov (United States)

    Lugarini, F; Hrupka, B J; Schwartz, G J; Plata-Salaman, C R; Langhans, W

    2005-01-31

    To investigate the possible involvement of leptin signaling in lipopolysaccharide (LPS) anorexia, we compared the anorectic effect of LPS in genetically obese (fa/fa) Zucker rats and in their lean (Fa/?) counterparts. The effects of interleukin-1beta (IL-1beta) and muramyl dipeptide (MDP) were also tested. LPS [100 microg/kg body weight (BW)], IL-1beta (2 microg/kg BW) and MDP (2.2 mg/kg BW) injected intraperitoneally (i.p.) at lights out reduced food intake similarly in obese and lean rats. LPS injection at 500 or 1000 microg/kg BW (i.p.) also reduced food intake and BW similarly in obese and lean rats, but obese regained BW faster than lean rats. LPS (2.45 microg or 9.8 microg/h/rat) administered chronically with i.p. implanted osmotic pumps reduced food intake similarly on experimental day 1, regardless of the genotype. After day 3, the lean rats' anorectic response and recovery were dose-dependent, whereas the anorectic response in obese rats was minimally affected by dose (significant dose effect only on day 3). Again, obese rats regained lost BW faster than lean rats. These results do not support a role for leptin as the sole mediator of anorexia induced by bacterial products (LPS and MDP) and IL-1beta.

  15. Effect of simulated weightlessness and chronic 1,25-dihydroxyvitamin D administration on bone metabolism

    Science.gov (United States)

    Halloran, B. P.; Bikle, D. D.; Globus, R. K.; Levens, M. J.; Wronski, T. J.; Morey-Holton, E.

    1985-01-01

    Weightlessness, as experienced during space flight, and simulated weightlessness induce osteopenia. Using the suspended rat model to simulate weightlessness, a reduction in total tibia Ca and bone formation rate at the tibiofibular junction as well as an inhibition of Ca-45 and H-3-proline uptake by bone within 5-7 days of skeletal unloading was observed. Between days 7 and 15 of unloading, uptake of Ca-45 and H-3-proline, and bone formation rate return to normal, although total bone Ca remains abnormally low. To examine the relationship between these characteristic changes in bone metabolism induced by skeletal unloading and vitamin D metabolism, the serum concentrations of 25-hydroxyvitamin D (25-OH-D), 24, 25-dihydroxyvitamin D (24,25(OH)2D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) at various times after skeletal unloading were measured. The effect of chronic infusion of 1,25(OH)2D3 on the bone changes associated with unloading was also determined.

  16. [Neurologic complications of cocaine abuse].

    Science.gov (United States)

    Van Viet, H; Chevalier, P; Sereni, C; Bornet, P; Bautier, P; Degos, C F; Rullière, R

    1990-06-02

    Cocaine is increasingly used by drug addicts. It is considered harmless, but numerous, varied and often serious complications due to its abuse have been published. Among these, neurological complications are in the forefront. They include generalized or partial epileptic seizures, ischaemic or haemorrhagic cerebral vascular accidents, visual loss caused by optic neuropathy or by retinal artery occlusion, headaches and exacerbation of tics. Infections of the central nervous system are possible via endocarditis or septicaemia of venous or nasal origin. Neurological disorders may also occur as a consequence of a major cardiovascular complication induced by cocaine (myocardial infarction and/or dysrhythmia, aortic dissection). These neurological complications are unpredictable, and they weigh heavily on the functional and sometimes vital prognosis in habitual or occasional cocaine abusers.

  17. A Critical Role for the GluA1 Accessory Protein, SAP97, in Cocaine Seeking.

    Science.gov (United States)

    White, Samantha L; Ortinski, Pavel I; Friedman, Shayna H; Zhang, Lei; Neve, Rachael L; Kalb, Robert G; Schmidt, Heath D; Pierce, R Christopher

    2016-02-01

    A growing body of evidence indicates that the transport of GluA1 subunit-containing calcium-permeable AMPA receptors (CP-AMPARs) to synapses in subregions of the nucleus accumbens promotes cocaine seeking. Consistent with these findings, the present results show that administration of the CP-AMPAR antagonist, Naspm, into the caudal lateral core or caudal medial shell of the nucleus accumbens attenuated cocaine priming-induced reinstatement of drug seeking. Moreover, viral-mediated overexpression of 'pore dead' GluA1 subunits (via herpes simplex virus (HSV) GluA1-Q582E) in the lateral core or medial shell attenuated the reinstatement of cocaine seeking. The overexpression of wild-type GluA1 subunits (via HSV GluA1-WT) in the medial shell, but not the lateral core, enhanced the reinstatement of cocaine seeking. These results indicate that activation of GluA1-containing AMPARs in subregions of the nucleus accumbens reinstates cocaine seeking. SAP97 and 4.1N are proteins involved in GluA1 trafficking to and stabilization in synapses; SAP97-GluA1 interactions also influence dendritic growth. We next examined potential roles of SAP97 and 4.1N in cocaine seeking. Viral-mediated expression of a microRNA that reduces SAP97 protein expression (HSV miSAP97) in the medial accumbens shell attenuated cocaine seeking. In contrast, a virus that overexpressed a dominant-negative form of a 4.1N C-terminal domain (HSV 4.1N-CTD), which prevents endogenous 4.1N binding to GluA1 subunits, had no effect on cocaine seeking. These results indicate that the GluA1 subunit accessory protein SAP97 may represent a novel target for pharmacotherapeutic intervention in the treatment of cocaine craving.

  18. Cocaine distribution in wild Erythroxylum species.

    Science.gov (United States)

    Bieri, Stefan; Brachet, Anne; Veuthey, Jean-Luc; Christen, Philippe

    2006-02-20

    Cocaine distribution was studied in leaves of wild Erythroxylum species originating from Bolivia, Brazil, Ecuador, Paraguay, Peru, Mexico, USA, Venezuela and Mauritius. Among 51 species, 28 had never been phytochemically investigated before. Cocaine was efficiently and rapidly extracted with methanol, using focused microwaves at atmospheric pressure, and analysed without any further purification by capillary gas chromatography coupled to mass spectrometry. Cocaine was reported for the first time in 14 species. Erythroxylum laetevirens was the wild species with the highest cocaine content. Its qualitative chromatographic profile also revealed other characteristic tropane alkaloids. Finally, its cocaine content was compared to those of two cultivated coca plants as well as with a coca tea bag sample.

  19. Effect of melatonin administration on subjective sleep quality in chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    D.M. Nunes

    2008-10-01

    Full Text Available Disturbed sleep is common in chronic obstructive pulmonary disease (COPD. Conventional hypnotics worsen nocturnal hypoxemia and, in severe cases, can lead to respiratory failure. Exogenous melatonin has somnogenic properties in normal subjects and can improve sleep in several clinical conditions. This randomized, double-blind, placebo-controlled study was carried out to determine the effects of melatonin on sleep in COPD. Thirty consecutive patients with moderate to very severe COPD were initially recruited for the study. None of the participants had a history of disease exacerbation 4 weeks prior to the study, obstructive sleep apnea, mental disorders, current use of oral steroids, methylxanthines or hypnotic-sedative medication, nocturnal oxygen therapy, and shift work. Patients received 3 mg melatonin (N = 12 or placebo (N = 13, orally in a single dose, 1 h before bedtime for 21 consecutive days. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI and daytime sleepiness was measured by the Epworth Sleepiness Scale. Pulmonary function and functional exercise level were assessed by spirometry and the 6-min walk test, respectively. Twenty-five patients completed the study protocol and were included in the final analysis. Melatonin treatment significantly improved global PSQI scores (P = 0.012, particularly sleep latency (P = 0.008 and sleep duration (P = 0.046. No differences in daytime sleepiness, lung function and functional exercise level were observed. We conclude that melatonin can improve sleep in COPD. Further long-term studies involving larger number of patients are needed before melatonin can be safely recommended for the management of sleep disturbances in these patients.

  20. Variable effects of chronic subcutaneous administration of rotenone on striatal histology.

    Science.gov (United States)

    Zhu, Chunni; Vourc'h, Patrick; Fernagut, Pierre-Olivier; Fleming, Sheila M; Lacan, Sanja; Dicarlo, Cheryl D; Seaman, Ronald L; Chesselet, Marie-Françoise

    2004-10-25

    When infused in rats, rotenone, a mitochondrial complex I inhibitor, induces alterations that resemble the histological changes of Parkinson's disease, particularly degeneration of the nigrostriatal dopaminergic system. However, the specificity of rotenone effects has been challenged recently. We have re-examined the alterations caused by rotenone in the substantia nigra and the striatum of rats after infusion of rotenone (2 mg/kg per day s.c.) for 21 days. Three patterns of striatal tyrosine-hydroxylase immunoreactivity (TH-IR) were observed: 46% of animals showed no reduction, and 46% of animals showed diffuse reduction in TH-IR, whereas one animal presented a focal loss of TH-IR in the striatum. Confocal microscopy analysis showed that the vesicular monoamine transporter (VMAT2) was decreased in parallel with TH-IR, strongly suggesting a loss of striatal DA nerve terminals in animals with diffuse or central TH-IR loss. However, no significant loss of TH-IR neurons was observed in the substantia nigra. Analysis of NeuN and DARPP-32 immunoreactivity, and Nissl staining, in the striatum showed no striatal neuronal loss in animals with either preserved TH-IR or diffuse TH-IR reduction. However, in the animal with focal TH-IR loss, severe neuronal loss was evident in the center and the periphery of the striatum, together with microglial activation detected by OX-6 and OX-42 staining. Thus, in most cases, chronic subcutaneous infusion of low doses of rotenone does not induce significant striatal neuronal loss, despite TH-IR and VMAT-IR reduction in a subset of animals, supporting the use of rotenone as a model of Parkinson's disease under carefully controlled experimental conditions.

  1. Chronic administration of resveratrol prevents morphological changes in prefrontal cortex and hippocampus of aged rats.

    Science.gov (United States)

    Monserrat Hernández-Hernández, Elizabeth; Serrano-García, Carolina; Antonio Vázquez-Roque, Rubén; Díaz, Alfonso; Monroy, Elibeth; Rodríguez-Moreno, Antonio; Florán, Benjamin; Flores, Gonzalo

    2016-05-01

    Resveratrol may induce its neuroprotective effects by reducing oxidative damage and chronic inflammation apart from improving vascular function and activating longevity genes, it also has the ability to promote the activity of neurotrophic factors. Morphological changes in dendrites of the pyramidal neurons of the prefrontal cortex (PFC) and hippocampus have been reported in the brain of aging humans, or in humans with neurodegenerative diseases such as Alzheimer's disease. These changes are reflected particularly in the decrement of both the dendritic tree and spine density. Here we evaluated the effect of resveratrol on the dendrites of pyramidal neurons of the PFC (Layers 3 and 5), CA1- and CA3-dorsal hippocampus (DH) as well as CA1-ventral hippocampus, dentate gyrus (DG), and medium spiny neurons of the nucleus accumbens of aged rats. 18-month-old rats were administered resveratrol (20 mg/kg, orally) daily for 60 days. Dendritic morphology was studied by the Golgi-Cox stain procedure, followed by Sholl analysis on 20-month-old rats. In all resveratrol-treated rats, a significant increase in dendritic length and spine density in pyramidal neurons of the PFC, CA1, and CA3 of DH was observed. Interestingly, the enhancement in dendritic length was close to the soma in pyramidal neurons of the PFC, whereas in neurons of the DH and DG, the increase in dendritic length was further from the soma. Our results suggest that resveratrol induces modifications of dendritic morphology in the PFC, DH, and DG. These changes may explain the therapeutic effect of resveratrol in aging and in Alzheimer's disease.

  2. Addiction-Related Effects of DOV 216,303 and Cocaine

    DEFF Research Database (Denmark)

    Sørensen, Gunnar; Husum, Henriette; Brennum, Lise T

    2014-01-01

    DOV 216,303, an inhibitor of serotonin, noradrenaline and dopamine reuptake, belongs to a new line of drugs called 'triple reuptake inhibitors' that have been proposed for treatment of depression. The addictive drug cocaine has similar mechanism of action and exerts rewarding effects by blocking...... of DOV 216,303, we conducted a comparative study of addiction-related effects of DOV 216,303 and cocaine in mice using acute self-administration, conditioned place preference (CPP) and drug-induced hyperlocomotion. Effects on accumbal extracellular dopamine levels were determined using microdialysis......, and we measured monoamine receptor occupancy as well as brain and plasma exposure. DOV 216,303 was self-administered acutely in the same dose range as cocaine. However, in the CPP model, DOV 216,303 did not induce place preference at doses where cocaine caused place preference. Higher doses of DOV 216...

  3. Role for the mesocortical dopamine system in the motivating effects of cocaine.

    Science.gov (United States)

    Koob, G F; Caine, B; Markou, A; Pulvirenti, L; Weiss, F

    1994-01-01

    The search for a neurobiological substrate for the stimulant and reinforcing properties of cocaine has focused for some time on a particular part of the forebrain, the mesocorticolimbic dopamine (DA) system. This mesocorticolimbic DA system innervates the region of the nucleus accumbens (NACC) (ventral striatum) in the anterior part of the basal forebrain and appears to play a critical role in mediating the acute reinforcing effects of cocaine and amphetamine. This chapter reviews the role of mesocorticolimbic DA in the reinforcing properties of psychomotor stimulants as measured by intravenous (IV) drug self-administration in rats. In addition, the primary neuropharmacological mechanism for cocaine reinforcement provides a rich substrate for studying nondopaminergic modulation of the reinforcing actions of cocaine.

  4. Distribution of cadmium in gravid CF-1 mice following chronic administration

    Energy Technology Data Exchange (ETDEWEB)

    Reihart, M.J.; Mahalik, M.P.; Hitner, H.W.; Prozialeck, W.C. (PCOM, Philadelphia, PA (United States))

    1991-03-11

    Previous studies, in which cadmium (Cd{sup 2+}) was administered via osmotic minipumps to gravid CF-1 mice showed that Cd{sup 2+} produces dose-dependent teratogenic effects. The present studies examined the patterns of distribution when Cd{sup 2+} is given by this route to gravid and non-gravid mice. A total dose of 5.6 umoles CdCl{sub 2} containing 1 uCi {sup 109}Cd{sup 2+} was administered via 14 day Alzet osmotic minipumps implanted subcutaneously on day 5 of gestation. On day 12 and day 18 of gestation, the animals were sacrificed. Samples of various tissues were removed, solubilized and counted for radioactivity in a liquid scintillation counter. The results showed that the highest levels of Cd were present in the maternal liver and kidney. The levels of Cd{sup 2+} in the kidney on day 18 were much higher than those on day 12 suggesting a gradual redistribution of Cd{sup 2+} accumulated in the placenta, little was present in the amnionic fluid or fetuses. These patterns of distribution for Cd{sup 2+} administered by osmotic minipumps are similar to those previously reported for other parenteral routes of administration. The authors finding that Cd{sup 2+} accumulates in the placenta but does not readily cross into the amniotic fluid or fetus is consistent with the hypothesis that Cd{sup 2+} may produce some of its teratogenic effects by selectively damaging the placenta.

  5. Regulation of rat MOR-1 gene expression after chronic intracerebroventricular administration of morphine.

    Science.gov (United States)

    Zhu, Zhi-Ping; Badisa, Ramesh B; Palm, Donald E; Goodman, Carl B

    2012-02-01

    The µ-opioid receptor is the primary site for the action of morphine. In the present study, we investigated the regulation of the µ-opioid receptor mRNA levels in the locus ceruleus, ventral tegmental area, nucleus accumbens and hypothalamus of the rat brain following intracerebroventricular administration of morphine for 7 days. The isolated mRNA from these regions was subjected to real-time quantitative RT-PCR to determine the regulation of µ-opioid receptor gene expression. It was observed that 7 days of treatment with morphine significantly down-regulated the µ-opioid receptor mRNA levels in the hypothalamus of the brain in comparison to the control group. However, the µ-opioid receptor levels in the locus ceruleus, ventral tegmental area and nucleus accumbens regions remained the same as the control levels. Down-regulation of µ-opioid receptor mRNA levels in the hypothalamus region of the brain indicates the probable role of opioids to influence neuroendocrine function. The results further indicate that cellular adaptation for morphine tolerance is tissue-specific. These findings help us to understand the mechanism of morphine tolerance in various regions of the brain.

  6. International Conference on Harmonisation; guidance on the duration of chronic toxicity testing in animals (rodent and nonrodent toxicity testing); availability. Notice. Food and Drug Administration, HHS.

    Science.gov (United States)

    1999-06-25

    The Food and Drug Administration (FDA) is publishing a guidance entitled "S4A Duration of Chronic Toxicity Testing in Animals (Rodent and Nonrodent Toxicity Testing)." The guidance was prepared under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and is intended to provide guidance on the duration of chronic toxicity testing in rodents and nonrodents as part of the safety evaluation of a drug product. FDA is also noting circumstances in which it may accept durations of chronic toxicity testing in nonrodents that differ from the duration generally recommended by ICH.

  7. 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 expla

  8. [INDICES OF THE OXIDATIVE STATUS IN CHRONIC ADMINISTRATION OF COLLOID CARBONATE CALCIUM PRAPARATION WITH FAUCET AND LOW-MINERALIZED DRINKING WATER IN RATS].

    Science.gov (United States)

    Khripach, L V; Mikhaylova, R I; Koganova, Z I; Knyazeva, T D; Alekseeva, A V; Savostikova, O N; Ryzhova, I N; Kruglova, E V; Revzova, T L

    2015-01-01

    There are discussed the changes of an array of indices of the oxidative status in chronic administration of colloidal calcium carbonate preparation with faucet and low-mineralized drinking water to rats. Slight differences between significant effects of administration of 3 and 30 mg/L of preparation permit to suggest that the process of its incoming delivery into organism of rats has a bottleneck in the nature of total capacity of macrophages of intestinal lymphoid tissue to absorption of particles.

  9. Dopamine transporter-dependent and -independent striatal binding of the benztropine analog JHW 007, a cocaine antagonist with low abuse liability

    Science.gov (United States)

    The benztropine analog JHW 007 displays high affinity for the dopamine transporter (DAT), but unlike typical DAT ligands, has relatively low abuse liability and blocks effects of cocaine,including its self-administration. To determine sites responsible for the cocaine-antagonist effects of JHW 007, ...

  10. Pharmacological characterization of a dopamine transporter ligand that functions as a cocaine antagonist.

    Science.gov (United States)

    Desai, Rajeev I; Grandy, David K; Lupica, Carl R; Katz, Jonathan L

    2014-01-01

    An N-butyl analog of benztropine, JHW007 [N-(n-butyl)-3α-[bis(4'-fluorophenyl)methoxy]-tropane], binds to dopamine transporters (DAT) but has reduced cocaine-like behavioral effects and antagonizes various effects of cocaine. The present study further examined mechanisms underlying these effects. Cocaine dose-dependently increased locomotion, whereas JHW007 was minimally effective but increased activity 24 hours after injection. JHW007 (3-10 mg/kg) dose-dependently and fully antagonized the locomotor-stimulant effects of cocaine (5-60 mg/kg), whereas N-methyl and N-allyl analogs and the dopamine (DA) uptake inhibitor GBR12909 [1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride] stimulated activity and failed to antagonize effects of cocaine. JHW007 also blocked the locomotor-stimulant effects of the DAT inhibitor GBR12909 but not stimulation produced by the δ-opioid agonist SNC 80 [4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazin-1-yl](3-methoxyphenyl)methyl]-N,N-diethylbenzamide], which increases activity through nondopaminergic mechanisms. JHW007 blocked locomotor-stimulant effects of cocaine in both DA D2- and CB1-receptor knockout and wild-type mice, indicating a lack of involvement of these targets. Furthermore, JHW007 blocked effects of cocaine on stereotyped rearing but enhanced stereotyped sniffing, suggesting that interference with locomotion by enhanced stereotypies is not responsible for the cocaine-antagonist effects of JHW007. Time-course data indicate that administration of JHW007 antagonized the locomotor-stimulant effects of cocaine within 10 minutes of injection, whereas occupancy at the DAT, as determined in vivo, did not reach a maximum until 4.5 hours after injection. The σ1-receptor antagonist BD 1008 [N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine dihydrobromide] blocked the locomotor-stimulant effects of cocaine. Overall, these findings suggest that JHW007 has cocaine-antagonist effects

  11. Ethanol and cocaine: environmental place conditioning, stereotypy, and synergism in planarians.

    Science.gov (United States)

    Tallarida, Christopher S; Bires, Kristopher; Avershal, Jacob; Tallarida, Ronald J; Seo, Stephanie; Rawls, Scott M

    2014-09-01

    More than 90% of individuals who use cocaine also report concurrent ethanol use, but only a few studies, all conducted with vertebrates, have investigated pharmacodynamic interactions between ethanol and cocaine. Planaria, a type of flatworm often considered to have the simplest 'brain,' is an invertebrate species especially amenable to the quantification of drug-induced behavioral responses and identification of conserved responses. Here, we investigated stereotypical and environmental place conditioning (EPC) effects of ethanol administered alone and in combination with cocaine. Planarians displayed concentration-related increases in C-shaped movements following exposure to ethanol (0.01-1%) (maximal effect: 9.9±1.1 C-shapes/5 min at 0.5%) or cocaine (0.1-5 mM) (maximal effect: 42.8±4.1 C-shapes/5 min at 5 mM). For combined administration, cocaine (0.1-5 mM) was tested with submaximal ethanol concentrations (0.01, 0.1%); the observed effect for the combination was enhanced compared to its predicted effect, indicating synergism for the interaction. The synergy with ethanol was specific for cocaine, as related experiments revealed that combinations of ethanol and nicotine did not result in synergy. For EPC experiments, ethanol (0.0001-1%) concentration-dependently increased EPC, with significant environmental shifts detected at 0.01 and 1%. Cocaine (0.001-1 μM) produced an inverted U-shaped concentration-effect curve, with a significant environmental shift observed at 0.01 μM. For combined exposure, variable cocaine concentrations (0.001-1 μM) were administered with a statistically ineffective concentration of ethanol (0.0001%). For each concentration of cocaine, the environmental shift was enhanced by ethanol, with significance detected at 1 μM. Cocaethylene, a metabolite of cocaine and ethanol, also produced C-shapes and EPC. Lidocaine (0.001-10 μM), an anesthetic and analog of cocaine, did not produce EPC or C-shaped movements. Evidence from planarians

  12. Pulmonary alterations in cocaine users

    Directory of Open Access Journals (Sweden)

    Mário Terra Filho

    Full Text Available CONTEXT: Brazilian researchers have recently recognized a marked increase in the number of people using abusable drugs and the consequences of this habit. It has become a major public health problem in a potentially productive segment of the general population. In the last few years, several medical articles have given special emphasis to pulmonary complications related to cocaine use. This review is based on this information and experience acquired with groups of cocaine users. OBJECTIVE: To present to physicians the pulmonary aspects of cocaine use and warn about the various effects this drug has on the respiratory system, stressing those related to long-term use. DESIGN: Narrative review. METHOD: Pulmonary complications are described. These may include infections (Staphylococcus aureus, pulmonary tuberculosis, acquired immunodeficiency syndrome/aids, etc., aspiration pneumonia, lung abscess, empyema, septic embolism, non-cardiogenic pulmonary edema, barotrauma, pulmonary granulomatosis, bronchiolitis obliterans and organizing pneumonia, pneumonitis and interstitial fibrosis, pneumonitis hypersensitivity, lung infiltrates and eosinophilia in individuals with bronchial hyperreactivity, diffuse alveolar hemorrhage, vasculitis, pulmonary infarction, pulmonary hypertension and alterations in gas exchange. It is concluded that physicians should give special attention to the various pulmonary and clinical manifestations related to cocaine use, particularly in young patients.

  13. The effects of cannabinoid CB1, CB2 and vanilloid TRPV1 receptor antagonists on cocaine addictive behavior in rats.

    Science.gov (United States)

    Adamczyk, Przemysław; Miszkiel, Joanna; McCreary, Andrew C; Filip, Małgorzata; Papp, Mariusz; Przegaliński, Edmund

    2012-03-20

    There is evidence that indicates that tonic activation of cannabinoid CB1 receptors plays a role in extinction/reinstatement of cocaine seeking-behavior but is not involved in the maintenance of cocaine self-administration. To further explore the importance of other endocannabinoid-related receptors in an animal model of cocaine addiction, the present paper examines cannabinoid CB2 receptor antagonist N-((1S)-endo-1,3,3-trimethylbicyclo(2.2.1)heptan-2-yl)-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528) and the transient receptor potential vanilloid type-1 (TRPV1) receptor antagonist N-(3-methoxyphenyl)-4-chlorocinnamide (SB366791) on intravenous (i.v.) cocaine self-administration and extinction/reinstatement of cocaine-seeking behavior in rats. For comparison and reference purposes, the effect of the cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) was also examined. Moreover, for comparison effects of those drugs on operant lever responding for artificial (cocaine) vs. natural (food) reward, food self-administration was also evaluated. Our findings show that AM251 (1-3mg/kg), SR144528 (0.1-1mg/kg) and SB366791 (0.3-1mg/kg) did not affect cocaine self-administration. However, AM251 (0.1-1mg/kg), SR144528 (0.1-1mg/kg) and SB366791 (0.1-1mg/kg) decreased cocaine-induced reinstatement of cocaine-seeking behavior, and AM251 (0.3-1mg/kg) decreased cue-induced reinstatement. Moreover, AM251 (3mg/kg), SR144528 (0.1-1mg/kg) and SB366791 (0.1-1mg/kg) slightly decreased food self-administration behavior, but only AM251 (3mg/kg) reduced food reward. In conclusion, our results indicate for the first time, that tonic activation of CB2 or TRPV1 receptors is involved in cocaine-induced reinstatement of cocaine-seeking behavior, but their activity is not necessary for the rewarding effect of this psychostimulant. In contrast to CB1 receptors, neither CB2 nor

  14. Chronic administration of imipramine but not agomelatine and moclobemide affects the nitrergic relaxation of rabbit corpus cavernosum smooth muscle.

    Science.gov (United States)

    Gocmez, Semil Selcen; Utkan, Tijen; Gacar, Nejat

    2013-08-15

    Sexual dysfunction is a common and underestimated effect of antidepressants. However, the mechanism by which these drugs cause erectile dysfunction is unclear. We investigated the reactivity of the corpus cavernosum of rabbits that were treated with either chronic imipramine, which is a tricyclic agent; agomelatine, which is a melatonergic agonist and serotonin 5HT(2c) antagonist; or moclobemide, which is a reversible inhibitor of monoamine-oxidase A. Twenty rabbits were randomly divided into four groups: the control group (n=5), the imipramine-treated group (n=5), which received i.p. injections of 10 mg/kg/day of imipramine, the moclobemide-treated group (n=5), which received i.p. injections of 20 mg/kg/day of moclobemide, and the agomelatine-treated group (n=5), which was orally administered 10 mg/kg/day of agomelatine. The reactivities of corpus cavernosum tissue obtained from the antidepressant-treated and the control groups were studied in organ chambers after the animals were subjected to 21 days of drug administration. The acetylcholine-induced endothelium-dependent and the electrical field stimulation (EFS)-induced neurogenic relaxation of the corpus cavernosum of the imipramine-treated group was significantly decreased compared with the control group. However, neither the acetylcholine- nor EFS-induced relaxation was changed in the moclobemide- or agomelatine-treated groups. There were no change in the relaxant response to the nitric oxide (NO) donor sodium nitroprusside and contractile response to KCl between the groups. This study suggests that chronic imipramine treatment but not agomelatine and moclobemide treatments causes significant functional changes in the penile erectile tissue of rabbits and that these changes may contribute to the development of impotence.

  15. 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.

  16. Rats markedly escalate their intake and show a persistent susceptibility to reinstatement only when cocaine is injected rapidly.

    Science.gov (United States)

    Wakabayashi, Ken T; Weiss, Mark J; Pickup, Kristen N; Robinson, Terry E

    2010-08-25

    When drugs enter the brain rapidly, liability for addiction is increased, but why this is the case is not well understood. Here we examined the influence of varying the speed of intravenous cocaine delivery on self-administration behavior in rats given limited or extended opportunity to take drug. The speed of cocaine delivery had no effect on self-administration behavior when rats were given only 1 h each day to take cocaine. When given sixfold more time to take cocaine, rats that received cocaine rapidly (5-45 s) increased their total intake eightfold. However, rats that received cocaine more slowly (>90 s) did not avail themselves of the opportunity to take much more drug: they increased their intake only twofold. Furthermore, when tested 45 d after the last self-administration session, a drug-priming injection reinstated drug-seeking behavior only in rats that in the past had cocaine injected rapidly (5 s), and this was associated with a persistent suppression in the ability of cocaine to induce immediate early gene expression. Cocaine may be potentially more addictive when it reaches the brain rapidly because (1) this promotes a marked escalation in intake and (2) it renders individuals more susceptible to relapse long after the discontinuation of drug use. This is presumably because the rapid uptake of drug to the brain preferentially promotes persistent changes in brain systems that regulate motivation for drug, and continuing exposure to large amounts of drug produces a vicious cycle of additional maladaptive changes in brain and behavior.

  17. Pulmonary administration of phosphoinositide 3-kinase inhibitor is a curative treatment for chronic obstructive pulmonary disease by alveolar regeneration.

    Science.gov (United States)

    Horiguchi, Michiko; Oiso, Yuki; Sakai, Hitomi; Motomura, Tomoki; Yamashita, Chikamasa

    2015-09-10

    Chronic obstructive pulmonary disease (COPD) is an intractable pulmonary disease, causing widespread and irreversible alveoli collapse. The discovery of a low-molecular-weight compound that induces regeneration of pulmonary alveoli is of utmost urgency to cure intractable pulmonary diseases such as COPD. However, a practically useful compound for regenerating pulmonary alveoli is yet to be reported. Previously, we have elucidated that Akt phosphorylation is involved in a differentiation-inducing molecular mechanism of human alveolar epithelial stem cells, which play a role in regenerating pulmonary alveoli. In the present study, we directed our attention to phosphoinositide 3-kinase (PI3K)-Akt signaling and examined whether PI3K inhibitors display the pulmonary alveolus regeneration. Three PI3K inhibitors with different PI3K subtype specificities (Wortmannin, AS605240, PIK-75 hydrochloride) were tested for the differentiation-inducing effect on human alveolar epithelial stem cells, and Wortmannin demonstrated the most potent differentiation-inducing activity. We evaluated Akt phosphorylation in pulmonary tissues of an elastase-induced murine COPD model and found that Akt phosphorylation in the pulmonary tissue was enhanced in the murine COPD model compared with normal mice. Then, the alveolus-repairing effect of pulmonary administration of Wortmannin to murine COPD model was evaluated using X-ray CT analysis and hematoxylin-eosin staining. As a result, alveolar damages were repaired in the Wortmannin-administered group to a similar level of normal mice. Furthermore, pulmonary administration of Wortmannin induced a significant recovery of the respiratory function, compared to the control group. These results indicate that Wortmannin is capable of inducing differentiation of human alveolar epithelial stem cells and represents a promising drug candidate for curative treatment of pulmonary alveolar destruction in COPD.

  18. The differential effects of chronic imipramine or citalopram administration on physiological and behavioral outcomes in naïve mice.

    Science.gov (United States)

    Strekalova, Tatyana; Anthony, Daniel C; Dolgov, Oleg; Anokhin, Konstantin; Kubatiev, Aslan; Steinbusch, Harry M W; Schroeter, Careen

    2013-05-15

    Tricyclics and selective serotonin reuptake inhibitors (SSRIs) are probably the most widely employed reference antidepressants in animal studies on depression. Using imipramine and citalopram, we sought to assess which drug would be more appropriate as pharmacological reference in paradigms of depression in C57BL6N mice by measuring their effect on liquid consumption, home cage activity, body weight and long-term memory in naïve animals treated with each compound at generally used dose of 15 mg/kg/day. Continuous logging of home cage movement, weekly monitoring of vertical activity in a novel cage, and body weight was recorded during four-week treatment period and for four weeks after discontinuation of the antidepressant; sucrose preference was evaluated at weekly intervals during drug administration. A novel object recognition memory test was performed in mice treated the antidepressants for two weeks. Compared to control, imipramine-treated mice displayed increased sucrose and water intake, as well as enhanced home-cage and novelty exploration activities, and reduced body weight. Imipramine also impaired learning in the object recognition task, but citalopram diminished object exploration sufficiently to invalidate the test. Citalopram-treated animals demonstrated no changes in a sucrose test and had elevated body mass. Thus basic physiological and behavioral outcomes in naïve mice were significantly altered by the chronic administration of imipramine and, to a lesser extent, citalopram. As altered variables are crucial for the evaluation of antidepressant-like effects in mice, our data suggest that, at commonly used doses, both drugs must be applied in mouse models of depression with caution.

  19. Intravenous fluid administration may improve post-operative course of patients with chronic subdural hematoma: a retrospective study.

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    Miroslaw Janowski

    Full Text Available BACKGROUND: The treatment of chronic subdural hematoma (cSDH is still charged of significant risk of hematoma recurrence. Patient-related predictors and the surgical procedures themselves have been addressed in many studies. In contrast, postoperative management has infrequently been subjected to detailed analysis. Moreover variable intravenous fluid administration (IFA was not reported in literature till now in the context of cSDH treatment. METHODOLOGY/PRINCIPAL FINDINGS: A total of 45 patients with cSDH were operated in our department via two burr hole craniostomy within one calendar year. Downward drainage was routinely left in hematoma cavity for a one day. Independent variables selected for the analysis were related to various aspects of patient management, including IFA. Two dependent variables were chosen as measure of clinical course: the rate of hematoma recurrence (RHR and neurological status at discharge from hospital expressed in points of Glasgow Outcome Scale (GOS. Univariate and multivariate regression analyses were performed. Hematoma recurrence with subsequent evacuation occurred in 7 (15% patients. Univariate regression analysis revealed that length of IFA after surgery influenced both dependent variables: RHR (p = 0.045 and GOS (p = 0.023. Multivariate regression performed by backward elimination method confirmed that IFA is a sole independent factor influencing RHR. Post hoc dichotomous division of patients revealed that those receiving at least 2000 ml/day over 3 day period revealed lower RHR than the group with less intensive IFA. (p = 0.031. CONCLUSIONS/SIGNIFICANCE: IFA has been found to be a sole factor influencing both: RHR and GOS. Based on those results we may recommend administration of at least 2000 ml per 3 days post-operatively to decrease the risk of hematoma recurrence.

  20. Oleoylethanolamide dose-dependently attenuates cocaine-induced behaviours through a PPARα receptor-independent mechanism.

    Science.gov (United States)

    Bilbao, Ainhoa; Blanco, Eduardo; Luque-Rojas, María Jesús; Suárez, Juan; Palomino, Ana; Vida, Margarita; Araos, Pedro; Bermúdez-Silva, Francisco J; Fernández-Espejo, Emilio; Spanagel, Rainer; Rodríguez de Fonseca, Fernando

    2013-01-01

    Oleoylethanolamide (OEA) is an acylethanolamide that acts as an agonist of nuclear peroxisome proliferator-activated receptor alpha (PPARα) to exert their biological functions, which include the regulation of appetite and metabolism. Increasing evidence also suggests that OEA may participate in the control of reward-related behaviours. However, direct experimental evidence for the role of the OEA-PPARα receptor interaction in drug-mediated behaviours, such as cocaine-induced behavioural phenotypes, is lacking. The present study explored the role of OEA and its receptor PPARα on the psychomotor and rewarding responsiveness to cocaine using behavioural tests indicative of core components of addiction. We found that acute administration of OEA (1, 5 or 20 mg/kg, i.p.) reduced spontaneous locomotor activity and attenuated psychomotor activation induced by cocaine (20 mg/kg) in C57Bl/6 mice. However, PPARα receptor knockout mice showed normal sensitization, although OEA was capable of reducing behavioural sensitization with fewer efficacies. Furthermore, conditioned place preference and reinstatement to cocaine were intact in these mice. Our results indicate that PPARα receptor does not play a critical, if any, role in mediating short- and long-term psychomotor and rewarding responsiveness to cocaine. However, further research is needed for the identification of the targets of OEA for its inhibitory action on cocaine-mediated responses.

  1. Acute total sleep deprivation potentiates cocaine-induced hyperlocomotion in mice.

    Science.gov (United States)

    Berro, L F; Santos, R; Hollais, A W; Wuo-Silva, R; Fukushiro, D F; Mári-Kawamoto, E; Costa, J M; Trombin, T F; Patti, C L; Grapiglia, S B; Tufik, S; Andersen, M L; Frussa-Filho, R

    2014-09-05

    Sleep deprivation is common place in modern society. Nowadays, people tend to self-impose less sleep in order to achieve professional or social goals. In the social context, late-night parties are frequently associated with higher availability of recreational drugs with abuse potential. Physiologically, all of these drugs induce an increase in dopamine release in the mesolimbic dopaminergic system, which leads to hyperlocomotion in rodents. Sleep deprivation also seems to play an important role in the events related to the neurotransmission of the dopaminergic system by potentiating its behavioral effects. In this scenario, the aim of the present study was to investigate the effects of total sleep deprivation (6h) on the acute cocaine-induced locomotor stimulation in male mice. Animals were sleep deprived or maintained in their home cages and subsequently treated with an acute i.p. injection of 15mg/kg cocaine or saline and observed in the open field. Total sleep deprivation for 6h potentiated the hyperlocomotion induced by acute cocaine administration. In addition, the cocaine sleep deprived group showed a decreased ratio central/total locomotion compared to the cocaine control group, which might be related to an increase in the impulsiveness of mice. Our data indicate that acute periods of sleep loss should be considered risk factors for cocaine abuse.

  2. Subunit Stabilization and Polyethylene Glycolation of Cocaine Esterase Improves In Vivo Residence Time

    Energy Technology Data Exchange (ETDEWEB)

    Narasimhan, Diwahar; Collins, Gregory T.; Nance, Mark R.; Nichols, Joseph; Edwald, Elin; Chan, Jimmy; Ko, Mei-Chuan; Woods, James H.; Tesmer, John J.G.; Sunahara, Roger K. (Michigan)

    2012-03-15

    No small-molecule therapeutic is available to treat cocaine addiction, but enzyme-based therapy to accelerate cocaine hydrolysis in serum has gained momentum. Bacterial cocaine esterase (CocE) is the fastest known native enzyme that hydrolyzes cocaine. However, its lability at 37 C has limited its therapeutic potential. Cross-linking subunits through disulfide bridging is commonly used to stabilize multimeric enzymes. Herein we use structural methods to guide the introduction of two cysteine residues within dimer interface of CocE to facilitate intermolecular disulfide bond formation. The disulfide-crosslinked enzyme displays improved thermostability, particularly when combined with previously described mutations that enhance stability (T172R-G173Q). The newly modified enzyme yielded an extremely stable form of CocE (CCRQ-CocE) that retained greater than 90% of its activity after 41 days at 37 C, representing an improvement of more than 4700-fold over the wild-type enzyme. CCRQ-CocE could also be modified by polyethylene glycol (PEG) polymers, which improved its in vivo residence time from 24 to 72 h, as measured by a cocaine lethality assay, by self-administration in rodents, and by measurement of inhibition of cocaine-induced cardiovascular effects in rhesus monkeys. PEG-CCRQ elicited negligible immune response in rodents. Subunit stabilization and PEGylation has thus produced a potential protein therapeutic with markedly higher stability both in vitro and in vivo.

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

    OpenAIRE

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

    2014-01-01

    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 ...

  4. Antihyperglycemic Effect on Chronic Administration of Butanol Fraction of Ethanol Extract of Moringa Stenopetala Leaves in Alloxan Induced Diabetic Mice

    Institute of Scientific and Technical Information of China (English)

    Alemayehu Toma; Eyasu Makonnen; Asfaw Debella; Birhanu Tesfaye

    2012-01-01

    Objective: The present study was conducted to evaluate the antihyperglycemic activity on chronic administration of the butanol fraction of the ethanol extract of Moringa Stenopetala leaves in alloxan induced diabetic mice. Methods: The mice were grouped in four groups; Normal control, Diabetic control, Butanol fraction treated and standard drug treated groups. The Diabetic mice received the butanol fraction of Moringa stenopetala daily for 28 days. Results: The butanol fraction of Moringastenopetala treatment resulted in significant reduction of fasting blood glucose level, serum total cholesterol and triglycerides level. This fraction also showed a tendency to improve body weight gain in diabetic mice. Its oral LD50 was found to be greater than 5000mg/Kg indicating its safety in mice. Conclusions: Though the mechanism of action of Moringa stenopetala seems to be similar to that of sulfonylureas, further studies should be done to confirm its mechanism of antidiabetic action. Furthermore the active principle(s) responsible for the antidabetic effects should also be identified.

  5. Ghrelin Administration Increases the Bax/Bcl-2 Gene Expression Ratio in the Heart of Chronic Hypoxic Rats

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    Mohammad Reza Aliparasti

    2015-06-01

    Full Text Available Purpose: Programmed cell death or apoptosis, is a biochemical procedure that initiates due to some conditions, including hypoxia. Bax and Bcl-2 are among the agents that regulate apoptosis. The amplification of the first one triggers the initiation of apoptosis, and the second one prevents it. Ghrelin is an endogenous peptide that antiapoptosis is its new effect. The aim of this study is to examine the effect of ghrelin on the Bax/Bcl-2 ratio. Methods: Twenty four wistar rats were divided randomly in three groups; control, hypoxic + saline and hypoxic + ghrelin. Hypoxic animals lived in O2 11% for 2 weeks and received either saline or ghrelin subcutaneously daily. The bax and Bcl-2 gene expression were measured by Real-Time RT-PCR. Results: Chronic hypoxia increased the Bax gene expression significantly compared with normal animals (P = 0.008, but the Bcl-2 was not affected by hypoxia. The Bax/Bcl-2 ratio also amplified significantly (P=0.005. Ghrelin administration significantly increased the Bax/Bcl-2 ratio in the hypoxic animals compared to the hypoxic + saline and normal groups (p=0.042 and P= 0.001, respectively. Conclusion: In the present study, animals’ treatment with ghrelin leads to an increment of Bax/Bcl-2 ratio, which indicates a controversy related to cardioprotection of ghrelin.

  6. Ghrelin Administration Increases the Bax/Bcl-2 Gene Expression Ratio in the Heart of Chronic Hypoxic Rats

    Science.gov (United States)

    Aliparasti, Mohammad Reza; Alipour, Mohammad Reza; Almasi, Shohreh; Feizi, Hadi

    2015-01-01

    Purpose: Programmed cell death or apoptosis, is a biochemical procedure that initiates due to some conditions, including hypoxia. Bax and Bcl-2 are among the agents that regulate apoptosis. The amplification of the first one triggers the initiation of apoptosis, and the second one prevents it. Ghrelin is an endogenous peptide that antiapoptosis is its new effect. The aim of this study is to examine the effect of ghrelin on the Bax/Bcl-2 ratio. Methods: Twenty four wistar rats were divided randomly in three groups; control, hypoxic + saline and hypoxic + ghrelin. Hypoxic animals lived in O2 11% for 2 weeks and received either saline or ghrelin subcutaneously daily. The bax and Bcl-2 gene expression were measured by Real-Time RT-PCR. Results: Chronic hypoxia increased the Bax gene expression significantly compared with normal animals (P = 0.008), but the Bcl-2 was not affected by hypoxia. The Bax/Bcl-2 ratio also amplified significantly (P=0.005). Ghrelin administration significantly increased the Bax/Bcl-2 ratio in the hypoxic animals compared to the hypoxic + saline and normal groups (p=0.042 and P= 0.001, respectively). Conclusion: In the present study, animals’ treatment with ghrelin leads to an increment of Bax/Bcl-2 ratio, which indicates a controversy related to cardioprotection of ghrelin. PMID:26236657

  7. Chronic Binge Alcohol Administration Dysregulates Hippocampal Genes Involved in Immunity and Neurogenesis in Simian Immunodeficiency Virus-Infected Macaques

    Directory of Open Access Journals (Sweden)

    John K. Maxi

    2016-11-01

    Full Text Available Alcohol use disorders (AUD exacerbate neurocognitive dysfunction in Human Immunodeficiency Virus (HIV+ patients. We have shown that chronic binge alcohol (CBA administration (13–14 g EtOH/kg/wk prior to and during simian immunodeficiency virus (SIV infection in rhesus macaques unmasks learning deficits in operant learning and memory tasks. The underlying mechanisms of neurocognitive alterations due to alcohol and SIV are not known. This exploratory study examined the CBA-induced differential expression of hippocampal genes in SIV-infected (CBA/SIV+; n = 2 macaques in contrast to those of sucrose administered, SIV-infected (SUC/SIV+; n = 2 macaques. Transcriptomes of hippocampal samples dissected from brains obtained at necropsy (16 months post-SIV inoculation were analyzed to determine differentially expressed genes. MetaCore from Thomson Reuters revealed enrichment of genes involved in inflammation, immune responses, and neurodevelopment. Functional relevance of these alterations was examined in vitro by exposing murine neural progenitor cells (NPCs to ethanol (EtOH and HIV trans-activator of transcription (Tat protein. EtOH impaired NPC differentiation as indicated by decreased βIII tubulin expression. These findings suggest a role for neuroinflammation and neurogenesis in CBA/SIV neuropathogenesis and warrant further investigation of their potential contribution to CBA-mediated neurobehavioral deficits.

  8. Subcutaneous vs intravenous administration of immunoglobulin in chronic inflammatory demyelinating polyneuropathy: an Italian cost-minimization analysis.

    Science.gov (United States)

    Lazzaro, Carlo; Lopiano, Leonardo; Cocito, Dario

    2014-07-01

    Prior researches have suggested that home-based subcutaneous immunoglobulin (SCIG) is equally effective and can be less expensive than hospital-based intravenous immunoglobulin (IVIG) in treating chronic inflammatory demyelinating polyneuropathy (CIDP) patients. This economic evaluation aims at comparing costs of SCIG vs IVIG for CIDP patients in Italy. A 1-year model-based cost-minimization analysis basically populated via neurologists' opinion was undertaken from a societal perspective. Health care resources included immunoglobulin; drugs for premedication and complications (rash, headache, and hypertension) management; time of various health care professionals; pump for SCIG self-administration; infusion disposables. Non-health care resources encompassed transport and parking; losses of working and leisure time for patients and caregivers. Unit or yearly costs for resources valuation were mainly obtained from published sources. Costs were expressed in Euro () 2013. An extensive one-way sensitivity analysis (OWSA) and a scenario SA tested the robustness of the base case findings. Overall costs per patient amount to 49,534.75 (SCIG) and 50,895.73 (IVIG); saving in favour of SCIG reaches 1360.98. For both SCIG and IVIG, the cost driver was immunoglobulin (94.06 vs 86.06 % of the overall costs, respectively). Sensitivity analyses confirmed the consistency of the baseline results. SCIG may be a cost-saving therapy for Italian CIDP patients.

  9. Three months of chronic ethanol administration and the behavioral outcome of rats after lateral fluid percussion brain injury.

    Science.gov (United States)

    Masse, J; Billings, B; Dhillon, H S; Mace, D; Hicks, R; Barron, S; Kraemer, P J; Dendle, P; Prasad, R M

    2000-05-01

    This study examined the effects of 3 months of chronic ethanol administration (CEAn) on the behavioral outcome in rats after lateral fluid percussion (FP) brain injury. Rats were given either an ethanol liquid diet (ethanol diet groups) or a pair-fed isocaloric sucrose control diet (control diet groups) for 3 months. Then, rats from both diet groups were subjected to either lateral FP brain injury of moderate severity (1.8 atm) or to sham operation. Postinjury behavioral measurements revealed that brain injury caused significant spatial learning disability in both diet groups. There were no significant differences in spatial learning ability in the sham or brain-injured animals between the control and ethanol diets. However, a trend towards cognitive impairment in the sham animals and a trend towards reduced deficits in the brain-injured animals were observed in the ethanol diet group. Histologic analysis of injured animals from both diet groups revealed similar extents of ipsilateral cortical and hippocampal CA3 damage. These results, in general, suggest that 3 months of CEAn does not significantly alter the behavioral and morphologic outcome of experimental brain injury.

  10. Disulfiram Attenuates Drug-Primed Reinstatement of Cocaine Seeking via Inhibition of Dopamine β-Hydroxylase

    Science.gov (United States)

    Schroeder, Jason P; Cooper, Debra A; Schank, Jesse R; Lyle, Megan A; Gaval-Cruz, Meriem; Ogbonmwan, Yvonne E; Pozdeyev, Nikita; Freeman, Kimberly G; Iuvone, P Michael; Edwards, Gaylen L; Holmes, Philip V; Weinshenker, David

    2010-01-01

    The antialcoholism medication disulfiram (Antabuse) inhibits aldehyde dehydrogenase (ALDH), which results in the accumulation of acetaldehyde upon ethanol ingestion and produces the aversive ‘Antabuse reaction' that deters alcohol consumption. Disulfiram has also been shown to deter cocaine use, even in the absence of an interaction with alcohol, indicating the existence of an ALDH-independent therapeutic mechanism. We hypothesized that disulfiram's inhibition of dopamine β-hydroxylase (DBH), the catecholamine biosynthetic enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons, underlies the drug's ability to treat cocaine dependence. We tested the effects of disulfiram on cocaine and food self-administration behavior and drug-primed reinstatement of cocaine seeking in rats. We then compared the effects of disulfiram with those of the selective DBH inhibitor, nepicastat. Disulfiram, at a dose (100 mg/kg, i.p.) that reduced brain NE by ∼40%, did not alter the response for food or cocaine on a fixed ratio 1 schedule, whereas it completely blocked cocaine-primed (10 mg/kg, i.p.) reinstatement of drug seeking following extinction. A lower dose of disulfiram (10 mg/kg) that did not reduce NE had no effect on cocaine-primed reinstatement. Nepicastat recapitulated the behavioral effects of disulfiram (100 mg/kg) at a dose (50 mg/kg, i.p.) that produced a similar reduction in brain NE. Food-primed reinstatement of food seeking was not impaired by DBH inhibition. Our results suggest that disulfiram's efficacy in the treatment of cocaine addiction is associated with the inhibition of DBH and interference with the ability of environmental stimuli to trigger relapse. PMID:20736996

  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. Long-lasting memory deficits in mice withdrawn from cocaine are concomitant with neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis

    Science.gov (United States)

    Ladrón de Guevara-Miranda, David; Millón, Carmelo; Rosell-Valle, Cristina; Pérez-Fernández, Mercedes; Missiroli, Michele; Serrano, Antonia; Pavón, Francisco J.; Rodríguez de Fonseca, Fernando; Martínez-Losa, Magdalena; Álvarez-Dolado, Manuel; Santín, Luis J.

    2017-01-01

    ABSTRACT Cocaine addiction disorder is notably aggravated by concomitant cognitive and emotional pathology that impedes recovery. We studied whether a persistent cognitive/emotional dysregulation in mice withdrawn from cocaine holds a neurobiological correlate within the hippocampus, a limbic region with a key role in anxiety and memory but that has been scarcely investigated in cocaine addiction research. Mice were submitted to a chronic cocaine (20 mg/kg/day for 12 days) or vehicle treatment followed by 44 drug-free days. Some mice were then assessed on a battery of emotional (elevated plus-maze, light/dark box, open field, forced swimming) and cognitive (object and place recognition memory, cocaine-induced conditioned place preference, continuous spontaneous alternation) behavioral tests, while other mice remained in their home cage. Relevant hippocampal features [basal c-Fos activity, GABA+, parvalbumin (PV)+ and neuropeptide Y (NPY)+ interneurons and adult neurogenesis (cell proliferation and immature neurons)] were immunohistochemically assessed 73 days after the chronic cocaine or vehicle protocol. The cocaine-withdrawn mice showed no remarkable exploratory or emotional alterations but were consistently impaired in all the cognitive tasks. All the cocaine-withdrawn groups, independent of whether they were submitted to behavioral assessment or not, showed enhanced basal c-Fos expression and an increased number of GABA+ cells in the dentate gyrus. Moreover, the cocaine-withdrawn mice previously submitted to behavioral training displayed a blunted experience-dependent regulation of PV+ and NPY+ neurons in the dentate gyrus, and neurogenesis in the hippocampus. Results highlight the importance of hippocampal neuroplasticity for the ingrained cognitive deficits present during chronic cocaine withdrawal. PMID:28138095

  13. Long-lasting memory deficits in mice withdrawn from cocaine are concomitant with neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis

    Directory of Open Access Journals (Sweden)

    David Ladrón de Guevara-Miranda

    2017-03-01

    Full Text Available Cocaine addiction disorder is notably aggravated by concomitant cognitive and emotional pathology that impedes recovery. We studied whether a persistent cognitive/emotional dysregulation in mice withdrawn from cocaine holds a neurobiological correlate within the hippocampus, a limbic region with a key role in anxiety and memory but that has been scarcely investigated in cocaine addiction research. Mice were submitted to a chronic cocaine (20 mg/kg/day for 12 days or vehicle treatment followed by 44 drug-free days. Some mice were then assessed on a battery of emotional (elevated plus-maze, light/dark box, open field, forced swimming and cognitive (object and place recognition memory, cocaine-induced conditioned place preference, continuous spontaneous alternation behavioral tests, while other mice remained in their home cage. Relevant hippocampal features [basal c-Fos activity, GABA+, parvalbumin (PV+ and neuropeptide Y (NPY+ interneurons and adult neurogenesis (cell proliferation and immature neurons] were immunohistochemically assessed 73 days after the chronic cocaine or vehicle protocol. The cocaine-withdrawn mice showed no remarkable exploratory or emotional alterations but were consistently impaired in all the cognitive tasks. All the cocaine-withdrawn groups, independent of whether they were submitted to behavioral assessment or not, showed enhanced basal c-Fos expression and an increased number of GABA+ cells in the dentate gyrus. Moreover, the cocaine-withdrawn mice previously submitted to behavioral training displayed a blunted experience-dependent regulation of PV+ and NPY+ neurons in the dentate gyrus, and neurogenesis in the hippocampus. Results highlight the importance of hippocampal neuroplasticity for the ingrained cognitive deficits present during chronic cocaine withdrawal.

  14. Long-lasting memory deficits in mice withdrawn from cocaine are concomitant with neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis.

    Science.gov (United States)

    Ladrón de Guevara-Miranda, David; Millón, Carmelo; Rosell-Valle, Cristina; Pérez-Fernández, Mercedes; Missiroli, Michele; Serrano, Antonia; Pavón, Francisco J; Rodríguez de Fonseca, Fernando; Martínez-Losa, Magdalena; Álvarez-Dolado, Manuel; Santín, Luis J; Castilla-Ortega, Estela

    2017-03-01

    Cocaine addiction disorder is notably aggravated by concomitant cognitive and emotional pathology that impedes recovery. We studied whether a persistent cognitive/emotional dysregulation in mice withdrawn from cocaine holds a neurobiological correlate within the hippocampus, a limbic region with a key role in anxiety and memory but that has been scarcely investigated in cocaine addiction research. Mice were submitted to a chronic cocaine (20 mg/kg/day for 12 days) or vehicle treatment followed by 44 drug-free days. Some mice were then assessed on a battery of emotional (elevated plus-maze, light/dark box, open field, forced swimming) and cognitive (object and place recognition memory, cocaine-induced conditioned place preference, continuous spontaneous alternation) behavioral tests, while other mice remained in their home cage. Relevant hippocampal features [basal c-Fos activity, GABA(+), parvalbumin (PV)(+) and neuropeptide Y (NPY)(+) interneurons and adult neurogenesis (cell proliferation and immature neurons)] were immunohistochemically assessed 73 days after the chronic cocaine or vehicle protocol. The cocaine-withdrawn mice showed no remarkable exploratory or emotional alterations but were consistently impaired in all the cognitive tasks. All the cocaine-withdrawn groups, independent of whether they were submitted to behavioral assessment or not, showed enhanced basal c-Fos expression and an increased number of GABA(+) cells in the dentate gyrus. Moreover, the cocaine-withdrawn mice previously submitted to behavioral training displayed a blunted experience-dependent regulation of PV(+) and NPY(+) neurons in the dentate gyrus, and neurogenesis in the hippocampus. Results highlight the importance of hippocampal neuroplasticity for the ingrained cognitive deficits present during chronic cocaine withdrawal.

  15. 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.

  16. The interactive effects of environmental enrichment and extinction interventions in attenuating cue-elicited cocaine-seeking behavior in rats.

    Science.gov (United States)

    Thiel, Kenneth J; Engelhardt, Ben; Hood, Lauren E; Peartree, Natalie A; Neisewander, Janet L

    2011-01-01

    Cues associated with cocaine can elicit craving and relapse. Attempts have been made to employ extinction therapy, which is aimed at attenuating the incentive motivational effects of cocaine cues, as a treatment for cocaine addiction; however, this approach has been largely unsuccessful perhaps due to the inability to extinguish all cues associated with cocaine use while in a clinic. Recently, environmental enrichment (EE) during abstinence has been proposed as a strategy to attenuate cue-elicited cocaine craving. The present study used an animal model to examine whether the utility of extinction toward attenuating cue-elicited cocaine-seeking behavior could be enhanced by also providing EE. All rats were trained to self-administer cocaine while housed in isolated conditions and then subsequently underwent 17 days of forced abstinence, during which they were either housed in pairs or under EE and they either received daily 1-h extinction sessions or similar handling without exposure to the self-administration environment. Following this intervention period, all rats were tested for cue-elicited cocaine-seeking behavior. To examine whether effects of these interventions persist, all rats were subsequently single-housed for an additional 7-day forced abstinence period, followed by a second test for cue-elicited cocaine-seeking behavior. We found that although daily extinction training and EE each attenuated subsequent cue-elicited cocaine-seeking behavior, the combined treatment of extinction training+EE completely prevented it. However, once these interventions were discontinued, their protective effects diminished. These findings suggest that combining behavioral therapy approaches may improve outcomes; however, future work is needed to improve the longevity of these strategies beyond their implementation.

  17. Reaction Mechanism for Cocaine Esterase-Catalyzed Hydrolyses of (+)- and (−)-Cocaine: Unexpected Common Rate-Determining Step

    OpenAIRE

    Liu, Junjun; Zhao, Xinyun; Yang, Wenchao; Zhan, Chang-Guo

    2011-01-01

    First-principles quantum mechanical/molecular mechanical (QM/MM)-free energy (FE) calculations have been performed to examine catalytic mechanism for cocaine esterase (CocE)-catalyzed hydrolysis of (+)-cocaine in comparison with CocE-catalyzed hydrolysis of (−)-cocaine. It has been shown that the acylation of (+)-cocaine consists of nucleophilic attack of hydroxyl group of Ser117 on carbonyl carbon of (+)-cocaine benzoyl ester and the dissociation of (+)-cocaine benzoyl ester. The first react...

  18. Molecular approaches to treatments for cocaine abuse

    Science.gov (United States)

    Flippen-Anderson, Judith L.; George, Clifford; Deschamps, Jeffrey R.

    2003-02-01

    Cocaine is a potent stimulant of the central nervous system with severe addiction potential. Its abuse is a major problem worldwide. The exact mechanism of action of cocaine is still uncertain but it is known that its reinforcing and stimulant effects are related to its ability to inhibit the membrane bound dopamine transporter (DAT). This paper discusses efforts that are underway to identify ligands for possible use in the treatment of cocaine abuse. Much of this effort has been focussed on understanding cocaine interactions at DAT receptor sites.

  19. Chronic NMDA administration to rats increases brain pro-apoptotic factors while decreasing anti-Apoptotic factors and causes cell death

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    Rapoport Stanley I

    2009-09-01

    Full Text Available Abstract Background Chronic N-Methyl-d-aspartate (NMDA administration to rats is reported to increase arachidonic acid signaling and upregulate neuroinflammatory markers in rat brain. These changes may damage brain cells. In this study, we determined if chronic NMDA administration (25 mg/kg i.p., 21 days to rats would alter expression of pro- and anti-apoptotic factors in frontal cortex, compared with vehicle control. Results Using real time RT-PCR and Western blotting, chronic NMDA administration was shown to decrease mRNA and protein levels of anti-apoptotic markers Bcl-2 and BDNF, and of their transcription factor phospho-CREB in the cortex. Expression of pro-apoptotic Bax, Bad, and 14-3-3ζ was increased, as well as Fluoro-Jade B (FJB staining, a marker of neuronal loss. Conclusion This alteration in the balance between pro- and anti-apoptotic factors by chronic NMDA receptor activation in this animal model may contribute to neuronal loss, and further suggests that the model can be used to examine multiple processes involved in excitotoxicity.

  20. Cocaine-induced behavioral sensitization decreases the expression of endocannabinoid signaling-related proteins in the mouse hippocampus.

    Science.gov (United States)

    Blanco, Eduardo; Galeano, Pablo; Palomino, Ana; Pavón, Francisco J; Rivera, Patricia; Serrano, Antonia; Alen, Francisco; Rubio, Leticia; Vargas, Antonio; Castilla-Ortega, Estela; Decara, Juan; Bilbao, Ainhoa; de Fonseca, Fernando Rodríguez; Suárez, Juan

    2016-03-01

    In the reward mesocorticolimbic circuits, the glutamatergic and endocannabinoid systems are implicated in neurobiological mechanisms underlying cocaine addiction. However, the involvement of both systems in the hippocampus, a critical region to process relational information relevant for encoding drug-associated memories, in cocaine-related behaviors remains unknown. In the present work, we studied whether the hippocampal gene/protein expression of relevant glutamate signaling components, including glutamate-synthesizing enzymes and metabotropic and ionotropic receptors, and the hippocampal gene/protein expression of cannabinoid type 1 (CB1) receptor and endocannabinoid metabolic enzymes were altered following acute and/or repeated cocaine administration resulting in conditioned locomotion and locomotor sensitization. Results showed that acute cocaine administration induced an overall down-regulation of glutamate-related gene expression and, specifically, a low phosphorylation level of GluA1. In contrast, locomotor sensitization to cocaine produced an up-regulation of several glutamate receptor-related genes and, specifically, an increased protein expression of the GluN1 receptor subunit. Regarding the endocannabinoid system, acute and repeated cocaine administration were associated with an increased gene/protein expression of CB1 receptors and a decreased gene/protein expression of the endocannabinoid-synthesis enzymes N-acyl phosphatidylethanolamine D (NAPE-PLD) and diacylglycerol lipase alpha (DAGLα). These changes resulted in an overall decrease in endocannabinoid synthesis/degradation ratios, especially NAPE-PLD/fatty acid amide hydrolase and DAGLα/monoacylglycerol lipase, suggesting a reduced endocannabinoid production associated with a compensatory up-regulation of CB1 receptor. Overall, these findings suggest that repeated cocaine administration resulting in locomotor sensitization induces a down-regulation of the endocannabinoid signaling that could

  1. Effects of chronic ethanol administration on expression of BDNF and trkB mRNAs in rat hippocampus after experimental brain injury.

    Science.gov (United States)

    Zhang, L; Dhillon, H S; Barron, S; Hicks1, R R; Prasad, R M; Seroogy, K B

    2000-06-23

    Previous evidence indicates that both chronic alcohol treatment and traumatic brain injury modulate expression of certain neurotrophins and neurotrophin receptors in cortical tissue. However, the combined effects of chronic alcohol and brain trauma on expression of neurotrophins and their receptors have not been investigated. In the present study, we examined the effects of 6 weeks of chronic ethanol administration on lateral fluid percussion (FP) brain injury-induced alterations in expression of mRNAs for the neurotrophin brain-derived neurotrophic factor (BDNF) and its high affinity receptor, trkB, in rat hippocampus. In both the control- (pair-fed isocaloric sucrose) diet and the chronic ethanol-diet groups, unilateral FP brain injury induced a bilateral increase in levels of both BDNF and trkB mRNAs in the dentate gyrus granule cell layer, and of BDNF mRNA in hippocampal region CA3. However, no significant differences in expression were found between the control-diet and ethanol-diet groups, in either the sham-injured or FP-injured animals. These findings suggest that 6 weeks of chronic ethanol administration does not alter the plasticity of hippocampal BDNF/trkB expression in response to experimental brain injury.

  2. Hostility is associated with a heightened prolactin response to meta-chlorophenylpiperazine in abstinent cocaine addicts.

    Science.gov (United States)

    Handelsman, L; Kahn, R S; Sturiano, C; Rinaldi, P J; Gabriel, S; Schmeidler, J P; Bernstein, D P; Siever, L; Cooper, T B

    1998-07-27

    The prolactin (PRL) response to the administration of serotonin (5HT) agonists is an index of central nervous system 5HT activity. This index is blunted in association with hostile aggression in personality and depressive disorder patients without substance abuse. We tested whether the PRL response to the oral administration of the partial 5HT agonist meta-chlorophenylpiperazine (MCPP), 0.35 mg/kg, was associated with a measure of trait hostility, the Buss Durkee Hostility Inventory (BDHI), in cocaine addicts who were completing a 3-week detoxification and rehabilitation program. We also tested whether the cocaine addicts differed from healthy volunteers on their PRL, cortisol (CORT) or temperature responses to MCPP. The PRL response to MCPP was positively associated with the total score on the BDHI. There were, however, no differences in the neuroendocrine or temperature responses to MCPP between the cocaine-dependent group and the healthy volunteers once age effects were controlled for.

  3. [Cocaine-related gastric perforation].

    Science.gov (United States)

    Ring, A; Stein, E; Stern, J

    2010-06-01

    Since the 1980s the abuse of cocaine has been -associated with gastroduodenal perforations in the United States. Here, we report the case of a 28-year-old man who came to our hospital with severe abdominal pain after smoking cocaine. Physical examination revealed generalised abdominal guarding. His X-ray did not show any free intraperitoneal air. However, there was a slightly elevated white blood cell count. Upon laparoscopic exploration of the abdomen, the -patient was found to have a generalised peritonitis secondary to a perforation of the prepyloric anterior wall. The operative procedure consisted of ulcer excision and primary closure with a pyloroplasty as well as an extensive abdominal irrigation after laparotomy.

  4. The neurosteroid dehydroepiandrosterone sulfate, but not androsterone, enhances the antidepressant effect of cocaine examined in the forced swim test--Possible role of serotonergic neurotransmission.

    Science.gov (United States)

    Krzascik, Pawel; Zajda, Malgorzata Elzbieta; Majewska, Maria Dorota

    2015-04-01

    One of the mechanisms of cocaine's actions in the central nervous system is its antidepressant action. This effect might be responsible for increased usage of the drug by individuals with mood disorders. Higher endogenous levels of the excitatory neurosteroid dehydroepiandrosterone sulfate (DHEAS) were reported to correlate with successful abstinence from cocaine use in addicts, but a clinical trial showed that supplementation with a high dose of DHEA increased cocaine usage instead. Such ambiguous effects of DHEA(S) could potentially be linked to its influence on the antidepressant effect of cocaine. In this study we tested DHEAS and its metabolite, androsterone, for interactions with cocaine in animal model of depression (forced swim test) and examined the effects of both steroids and cocaine on serotoninergic neurotransmission. All substances were also tested for influence on locomotor activity. A cocaine dose of 5mg/kg, which had no significant effect on locomotor activity, was chosen for the forced swim test. Neither DHEAS nor androsterone showed any antidepressant action in this test, while cocaine manifested a clear antidepressant effect. Androsterone slightly reduced the antidepressant influence of cocaine while DHEAS markedly, dose-dependently enhanced it. Such an effect might be caused by the influence of DHEAS on serotonin neurotransmission, as this steroid decreased serotonin concentration and turnover in the striatum. When DHEAS and cocaine were administered together, the levels of serotonin in the striatum and hippocampus remained unchanged. This phenomenon may explain the additive antidepressant action of DHEAS and cocaine and why co-administration of DHEAS and cocaine increases drug use.

  5. Metabotropic glutamate receptor 7 modulates the rewarding effects of cocaine in rats: involvement of a ventral pallidal GABAergic mechanism.

    Science.gov (United States)

    Li, Xia; Li, Jie; Peng, Xiao-Qing; Spiller, Krista; Gardner, Eliot L; Xi, Zheng-Xiong

    2009-06-01

    The metabotropic glutamate receptor 7 (mGluR7) has received much attention as a potential target for the treatment of epilepsy, major depression, and anxiety. In this study, we investigated the possible involvement of mGluR7 in cocaine reward in animal models of drug addiction. Pretreatment with the selective mGluR7 allosteric agonist N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082; 1-20 mg/kg, i.p.) dose-dependently inhibited cocaine-induced enhancement of electrical brain-stimulation reward and intravenous cocaine self-administration under both fixed-ratio and progressive-ratio reinforcement conditions, but failed to alter either basal or cocaine-enhanced locomotion or oral sucrose self-administration, suggesting a specific inhibition of cocaine reward. Microinjections of AMN082 (1-5 microg/microl per side) into the nucleus accumbens (NAc) or ventral pallidum (VP), but not dorsal striatum, also inhibited cocaine self-administration in a dose-dependent manner. Intra-NAc or intra-VP co-administration of 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP, 5 microg/microl per side), a selective mGluR7 allosteric antagonist, significantly blocked AMN082's action, suggesting an effect mediated by mGluR7 in these brain regions. In vivo microdialysis demonstrated that cocaine (10 mg/kg, i.p.) priming significantly elevated extracellular DA in the NAc or VP, while decreasing extracellular GABA in VP (but not in NAc). AMN082 pretreatment selectively blocked cocaine-induced changes in extracellular GABA, but not in DA, in both naive rats and cocaine self-administration rats. These data suggest: (1) mGluR7 is critically involved in cocaine's acute reinforcement; (2) GABA-, but not DA-, dependent mechanisms in the ventral striatopallidal pathway appear to underlie AMN082's actions; and (3) AMN082 or other mGluR7-selective agonists may be useful in the treatment of cocaine addiction.

  6. Intense sweetness surpasses cocaine reward.

    Directory of Open Access Journals (Sweden)

    Magalie Lenoir

    Full Text Available BACKGROUND: Refined sugars (e.g., sucrose, fructose were absent in the diet of most people until very recently in human history. Today overconsumption of diets rich in sugars contributes together with other factors to drive the current obesity epidemic. Overconsumption of sugar-dense foods or beverages is initially motivated by the pleasure of sweet taste and is often compared to drug addiction. Though there are many biological commonalities between sweetened diets and drugs of abuse, the addictive potential of the former relative to the latter is currently unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that when rats were allowed to choose mutually-exclusively between water sweetened with saccharin-an intense calorie-free sweetener-and intravenous cocaine-a highly addictive and harmful substance-the large majority of animals (94% preferred the sweet taste of saccharin. The preference for saccharin was not attributable to its unnatural ability to induce sweetness without calories because the same preference was also observed with sucrose, a natural sugar. Finally, the preference for saccharin was not surmountable by increasing doses of cocaine and was observed despite either cocaine intoxication, sensitization or intake escalation-the latter being a hallmark of drug addiction. CONCLUSIONS: Our findings clearly demonstrate that intense sweetness can surpass cocaine reward, even in drug-sensitized and -addicted individuals. We speculate that the addictive potential of intense sweetness results from an inborn hypersensitivity to sweet tastants. In most mammals, including rats and humans, sweet receptors evolved in ancestral environments poor in sugars and are thus not adapted to high concentrations of sweet tastants. The supranormal stimulation of these receptors by sugar-rich diets, such as those now widely available in modern societies, would generate a supranormal reward signal in the brain, with the potential to override self

  7. Impact of chronic nicotine administration on bone mineral content in young and adult rats: a comparative study.

    Science.gov (United States)

    Farag, Mahmoud M; Selima, Eman A; Salama, Mona A

    2013-11-15

    The aim of this study was to evaluate the effects of chronic nicotine administration on bone mineral homeostasis in rapidly growing young rats in comparison to effects in adult male rats. Two doses of nicotine (3 and 4.5mg/kg/day, as nicotine hydrogen tartrate) were used and rat treatment was continued for 6 months. In this study, all nicotine-treated rats weighed less than control rats and the effect was dose-dependent. Also, rats treated with nicotine had lower femoral wet weight and showed a significant reduction in femoral mid-shaft cortical width and femoral and lumbar vertebral ash weights. These effects were associated with a significant reduction of ash calcium and phosphorus contents of the femora and lumbar vertebrae. The bone mineral-lowering effects of nicotine were more severe in the lumbar vertebral spongy bone than in the femoral compact bone and these changes were more marked in adult rats than in young rats. An additional interesting observation was that the femora of young rats treated with nicotine were significantly shorter than those of control young rats. Also, the values of the femoral ash weight per unit length were significantly decreased in nicotine-treated adult rats but not in nicotine-treated young rats. Thus, these results show that nicotine-induced changes in bone vary with age. The clinical relevance of this study is that it may provide justification to insist that all people in general and the risky young group in particular should be warned against the hazards of the negative effects of nicotine on bone.

  8. EFFECTS OF CHRONIC ADMINISTRATION OF EFAVIRENZ ON THE BRAIN AND INFERIOR COLLICULUS WEIGHTS OF ADULT WISTAR RATS

    Directory of Open Access Journals (Sweden)

    J. O. Adjene

    2009-01-01

    Full Text Available The effects of chronic administration of Efavirenz commonly used as part of highly active antiretroviral therapy (HAART for the treatment of Human Immunodeficiency Virus (HIV type-1 on the weight of the brain and inferior colliculus of adult wistar rats was carefully studied. The rats of both sexes (n=16, with an average weight of 200g were randomly assigned into treatment (n=8 and control (n=8 groups. The rats in the treatment group received 600 mg/70 kg body weight of Efavirenz dissolved in distilled water daily for 30 days (thirty days through the orogastric tube. The control group received equal volume of distilled water daily for 30 days through the same route. The rats were fed with grower's mash obtained from Edo Feeds and Flour Mill Limited, Ewu, Edo state, Nigeria and given water liberally. The rats were sacrificed by cervical dislocation method on the thirty-first day of the experiment and the brains were carefully dissected out, dried, weighed and recorded using the Mettler Toledo weighing balance. The findings indicate that there was a significant decrease (P < 0.05 in the dry brain weight and an increase in the relative dry brain weight of the treatment group as compared with the control group in this experiment. There was also a significant increase (P < 0.05 in the weight of the dry inferior colliculus per total dry brain weight in the treatment group when compared with the control group. However, the relative dry inferior colliculus weight was significantly higher (P < 0.05 in the treatment group also than that of the control group in this experiment

  9. 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.

  10. Bilateral Transcranial Magnetic Stimulation of the Prefrontal Cortex reduces cocaine intake: a pilot study.

    Directory of Open Access Journals (Sweden)

    Corinna Bolloni

    2016-08-01

    Full Text Available Background: Chronic cocaine consumption is associated to a decrease in mesolimbic dopamine transmission that maintains drug intake. Transcranial Magnetic Stimulation (TMS is gaining reliability a useful therapeutic tool in drug addiction since it can modulate cortico-limbic activity resulting in reduction of drug craving. Aims: In the present study we investigated the therapeutic effect of bilateral TMS of prefrontal cortex (PFC in reducing cocaine intake, in a sample of treatment-seeking patients with current cocaine use disorder (DSM-V. Methods: 10 cocaine addicts (DSM-V were randomly assigned to the active or sham stimulation protocol in a double-blind experimental design. Twelve repetitive TMS (rTMS sessions were administered 3 times a week for 4 weeks at 100% of motor threshold, over bilateral PFC. Cocaine intake (ng/mg was assessed by hair analysis at baseline (before treatment, T0, after one month (end of treatment, T1, 3 (T2 and 6 (T3 months later. All subjects received psychological support weekly. Results: The two-way ANOVA for repeated measures did not show a significant effect of the interaction between time and treatment (F4,32= 0.35; p=.87. Despite that result indicated no difference in the effect of the two conditions (active vs sham along time, a decreasing trend in cocaine consumption in active TMS group (F3,23=3.42; p=.04 vs sham (F3,15=1.88; p=.20 was observed when we performed exploratory analysis with time as factor . Indeed, Post-hoc comparisons showed a significant reduction in the amount of cocaine detected from the onset to three months later (T0-T2; p=.02 and to the end of treatment (T0-T3; p=.01 in addicts from the active group. Conclusions: Bilateral rTMS of PFC at 10 Hz did not show a significant effect on cocaine intake compared to sham. However, a long-term reduction in cocaine intake in active TMS treated patients was observed when we considered the time as factor. Further studies are required to confirm these

  11. Co-sensitivity to the incentive properties of palatable food and cocaine in rats; implications for co-morbid addictions.

    Science.gov (United States)

    Levy, AnneMarie; Salamon, Avi; Tucci, Mark; Limebeer, Cheryl L; Parker, Linda A; Leri, Francesco

    2013-09-01

    Several lines of evidence suggest that there may be a shared vulnerability to acquire behaviors motivated by strong incentive stimuli. Non-food restricted male Sprague-Dawley rats (n = 78) underwent place conditioning with Oreos, and were subsequently tested on cocaine self-administration (SA) on fixed and progressive ratios, as well as extinction and reinstatement by cocaine primes and by consumption of Oreos. Although there was a group preference for the Oreo-paired compartment, at the individual level some rats (69%) displayed a preference and others did not. In cocaine SA, 'preference' rats achieved higher break points on a progressive ratio, and displayed greater responding during extinction and cocaine-induced reinstatement. Within the context of this study, Oreo-cocaine cross-reinstatement was not observed. In a control study, rats (n = 29) conditioned with a less palatable food (rice cakes) also displayed individual differences in place preference, but not on subsequent cocaine tests. These findings indicate that there is a relationship between incentive learning promoted by palatable foods and by cocaine. This supports the hypothesis that co-morbid food-drug addictions may result from a shared vulnerability to acquire behaviors motivated by strong incentives.

  12. Cardiotoxic effects of cocaine and anabolic-androgenic steroids in the athlete.

    Science.gov (United States)

    Welder, A A; Melchert, R B

    1993-04-01

    Cocaine and anabolic-androgenic steroid abuse have become major drug problems in the United States. Cocaine has been designated as "the drug of greatest national health concern" while as many as 1 million Americans have used or are currently using anabolic-androgenic steroids to promote athletic performance and/or improve physical appearance. Unfavorable cardiovascular events have been linked to both cocaine and anabolic-androgenic steroid abuse in healthy, physically active individuals. Deaths of several United States athletes in 1986 focused attention on the life-threatening cardiovascular consequences of cocaine abuse. Reports of myocardial injury with anabolic-androgenic steroid abuse are anecdotal. Nevertheless, case reports have illustrated the alarming cardiotoxic potential of these steroids in athletes. Anabolic-androgenic steroids were correlated to myocardial infarction in weight lifters and cardiomyopathy in a former professional football player. From the total emergency room episodes where cocaine was mentioned in 1990, approximately 66% of these episodes occurred in young individuals 18-29 years of age. Over 500,000 of the individuals currently taking anabolic-androgenic steroids for nonmedical purposes are high-school children. Because cocaine and anabolic-androgenic steroids are used improperly, more focus needs to be paid to the toxic mechanisms of their adverse effects. Therefore, the purpose of this review is to discuss mechanisms whereby exercise and/or exercise training may alter the cardiovascular responses to these drugs. Furthermore, we would like to illustrate that contrary to the popular belief, acute and chronic abuse of cocaine and anabolic-androgenic steroids have a negative impact on exercise performance.

  13. Personality profile in young current regular users of cocaine.

    Science.gov (United States)

    Herrero, M Jesús; Domingo-Salvany, Antonia; Torrens, Marta; Brugal, M Teresa; Gutiérrez, Fernando

    2008-01-01

    This study examined the relationship between the personality profile of a sample of cocaine users and the presence of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnoses and the severity of substance use. A total of 120 participants (46 women, mean age: 23.8 years) from nonclinical settings in Barcelona, Spain, 2003-2006, were assessed using the Psychiatric Research Interview for Substance and Mental Disorders (PRISM) and the Temperament and Character Inventory-Revised version (TCI-R). Most of the participants had completed more than primary education, nearly half of them were employed, one third lived with parents, and near a quarter had some criminal record. Snorting was the main route of cocaine administration. They were using a mean of 1.82 substances. Cocaine users with low Self-Directedness, low Cooperativeness, and high Self-Transcendence scores in the TCI-R, with high severity of substance use and psychiatric comorbidity, would be suggestive of a possible specific phenotype. The limitations and implications of the study are discussed.

  14. Addiction-related effects of DOV 216,303 and cocaine: A comparative study in the mouse.

    Science.gov (United States)

    Sørensen, Gunnar; Husum, Henriette; Brennum, Lise T; Bundgaard, Christoffer; Montezinho, Liliana C P; Mørk, Arne; Wörtwein, Gitta; Woldbye, David P D

    2014-06-01

    DOV 216,303, an inhibitor of serotonin, noradrenaline and dopamine reuptake, belongs to a new line of drugs called 'triple reuptake inhibitors' that have been proposed for treatment of depression. The addictive drug cocaine has similar mechanism of action and exerts rewarding effects by blocking reuptake of dopamine, leading to increased extracellular concentrations of dopamine in the nucleus accumbens. Thus, DOV 216,303 and other triple reuptake inhibitors might be speculated to exhibit abuse potential, limiting their future therapeutic use. To further elucidate potential addictive properties of DOV 216,303, we conducted a comparative study of addiction-related effects of DOV 216,303 and cocaine in mice using acute self-administration, conditioned place preference (CPP) and drug-induced hyperlocomotion. Effects on accumbal extracellular dopamine levels were determined using microdialysis, and we measured monoamine receptor occupancy as well as brain and plasma exposure. DOV 216,303 was self-administered acutely in the same dose range as cocaine. However, in the CPP model, DOV 216,303 did not induce place preference at doses where cocaine caused place preference. Higher doses of DOV 216,303 than cocaine were needed to induce hyperlocomotion and increase extracellular accumbal dopamine with effective doses being higher than effective doses used in depression models. Moreover, DOV 216,303 displayed a pharmacokinetic profile with lower potential for addiction than cocaine. Thus, high levels of DAT occupancy were reached slower and decayed more slowly after DOV 216,303 than cocaine administration. The present study shows that acute administration of DOV 216,303 displays some addictive-like properties in mice, but these were less pronounced than cocaine, most likely due to different pharmacokinetic profiles.

  15. Opiate and Cocaine Exposed Newborns: Growth Outcomes.

    Science.gov (United States)

    Butz, Arlene M.; Kaufmann, Walter E.; Royall, Richard; Kolodner, Ken; Pulsifer, Margaret B.; Lears, Mary Kathleen; Henderson, Robin; Belcher, Harolyn; Sellers, Sherri; Wilson, Modena

    1999-01-01

    Examines growth parameters at birth in 204 infants born to mothers who used cocaine and/or opiates during pregnancy. Outcome measures included birth weight, length, and head circumference. Study provides support that in utero cocaine exposure may confer more risk for somatic growth retardation at birth than opiate exposure. (Author/GCP)

  16. Osteonecrosis following alcohol, cocaine, and steroid use.

    LENUS (Irish Health Repository)

    Ziraldo, Laura

    2012-02-01

    Alcohol, steroids and cocaine have all been shown to be independent risk factors for osteonecrosis when taken in excess. Here we present a case of a young girl who developed debilitating osteonecrosis secondary to low doses of alcohol, steroids and cocaine. We feel it is important to highlight to those caring for such patients of the potential devastating complication of these three agents.

  17. A Simple Economic Model of Cocaine Production

    Science.gov (United States)

    1994-01-01

    the production dhain that are vulnerable to itr o as well as providing a clearer picture of the path that cocaine takes before reading retail markts in...In fact, given the volatility of cocaine product prices in PBC, it is probably not uncommon for segments of production to be unprofitable at times

  18. Cilioretinal artery occlusion following intranasal cocaine insufflations

    Directory of Open Access Journals (Sweden)

    Balaji Kannan

    2011-01-01

    Full Text Available Cocaine is used to produce a euphoric effect by abusers, who may be unaware of the devastating systemic and ocular side effects of this drug. We describe the first known case of cilioretinal artery occlusion after intranasal cocaine abuse.

  19. Levamisole-contaminated cocaine : a hairy affair

    NARCIS (Netherlands)

    van der Veer, Tjeerd; Pennings, Ed; Tervaert, J W Cohen; Korswagen, Lindy-Anne

    2015-01-01

    Levamisole-contaminated cocaine can induce severe systemic vasculitis. The diagnosis can be challenging, especially when substance abuse is uncertain. We present the case of a 42-year-old woman suffering from vasculitis due to levamisole-contaminated cocaine, who persistently denied substance abuse.

  20. Music-induced context preference following cocaine conditioning in rats.

    Science.gov (United States)

    Polston, J E; Glick, S D

    2011-08-01

    Traditional models of drug-seeking behavior have shown that exposure to associated environmental cues can trigger relapse. These learned associations take place during repeated drug administration, resulting in conditioned reinforcement. Although considerable investigation has occurred regarding simple conditioned stimuli, less is known about complex environmental cues, particularly those that may be salient in human addiction. Recent studies indicate that music can serve as a contextual conditioned stimulus in rats and influence drug-seeking behavior during abstinence. The purpose of the present study was to further assess the effectiveness of music as a conditioned stimulus in rats, to determine rats' preferences for two contrasting pieces of music, and to determine rats' preferences for music versus silence. To this end, we created an apparatus that gave instrumental control of musical choice (Miles Davis vs. Beethoven) to the rats themselves. After determining baseline musical preference, animals were conditioned with cocaine (10 mg/kg) to the music they initially preferred least, with alternating conditioning sessions pairing saline with the music preferred most. The animals were subsequently tested in a drug-free state to determine what effect this conditioning had on musical preference. The results indicate that music serves as an effective contextual conditioned stimulus, significantly increasing both musical preference and locomotor activity after repeated cocaine conditioning. Furthermore, we found that rats initially favor silence over music, but that this preference can be altered as a result of cocaine-paired conditioning. These findings demonstrate that, after repeated association with reward (cocaine), music can engender a conditioned context preference in rats; these findings are consistent with other evidence showing that musical contextual cues can reinstate drug-seeking behavior in rats.

  1. Cocaine induces nuclear export and degradation of neuronal retinoid X receptor-γ via a TNF-α/JNK- mediated mechanism.

    Science.gov (United States)

    Kovalevich, Jane; Yen, William; Ozdemir, Ahmet; Langford, Dianne

    2015-03-01

    Cocaine abuse represents an immense societal health and economic burden for which no effective treatment currently exists. Among the numerous intracellular signaling cascades impacted by exposure to cocaine, increased and aberrant production of pro-inflammatory cytokines in the CNS has been observed. Additionally, we have previously reported a decrease in retinoid-X-receptor-gamma (RXR-γ) in brains of mice chronically exposed to cocaine. Through obligate heterodimerization with a number of nuclear receptors, RXRs serve as master regulatory transcription factors, which can potentiate or suppress expression of a wide spectrum of genes. Little is known about the regulation of RXR levels, but previous studies indicate cellular stressors such as cytokines negatively regulate levels of RXRs in vitro. To evaluate the mechanism underlying the cocaine-induced decreases in RXR-γ levels observed in vivo, we exposed neurons to cocaine in vitro and examined pathways which may contribute to disruption in RXR signaling, including activation of stress pathways by cytokine induction. In these studies, we provide the first evidence that cocaine exposure disrupts neuronal RXR-γ signaling in vitro by promoting its nuclear export and degradation. Furthermore, we demonstrate this effect may be mediated, at least in part, by cocaine-induced production of TNF-α and its downstream effector c-Jun-NH-terminal kinase (JNK). Findings from this study are therefore applicable to both cocaine abuse and to pathological conditions characterized by neuroinflammatory factors, such as neurodegenerative disease.

  2. Dissociation of the effects of MTEP [3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]piperidine] on conditioned reinstatement and reinforcement: comparison between cocaine and a conventional reinforcer.

    Science.gov (United States)

    Martin-Fardon, R; Baptista, M A S; Dayas, C V; Weiss, F

    2009-06-01

    To advance understanding of the potential of metabotropic glutamate receptor (mGluR) 5 as treatment targets for cocaine addiction, the effects of MTEP [3-[(2-methyl-1,3-thiazol-4-yl) ethynyl]piperidine] (a selective mGluR5 antagonist) on conditioned reinstatement of cocaine seeking were examined. To test whether modification of conditioned reinstatement by MTEP is selective for drug-directed behavior or reflects general actions on motivated behavior, effects of MTEP on reinstatement induced by a stimulus conditioned to palatable conventional reward, sweetened condensed milk (SCM), were also evaluated. Previous data suggest that mGluR manipulations preferentially interfere with conditioned reinstatement compared with cocaine self-administration. Therefore, the effects of MTEP on cocaine self-administration were compared with MTEP's effects on SCM-reinforced behavior using the same cocaine doses and SCM concentrations employed for establishing conditioned reinstatement. Male Wistar rats were trained to associate a discriminative stimulus (S(D)) with response-contingent availability of cocaine or SCM and subjected to reinstatement tests after extinction of cocaine or SCM-reinforced behavior. MTEP (0.3-10 mg/kg i.p.) dose-dependently attenuated the response-reinstating effects of both the cocaine S(D) and SCM S(D). MTEP also decreased cocaine self-administration without a clear graded dose-response profile and did not modify SCM-reinforced responding. The findings implicate mGluR5-regulated glutamate transmission in appetitive behavior controlled by reward-related stimuli but without selectivity for cocaine seeking. However, the data suggest a differential role for mGluR5 in the acute reinforcing effects of cocaine versus conventional reward. These observations identify mGluR5 as potential treatment targets for cocaine relapse prevention, although the profile of action of mGluR5 antagonists remains to be more closely examined for potential anhedonic effects.

  3. Anorexic activity of cocaine and coca extract in naive and cocaine tolerant rats.

    Science.gov (United States)

    Vee, G L; Fink, G B; Constantine, G H

    1983-04-01

    Dose response curves for reducing limited access food consumption were determined for cocaine HCl IP, cocaine HCl PO, and whole Erythroxylum coca extract PO. The ED50's for cocaine HCl in drug naive rats were 19.6 mg/kg (IP) and 34.6 mg/kg (PO). When the dose of E. coca extract was expressed in terms of cocaine HCl content, the ED50 was 52.6 mg/kg (PO). When dose response curves were determined in rats that had received cocaine (45 mg/kg, PO) for 30 days, a shift to the right in the cocaine HCl curve (an ED50 of 98.4 mg/kg PO) indicated tolerance. However, the shift to the right was less for E. coca extract than for cocaine HCl. Although the anorexic activity of E. coca extract was less than that of an equivalent amount of cocaine in naive rats it was often more than that of equivalent doses of cocaine HCl in tolerant rats. Interaction with other constituents of E. coca extract appears to alter the potency of the cocaine content of the extract in different directions in naive and tolerant rats.

  4. Conditioned stress prevents cue-primed cocaine reinstatement only in stress-responsive rats.

    Science.gov (United States)

    Hadad, Natalie A; Wu, Lizhen; Hiller, Helmut; Krause, Eric G; Schwendt, Marek; Knackstedt, Lori A

    2016-07-01

    Neurobiological mechanisms underlying comorbid posttraumatic stress disorder (PTSD) and cocaine use disorder (CUD) are unknown. We aimed to develop an animal model of PTSD + CUD to examine the neurobiology underlying cocaine-seeking in the presence of PTSD comorbidity. Rats were exposed to cat urine once for 10-minutes and tested for anxiety-like behaviors one week later. Subsequently, rats underwent long-access (LgA) cocaine self-administration and extinction training. Rats were re-exposed to the trauma context and then immediately tested for cue-primed reinstatement of cocaine-seeking. Plasma and brains were collected afterwards for corticosterone assays and real-time qPCR analysis. Urine-exposed (UE; n = 23) and controls not exposed to urine (Ctrl; n = 11) did not differ in elevated plus maze behavior, but UE rats displayed significantly reduced habituation of the acoustic startle response (ASR) relative to Ctrl rats. A median split of ASR habituation scores was used to classify stress-responsive rats. UE rats (n = 10) self-administered more cocaine on Day 1 of LgA than control rats (Ctrl + Coc; n = 8). Re-exposure to the trauma context prevented cocaine reinstatement only in stress-responsive rats. Ctrl + Coc rats had lower plasma corticosterone concentrations than Ctrls, and decreased gene expression of corticotropin releasing hormone (CRH) and Glcci1 in the hippocampus. Rats that self-administered cocaine displayed greater CRH expression in the amygdala that was independent of urine exposure. While we did not find that cat urine exposure induced a PTSD-like phenotype in our rats, the present study underscores the need to separate stressed rats into cohorts based on anxiety-like behavior in order to study individual vulnerability to PTSD + CUD.

  5. Dopamine decreases NMDA currents in the oval bed nucleus of the stria terminalis of cocaine self-administering rats.

    Science.gov (United States)

    Krawczyk, Michal; deBacker, Julian; Mason, Xenos; Jones, Andrea A; Dumont, Eric C

    2014-06-03

    Dopamine (DA) and N-methyl-D-aspartate receptors (NMDARs) contribute in the neural processes underlying drug-driven behaviors. DA is a potent modulator of NMDAR, but few studies have investigated the functional interaction between DA and NMDAR in the context of substance abuse. We combined the rat model of cocaine self-administration with brain slice electrophysiology to study DA modulation of NMDA currents in the oval bed nucleus of the stria terminalis (ovBNST), a dense DA terminal field involved in maintenance of cocaine self-administration amongst other drug related behaviors. Long-Evans rats self-administered intravenous cocaine (0.75 mg/kg/injection) on a progressive ratio (PR) schedule of reinforcement for 15 days and whole-cell patch-clamp recordings were done on the 16th day. DA reduced NMDA currents in brain-slices from cocaine self-administering rats, but not in those of drug-naïve and sucrose self-administering, or when cocaine exposure was passive (yoked), revealing a mechanism unique to voluntary cocaine intake. DA reduced NMDA currents by activating G-protein-coupled D1- and D2-like receptors that converged on phospholipase C and protein phosphatases. Accordingly, our study reveals a mechanism that may contribute to dysfunctional synaptic plasticity associated with drug-driven behaviors during acute withdrawal.

  6. Left kidney: an unusual site of cocaine-related renal infarction. A case report.

    Science.gov (United States)

    Fabbian, F; Pala, M; De Giorgi, A; Tiseo, R; Molino, C; Mallozzi Menegatti, A; Travasoni, F; Misurati, E; Portaluppi, F; Manfredini, R

    2012-03-01

    Acute renal infarction is a well known, although relatively unfrequent, cause of flank pain resistant to administration of spasmolytic and nonsteroidal anti-inflammatory drugs. We present an original case of a 41-year-old man, complaining of acute severe left flank pain, resistant to common analgesic therapy, who was diagnosed of segmental renal infarction of a branch of left renal artery. Pathophysiology of renal damage in cocaine users is multifactorial, and it has been postulated that the right kidney was more prone to ischaemia. Left kidney represents an extremely unusual site of cocaine-related renal infarction.

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

    Directory of Open Access Journals (Sweden)

    EDUARDO eBLANCO-CALVO

    2014-01-01

    Full Text Available Addiction to major drugs of abuse such as cocaine has been recently linked to alterations on adult neurogenesis in the hippocampus. The endogenous cannabinoid system modulated this proliferative response since pharmacological activation/blockade of cannabinoid CB1 and CB2 receptors by modulating not only neurogenesis but also cell death in the brain. In the present study, we evaluated whether the endogenous cannabinoid system affects cocaine-induced alterations in cell proliferation . To this end we examined if pharmacological blockade of either CB1 (Rimonabant, 3 mg/kg or CB2 receptors (AM630, 3 mg/kg affects cell proliferation (labeled with BrdU, found in the subventricular zone (SVZ of the lateral ventricles and the dentate subgranular zone (SGZ. In addition, we measured cell apoptosis (monitored by the expression of cleaved caspase-3 and glial activation ( by analizing the expression of GFAP and Iba-1 in the striatum and hippocampus, during acute or repeated (4 days cocaine administration (20 mg/kg. Results showed that acute cocaine decreased the number of BrdU+ cells in SVZ and SGZ. In contrast, repeated cocaine reduced the number of BrdU+ cells in SVZ only. Both acute and repeated cocaine increased the number of cleaved caspase-3+, GFAP+ and Iba1+ cells in the hippocampus, an effect counteracted by AM630 or Rimonabant that increased the number of BrdU+, GFAP+ and Iba1+ cells in the hippocampus. These results indicate that changes on neurogenic, apoptotic and gliosis processes, which were produced as a consequence of repeated cocaine administration, were normalized by the pharmacological blockade of CB1 and CB2. The restoring effects of cannabinoid receptor blockade on hippocampal cell proliferation were associated with a prevention of the induction of conditioned locomotion, but not of cocaine-induced sensitization.

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

    Science.gov (United States)

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

    2014-01-01

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

  9. Effect of Beta-Asarone on Impairment of Spatial Working Memory and Apoptosis in the Hippocampus of Rats Exposed to Chronic Corticosterone Administration

    Science.gov (United States)

    Lee, Bombi; Sur, Bongjun; Cho, Seong-Guk; Yeom, Mijung; Shim, Insop; Lee, Hyejung; Hahm, Dae-Hyun

    2015-01-01

    β-asarone (BAS) is an active component of Acori graminei rhizoma, a traditional medicine used clinically in treating dementia and chronic stress in Korea. However, the cognitive effects of BAS and its mechanism of action have remained elusive. The purpose of this study was to examine whether BAS improved spatial cognitive impairment induced in rats following chronic corticosterone (CORT) administration. CORT administration (40 mg/kg, i.p., 21 days) resulted in cognitive impairment in the avoidance conditioning test (AAT) and the Morris water maze (MWM) test that was reversed by BAS (200 mg/kg, i.p). Additionally, as assessed by immunohistochemistry and RT-PCR analysis, the administration of BAS significantly alleviated memory-associated decreases in the expression levels of brain-derived neurotrophic factor (BDNF) and cAMP-response element-binding protein (CREB) proteins and mRNAs in the hippocampus. Also, BAS administration significantly restored the expression of Bax and Bcl-2 mRNAs in the hippocampus. Thus, BAS may be an effective therapeutic for learning and memory disturbances, and its neuroprotective effect was mediated, in part, by normalizing the CORT response, resulting in regulation of BDNF and CREB functions and anti-apoptosis in rats. PMID:26535083

  10. Chronic administration of l-sulpiride at non-neuroleptic doses reduces the duration of immobility in experimental models of "depression-like" behavior.

    Science.gov (United States)

    Vergoni, A V; Forgione, A; Bertolini, A

    1995-09-01

    It has been shown that long-term administration of l-sulpiride induces a down-regulation of beta receptor-associated adenylate cyclase activity in the frontal cortex of rats, and adaptive response that is typically associated with the chronic administration of antidepressants. Here we show that in two animal models of "depression-like" behavior (forced swim in rats and tail suspension in mice), the long-term (21 days) administration of l-sulpiride at a non-neuroleptic dose (2 mg/kg IP twice a day) significantly decreases the duration of immobility, the effect being similar to that of desipramine (20 mg/kg IP). The same dose (2 mg/kg) of l-sulpiride, acutely administered, has no effect at all. On the other hand, either chronic (21 days) or acute administration of neuroleptic doses of l-sulpiride have an opposite effect, and indeed increase the duration of immobility. These results are an in vivo support to the in vitro findings suggesting that low doses of l-sulpiride may have antidepressant-like activity.

  11. Dopamine transporter inhibition is required for cocaine-induced stereotypy

    OpenAIRE

    Tilley, Michael R.; Gu, Howard H.

    2008-01-01

    The primary mechanism by which cocaine induces stereotypy has been difficult to discern because cocaine has three high affinity targets, the reuptake transporters for dopamine (DAT), norepinephrine, and serotonin. To dissect out the role of DAT in cocaine effects, we generated a knock-in mouse line with a cocaine insensitive DAT (DAT-CI mice). DAT-CI mice provide a powerful tool that can directly test whether DAT inhibition is important for cocaine-induced stereotypy. We found that acute coca...

  12. Cocaine and metabolites by LC-MS/MS.

    Science.gov (United States)

    Snozek, Christine L H; Bjergum, Matthew W; Langman, Loralie J

    2012-01-01

    Abuse of the stimulant cocaine (COC) is a common problem in the United States and elsewhere. The drug can be used either as the powder or as the free base (crack COC), and causes feelings of alertness and euphoria; both forms of COC are powerfully addictive. The assay described here is designed to detect and quantitate parent COC, its major metabolite benzoylecgonine, and a selection of metabolites that can provide specific information about sample validity (m-hydroxybenzoylecgonine), potential toxicity (norcocaine), route of administration (anhydroecgonine methyl ester), and co-utilization with ethanol (cocaethylene).

  13. Microinjection of CART (cocaine- and amphetamine-regulated transcript) peptide into the nucleus accumbens inhibits the cocaine-induced upregulation of dopamine receptors and locomotor sensitization.

    Science.gov (United States)

    Peng, Qinghua; Sun, Xi; Liu, Ziyong; Yang, Jianghua; Oh, Ki-Wan; Hu, Zhenzhen

    2014-09-01

    Repeated exposure to addictive drugs enhances dopamine receptor (DR) signaling and the ultimate phosphorylation of the cyclic adenosine 5'-monophosphate (cAMP)-response element-binding protein (CREB)-regulated cocaine- and amphetamine-regulated transcript (CART) expression in the nucleus accumbens (NAcc). These effects are known to contribute to the expression of behavioral sensitization. CART peptides are neuropeptides that modulate drug reward and reinforcement. The present experiments investigated the effects of CART 55-102 microinjection into the NAcc on (1) the phosphorylation of CREB, (2) cAMP/protein kinase A (PKA) signaling and (3) extracellular signal-regulated kinase (ERK) phosphorylated kinase signaling. Here, we show that repeated microinjections into the NAcc of CART 55-102 peptides (1.0 or 2.5μg, 0.5μl/side) attenuates cocaine-induced enhancements of D1R, D2R and D3R phosphorylation in this sites. Furthermore, the microinjection of CART 55-102 followed by repeated injections of cocaine (15mg/kg) dose-dependently blocked the enhancement of cAMP levels, PKA activity and pERK and pCREB levels on the fifth day of cocaine administration. The cocaine-induced locomotor activity and behavioral sensitization in rats were also inhibited by the 5-day-microinjection of CART peptides. These results suggest that the phosphorylation of CREB by cocaine in the NAcc was blocked by the CART 55-102 peptide via the inhibition of D1R and D2R stimulation, D3R phosphorylation, cAMP/PKA signaling and ERK phosphorylated kinase signaling. These effects may have played a compensatory inhibitory role in the behavioral sensitization of rats that received microinjections of CART 55-102.

  14. Effects of Ketamine on Levels of Inflammatory Cytokines IL-6, IL-1β, and TNF-α in the Hippocampus of Mice Following Acute or Chronic Administration.

    Science.gov (United States)

    Li, Yanning; Shen, Ruipeng; Wen, Gehua; Ding, Runtao; Du, Ao; Zhou, Jichuan; Dong, Zhibin; Ren, Xinghua; Yao, Hui; Zhao, Rui; Zhang, Guohua; Lu, Yan; Wu, Xu

    2017-01-01

    Ketamine is an injectable anesthetic and recreational drug of abuse commonly used worldwide. Many experimental studies have shown that ketamine can impair cognitive function and induce psychotic states. Neuroinflammation has been suggested to play an important role in neurodegeneration. Meanwhile, ketamine has been shown to modulate the levels of inflammatory cytokines. We hypothesized that the effects of ketamine on the central nervous system are associated with inflammatory cytokines. Therefore, we set out to establish acute and chronic ketamine administration models in C57BL/6 mice, to evaluate spatial recognition memory and emotional response, to analyze the changes in the levels of the inflammatory cytokines interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in the mouse hippocampus, employing behavioral tests, Western blot, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and immunohistochemistry. Our results showed that ketamine at the dose of 60 mg/kg induced spatial recognition memory deficit and reduced anxiety-like behaviors in mice after chronic administration. Moreover, we found that ketamine increased the hippocampal levels of IL-6 and IL-1β after single, multiple and long-term administration in a dose-dependent manner. However, the expression level of TNF-α differed in the mouse hippocampus under different conditions. Single administration of ketamine increased the level of TNF-α, whereas multiple and long-term administration decreased it significantly. We considered that TNF-α expression could be controlled by a bi-directional regulatory pathway, which was associated with the dose and duration of ketamine administration. Our results suggest that the alterations in the levels of inflammatory cytokines IL-6, IL-1β, and TNF-α may be involved in the neurotoxicity of ketamine.

  15. Peripheral afferent mechanisms underlying acupuncture inhibition of cocaine behavioral effects in rats.

    Directory of Open Access Journals (Sweden)

    Seol Ah Kim

    Full Text Available Administration of cocaine increases locomotor activity by enhancing dopamine transmission. To explore the peripheral mechanisms underlying acupuncture treatment for drug addiction, we developed a novel mechanical acupuncture instrument (MAI for objective mechanical stimulation. The aim of this study was to evaluate whether acupuncture inhibition of cocaine-induced locomotor activity is mediated through specific peripheral nerves, the afferents from superficial or deep tissues, or specific groups of nerve fibers. Mechanical stimulation of acupuncture point HT7 with MAI suppressed cocaine-induced locomotor activity in a stimulus time-dependent manner, which was blocked by severing the ulnar nerve or by local anesthesia. Suppression of cocaine-induced locomotor activity was elicited after HT7 stimulation at frequencies of either 50 (for Meissner corpuscles or 200 (for Pacinian corpuscles Hz and was not affected by block of C/Aδ-fibers in the ulnar nerve with resiniferatoxin, nor generated by direct stimulation of C/Aδ-fiber afferents with capsaicin. These findings suggest that HT7 inhibition of cocaine-induced locomotor activity is mediated by A-fiber activation of ulnar nerve that originates in superficial and deep tissue.

  16. Addictive potential of modafinil and cross-sensitization with cocaine: a pre-clinical study.

    Science.gov (United States)

    Wuo-Silva, Raphael; Fukushiro, Daniela F; Borçoi, Aline R; Fernandes, Helaine A; Procópio-Souza, Roberta; Hollais, André W; Santos, Renan; Ribeiro, Luciana T C; Corrêa, Jussara M R M; Talhati, Fernanda; Saito, Luis P; Aramini, Tatiana C F; Kameda, Sonia R; Bittencourt, Lia R A; Tufik, Sergio; Frussa-Filho, Roberto

    2011-10-01

    Repeated or even a single exposure to drugs of abuse can lead to persistent locomotor sensitization, which is the result of an abundance of neuroplastic changes occurring within the circuitry involved in motivational behavior and is thought to play a key role in certain aspects of drug addiction. There is substantial controversy about the addictive potential of modafinil, a wake-promoting drug used to treat narcolepsy that is increasingly being used as a cognitive enhancer and has been proposed as a pharmacotherapy for cocaine dependence. Male mice were used to investigate the ability of modafinil to induce locomotor sensitization after repeated or single administration in mice. Bidirectional cross-sensitization with cocaine and modafinil-induced conditioned place preference were also evaluated. Both repeated and single exposure to moderate and high doses of modafinil produced a pronounced locomotor sensitization that cross-sensitized in a bidirectional way with cocaine. Remarkably, when cocaine and modafinil were repeatedly administered sequentially, their behavioral sensitization was additive. Supporting these behavioral sensitization data, modafinil produced a pronounced conditioned place preference in the mouse. Taken together, the present findings provide pre-clinical evidence for the addictive potential of modafinil. Our data