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Sample records for area attenuates cocaine

  1. Mirtazapine attenuates cocaine seeking in rats.

    Science.gov (United States)

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

    2017-09-01

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

  2. Post-Retrieval Extinction Attenuates Cocaine Memories

    OpenAIRE

    Sartor, Gregory C; Aston-Jones, Gary

    2013-01-01

    Recent studies have shown that post-retrieval extinction training attenuates fear and reward-related memories in both humans and rodents. This noninvasive, behavioral approach has the potential to be used in clinical settings to treat maladaptive memories that underlie several psychiatric disorders, including drug addiction. However, few studies to date have used a post-retrieval extinction approach to attenuate addiction-related memories. In the current study, we attempted to disrupt cocaine...

  3. Neurotensin Agonist Attenuates Nicotine Potentiation to Cocaine Sensitization

    Directory of Open Access Journals (Sweden)

    Paul Fredrickson

    2014-01-01

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

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

    International Nuclear Information System (INIS)

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

    2010-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2010-07-01

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

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

    Directory of Open Access Journals (Sweden)

    Nora D Volkow

    2010-07-01

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

  7. Inhibiting glycine transporter-1 facilitates cocaine-cue extinction and attenuates reacquisition of cocaine-seeking behavior.

    Science.gov (United States)

    Nic Dhonnchadha, Bríd Á; Pinard, Emmanuel; Alberati, Daniela; Wettstein, Joseph G; Spealman, Roger D; Kantak, Kathleen M

    2012-04-01

    Combining extinction training with cognitive-enhancing pharmacotherapy represents a novel strategy for improving the efficacy of exposure therapy for drug relapse prevention. We investigated if the selective glycine transporter-1 (GlyT-1) inhibitor RO4543338 could facilitate extinction of cocaine-conditioned responses and attenuate reacquisition of cocaine-seeking behavior. Rats were trained to self-administer cocaine (0.3mg/kg), which was associated with a 2-s light cue under a second-order schedule of i.v. drug injection. Rats received vehicle, 30 or 45mg/kg of RO4543338 prior to three 1-h extinction-training sessions spaced at weekly intervals. Responses were extinguished by substituting saline for cocaine while maintaining response-contingent cue presentations. Reacquisition of cocaine-seeking behavior during self-administration sessions began 1 week after the last extinction session. Control experiments were conducted under conditions that precluded explicit extinction of cocaine-conditioned responses. Compared to vehicle, 30 and 45mg/kg RO4543338 significantly decreased responding early in extinction training and during subsequent reacquisition sessions. The latter effect persisted for at least five sessions. In control studies, reacquisition of cocaine-seeking behavior was not altered when RO4543338 was administered either prior to weekly self-administration control sessions or prior to weekly control sessions in which cocaine and cues were omitted and the levers retracted. As the GlyT-1 inhibitor facilitated cocaine-cue extinction learning and attenuated subsequent reacquisition of cocaine-seeking behavior, this class of compounds may have utility as a pharmacological adjunct to cocaine-cue exposure therapy in addicts. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  8. 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......) conferred lesser nonspecific rate-suppressing effects, with no rate suppression for TBPB. In mutant mice lacking M(1) and M(4) receptors, xanomeline failed to diminish cocaine discrimination while rate-decreasing effects were intact. Our data suggest that central M(1) receptor activation attenuates cocaine...

  9. Muscarinic receptor M4 positive allosteric modulators attenuate central effects of cocaine

    DEFF Research Database (Denmark)

    Dall, Camilla; Weikop, Pia; Dencker, Ditte

    2017-01-01

    allosteric modulators VU0152100 and VU0467154 in a drug discrimination assay and a conditioned place preference assay, including extinction and reinstatement of place preference. Specificity of the cocaine discrimination effect was verified using knockout mice lacking either M1or M4receptors (M1-/-, M4....... As previously shown with VU0152100, VU0467154 almost eliminated cocaine-induced hyperactivity and striatal dopamine efflux. VU0467154 failed to attenuate acquisition of cocaine-conditioned place preference, but facilitated extinction and prevented reinstatement of the conditioned place preference. CONCLUSIONS...

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

    Science.gov (United States)

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

    2018-03-01

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

  11. Ceftriaxone attenuates cocaine relapse after abstinence through modulation of nucleus accumbens AMPA subunit expression.

    Science.gov (United States)

    LaCrosse, Amber L; Hill, Kristine; Knackstedt, Lori A

    2016-02-01

    Using the extinction-reinstatement model of cocaine relapse, we and others have demonstrated that the antibiotic ceftriaxone attenuates cue- and cocaine-primed reinstatement of cocaine-seeking. Reinstatement is contingent on the release of glutamate in the nucleus accumbens core (NAc) and manipulations that reduce glutamate efflux or block post-synaptic glutamate receptors attenuate reinstatement. We have demonstrated that the mechanism of action by which ceftriaxone attenuates reinstatement involves increased NAc GLT-1 expression and a reduction in NAc glutamate efflux during reinstatement. Here we investigated the effects of ceftriaxone (100 and 200 mg/kg) on context-primed relapse following abstinence without extinction training and examined the effects of ceftriaxone on GluA1, GluA2 and GLT-1 expression. We conducted microdialysis during relapse to determine if an increase in NAc glutamate accompanies relapse after abstinence and whether ceftriaxone blunts glutamate efflux. We found that both doses of ceftriaxone attenuated relapse. While relapse was accompanied by an increase in NAc glutamate, ceftriaxone (200 mg/kg) was unable to significantly reduce NAc glutamate efflux during relapse despite its ability to upregulate GLT-1. GluA1 was reduced in the NAc by both doses of ceftriaxone while GluA2 expression was unchanged, indicating that ceftriaxone altered AMPA subunit composition following cocaine. Finally, GLT-1 was not altered in the PFC by ceftriaxone. These results indicate that it is possible to attenuate context-primed relapse to cocaine-seeking through modification of post-synaptic receptor properties without attenuating glutamate efflux during relapse. Furthermore, increasing NAc GLT-1 protein expression is not sufficient to attenuate glutamate efflux. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  12. 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 ...

  13. Cocaine

    Science.gov (United States)

    ... Fitness Diseases & Conditions Infections Drugs & Alcohol School & Jobs Sports Expert Answers (Q&A) Staying Safe Videos for Educators Search English Español Cocaine KidsHealth / For Teens / Cocaine What's in this article? What Is Cocaine? Short-Term Effects Long-Term Effects Other Possible Problems How Can ...

  14. Differential role of ventral tegmental area acetylcholine and N-methyl-D-aspartate receptors in cocaine-seeking.

    Science.gov (United States)

    Solecki, Wojciech; Wickham, Robert J; Behrens, Shay; Wang, Jie; Zwerling, Blake; Mason, Graeme F; Addy, Nii A

    2013-12-01

    Exposure to drug-associated cues evokes drug-seeking behavior and is regarded as a major cause of relapse. Cues evoke burst firing of ventral tegmental area (VTA) dopamine (DA) neurons and phasic DA release in the nucleus accumbens (NAc). Cholinergic and glutamatergic input to the VTA is suggested to gate phasic DA activity. However, the role of VTA cholinergic and glutamatergic receptors in regulating phasic dopamine release and cue-induced drug-seeking in cocaine experienced subjects is not known. In male Sprague-Dawley rats, we found that VTA inactivation strongly inhibited, while VTA stimulation promoted, cocaine-seeking behavior during early withdrawal. Blockade of phasic activated D1 receptors in the NAc core also strongly inhibited cue-induced cocaine-seeking--suggesting an important role of phasic DA activity in the VTA to NAc core circuit. Next, we examined the role of VTA acetylcholine receptors (AChRs) and N-methyl-D-aspartate receptors (NMDARs) in regulating both NAc core phasic DA release and cue-induced cocaine-seeking. In cocaine naïve subjects, VTA infusion of the nicotinic acetylcholine receptor (AChR) antagonist mecamylamine, the muscarinic AChR antagonist scopolamine, or the NMDAR antagonist AP-5, led to robust attenuation of phasic DA release in the NAc core. During early cocaine withdrawal, VTA infusion of AP-5 had limited effects on NAc phasic DA release and cue-induced cocaine-seeking while VTA infusion of mecamylamine or scopolamine robustly inhibited both phasic DA release and cocaine-seeking. The results demonstrate that VTA AChRs, but not NMDARs, strongly regulate cue-induced cocaine-seeking and phasic DA release during early cocaine withdrawal. Copyright © 2013 Elsevier Ltd. All rights reserved.

  15. The galanin receptor agonist, galnon, attenuates cocaine-induced reinstatement and dopamine overflow in the frontal cortex.

    Science.gov (United States)

    Ogbonmwan, Yvonne E; Sciolino, Natale R; Groves-Chapman, Jessica L; Freeman, Kimberly G; Schroeder, Jason P; Edwards, Gaylen L; Holmes, Philip V; Weinshenker, David

    2015-07-01

    Relapse represents one of the most significant problems in the long-term treatment of drug addiction. Cocaine blocks plasma membrane monoamine transporters and increases dopamine (DA) overflow in the brain, and DA is critical for the motivational and primary reinforcing effects of the drug as well as cocaine-primed reinstatement of cocaine seeking in rats, a model of relapse. Thus, modulators of the DA system may be effective for the treatment of cocaine dependence. The endogenous neuropeptide galanin inhibits DA transmission, and both galanin and the synthetic galanin receptor agonist, galnon, interfere with some rewarding properties of cocaine. The purpose of this study was to further assess the effects of galnon on cocaine-induced behaviors and neurochemistry in rats. We found that galnon attenuated cocaine-induced motor activity, reinstatement and DA overflow in the frontal cortex at a dose that did not reduce baseline motor activity, stable self-administration of cocaine, baseline extracellular DA levels or cocaine-induced DA overflow in the nucleus accumbens (NAc). Similar to cocaine, galnon had no effect on stable food self-administration but reduced food-primed reinstatement. These results indicate that galnon can diminish cocaine-induced hyperactivity and relapse-like behavior, possibly in part by modulating DA transmission in the frontal cortex. © 2014 Society for the Study of Addiction.

  16. Modafinil attenuates reinstatement of cocaine seeking: role for cystine-glutamate exchange and metabotropic glutamate receptors.

    Science.gov (United States)

    Mahler, Stephen V; Hensley-Simon, Megan; Tahsili-Fahadan, Pouya; LaLumiere, Ryan T; Thomas, Charles; Fallon, Rebecca V; Kalivas, Peter W; Aston-Jones, Gary

    2014-01-01

    Modafinil may be useful for treating stimulant abuse, but the mechanisms by which it acts to do so are unknown. Indeed, a primary effect of modafinil is to inhibit dopamine transport, which typically promotes rather than inhibits motivated behavior. Therefore, we examined the role of nucleus accumbens extracellular glutamate and the group II metabotropic glutamate receptor (mGluR2/3) in modafinil effects. One group of rats was trained to self-administer cocaine for 10 days and extinguished, then given priming injections of cocaine to elicit reinstatement. Modafinil (300 mg/kg, intraperitoneal) inhibited reinstated cocaine seeking (but did not alter extinction responding by itself), and this effect was prevented by pre-treatment with bilateral microinjections of the mGluR2/3 antagonist LY-341495 (LY) into nucleus accumbens core. No reversal of modafinil effects was seen after unilateral accumbens core LY, or bilateral LY in the rostral pole of accumbens. Next, we sought to explore effects of modafinil on extracellular glutamate levels in accumbens after chronic cocaine. Separate rats were administered non-contingent cocaine, and after 3 weeks of withdrawal underwent accumbens microdialysis. Modafinil increased extracellular accumbens glutamate in chronic cocaine, but not chronic saline-pre-treated animals. This increase was prevented by reverse dialysis of cystine-glutamate exchange or voltage-dependent calcium channel antagonists. Voltage-dependent sodium channel blockade partly attenuated the increase in glutamate, but mGluR1 blockade did not. We conclude that modafinil increases extracellular glutamate in nucleus accumbens from glial and neuronal sources in cocaine-exposed rats, which may be important for its mGluR2/3-mediated antirelapse properties. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.

  17. Ceftriaxone attenuates acute cocaine-evoked dopaminergic neurotransmission in the nucleus accumbens of the rat.

    Science.gov (United States)

    Barr, J L; Rasmussen, B A; Tallarida, C S; Scholl, J L; Forster, G L; Unterwald, E M; Rawls, S M

    2015-11-01

    Ceftriaxone is a β-lactam antibiotic and glutamate transporter activator that reduces the reinforcing effects of psychostimulants. Ceftriaxone also reduces locomotor activation following acute psychostimulant exposure, suggesting that alterations in dopamine transmission in the nucleus accumbens contribute to its mechanism of action. In the present studies we tested the hypothesis that pretreatment with ceftriaxone disrupts acute cocaine-evoked dopaminergic neurotransmission in the nucleus accumbens. Adult male Sprague-Dawley rats were pretreated with saline or ceftriaxone (200 mg kg(-1) , i.p. × 10 days) and then challenged with cocaine (15 mg kg(-1) , i.p.). Motor activity, dopamine efflux (via in vivo microdialysis) and protein levels of tyrosine hydroxylase (TH), the dopamine transporter and organic cation transporter as well as α-synuclein, Akt and GSK3β were analysed in the nucleus accumbens. Ceftriaxone-pretreated rats challenged with cocaine displayed reduced locomotor activity and accumbal dopamine efflux compared with saline-pretreated controls challenged with cocaine. The reduction in cocaine-evoked dopamine levels was not counteracted by excitatory amino acid transporter 2 blockade in the nucleus accumbens. Pretreatment with ceftriaxone increased Akt/GSK3β signalling in the nucleus accumbens and reduced levels of dopamine transporter, TH and phosphorylated α-synuclein, indicating that ceftriaxone affects numerous proteins involved in dopaminergic transmission. These results are the first evidence that ceftriaxone affects cocaine-evoked dopaminergic transmission, in addition to its well-described effects on glutamate, and suggest that its ability to attenuate cocaine-induced behaviours, such as psychomotor activity, is due in part to reduced dopaminergic neurotransmission in the nucleus accumbens. © 2015 The British Pharmacological Society.

  18. Cocaine sensitization increases subthreshold activity in dopamine neurons from the ventral tegmental area.

    Science.gov (United States)

    Arencibia-Albite, Francisco; Vázquez-Torres, Rafael; Jiménez-Rivera, Carlos A

    2017-02-01

    The progressive escalation of psychomotor responses that results from repeated cocaine administration is termed sensitization. This phenomenon alters the intrinsic properties of dopamine (DA) neurons from the ventral tegmental area (VTA), leading to enhanced dopaminergic transmission in the mesocorticolimbic network. The mechanisms underlying this augmented excitation are nonetheless poorly understood. DA neurons display the hyperpolarization-activated, nonselective cation current, dubbed I h We recently demonstrated that I h and membrane capacitance are substantially reduced in VTA DA cells from cocaine-sensitized rats. The present study shows that 7 days of cocaine withdrawal did not normalize I h and capacitance. In cells from cocaine-sensitized animals, the amplitude of excitatory synaptic potentials, at -70 mV, was ∼39% larger in contrast to controls. Raise and decay phases of the synaptic signal were faster under cocaine, a result associated with a reduced membrane time constant. Synaptic summation was paradoxically elevated by cocaine exposure, as it consisted of a significantly reduced summation indexed but a considerably increased depolarization. These effects are at least a consequence of the reduced capacitance. I h attenuation is unlikely to explain such observations, since at -70 mV, no statistical differences exist in I h or input resistance. The neuronal shrinkage associated with a diminished capacitance may help to understand two fundamental elements of drug addiction: incentive sensitization and negative emotional states. A reduced cell size may lead to substantial enhancement of cue-triggered bursting, which underlies drug craving and reward anticipation, whereas it could also result in DA depletion, as smaller neurons might express low levels of tyrosine hydroxylase. This work uses a new approach that directly extracts important biophysical parameters from alpha function-evoked synaptic potentials. Two of these parameters are the cell membrane

  19. Cocaine

    Science.gov (United States)

    ... Withdrawal symptoms include: depression fatigue increased appetite unpleasant dreams and insomnia slowed thinking How can people get ... Vulnerability Peaks 1 to 6 Months Into Abstinence Why Females Are More Sensitive to Cocaine Nora's Blog ...

  20. Cocaine

    Science.gov (United States)

    ... Adolescent Brain Comorbidity College-Age & Young Adults Criminal Justice Drugged Driving Drug Testing Drugs and the Brain ... uses cocaine, opioids (heroin), or marijuana. ( January 2007 ) View all related publications Related NIDA Notes Articles EEG ...

  1. Cocaine

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    ... including: depression feeling very tired increased appetite bad dreams and trouble sleeping slowed thinking The right treatment, ... the body. Order Free Publications in: English Download PDF 806.08 KB Research Report: Cocaine Describes the ...

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

    Science.gov (United States)

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

    2011-03-01

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

  3. Chronic wheel running affects cocaine-induced c-Fos expression in brain reward areas in rats.

    Science.gov (United States)

    Zlebnik, Natalie E; Hedges, Valerie L; Carroll, Marilyn E; Meisel, Robert L

    2014-03-15

    Emerging evidence from human and animal studies suggests that exercise is a highly effective treatment for drug addiction. However, most work has been done in behavioral models, and the effects of exercise on the neurobiological substrates of addiction have not been identified. Specifically, it is unknown whether prior exercise exposure alters neuronal activation of brain reward circuitry in response to drugs of abuse. To investigate this hypothesis, rats were given 21 days of daily access to voluntary wheel running in a locked or unlocked running wheel. Subsequently, they were challenged with a saline or cocaine (15 mg/kg, i.p.) injection and sacrificed for c-Fos immunohistochemistry. The c-Fos transcription factor is a measure of cellular activity and was used to quantify cocaine-induced activation of reward-processing areas of the brain: nucleus accumbens (NAc), caudate putamen (CPu), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). The mean fold change in cocaine-induced c-Fos cell counts relative to saline-induced c-Fos cell counts was significantly higher in exercising compared to control rats in the NAc core, dorsomedial and dorsolateral CPu, the prelimbic area, and the OFC, indicating differential cocaine-specific cellular activation of brain reward circuitry between exercising and control animals. These results suggest neurobiological mechanisms by which voluntary wheel running attenuates cocaine-motivated behaviors and provide support for exercise as a novel treatment for drug addiction. Copyright © 2013 Elsevier B.V. All rights reserved.

  4. Attenuation of cocaine-induced locomotor sensitization in rats sustaining genetic or pharmacologic antagonism of ghrelin receptors.

    Science.gov (United States)

    Clifford, P Shane; Rodriguez, Juan; Schul, Destri; Hughes, Samuel; Kniffin, Tracey; Hart, Nigel; Eitan, Shoshana; Brunel, Luc; Fehrentz, Jean-Alain; Martinez, Jean; Wellman, Paul J

    2012-11-01

    Systemic infusions of the orexigenic peptide ghrelin (GHR) increase dopamine levels within the nucleus accumbens and augment cocaine-stimulated locomotion and conditioned place preference in rats; observations that suggest an important role for GHR and GHR receptors (GHR-Rs) in drug reinforcement. In the present studies, we examined the development of cocaine locomotor sensitization in rats, sustaining either pharmacologic antagonism or genetic ablation of GHR-Rs. In a pharmacologic study, adult male rats were injected (i.p.) with either 0, 3 or 6 mg/kg JMV 2959 (a GHR-R1 receptor antagonist), and 20 minutes later, with either vehicle or 10 mg/kg cocaine HCl on each of 7 consecutive days. Rats pretreated with JMV 2959 showed significantly attenuated cocaine-induced hyperlocomotion. In a second study, adult wild-type (WT) or mutant rats sustaining ENU-induced knockout of GHR-R [GHR-R ((-/-) )] received daily injections (i.p.) of vehicle (0.9% saline) or 10.0 mg/kg cocaine HCl for 14 successive days. GHR-R null rats treated repeatedly with cocaine showed diminished development of cocaine locomotor sensitization relative to WT rats treated with cocaine. To verify the lack of GHR-R function in the GHR-R ((-/-) ) rats, a separate feeding experiment was conducted in which WT rats, but not GHR-R ((-/-) ) rats, were noted to eat more after a systemic injection of 15 nmol GHR than after vehicle. These results suggest that GHR-R activity is required for the induction of locomotor sensitization to cocaine and complement an emerging literature implicating central GHR systems in drug reward. GHR is an orexigenic gut peptide that is transported across the blood-brain barrier and interacts with GHR-Rs located on ventral tegmental dopamine neurons. © 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction.

  5. The trace amine associated receptor 1 agonist RO5263397 attenuates the induction of cocaine behavioral sensitization in rats.

    Science.gov (United States)

    Thorn, David A; Zhang, Chaogui; Zhang, Yanan; Li, Jun-Xu

    2014-04-30

    The trace amine associated receptor (TAAR) 1 is a new G protein coupled receptor that critically modulates central dopaminergic system. Recently, several selective TAAR 1 ligands have been described to possess antipsychotic and antidepressant-like activities. However, it is unknown of the role of these ligands in modulating psychostimulant-induced neurobehavioral plasticity. This study examined the effects of a selective TAAR 1 agonist, RO5263397, on cocaine induced behavioral sensitization in rats, a rodent model of drug-induced behavioral plasticity. Daily treatment with 15mg/kg cocaine (i.p., 7 days) induced robust locomotor sensitization in rats. RO5263397 (1-10mg/kg, i.p.) alone did not significantly alter the locomotor activity. Acute treatment with RO5263397 (3.2 and 10mg/kg) did not significantly modify cocaine-induced hyperactivity; however, the induction of locomotor sensitization was significantly blocked after 7 days of daily RO5263397 treatment. More importantly, the expression of locomotor sensitization remained significantly attenuated when rats were re-tested 7 days after the last drug treatment. The marked attenuation of cocaine sensitization was also evidenced by the suppression of the dose-effect function (3.2-32mg/kg) of cocaine sensitization. Together, these data represent the first to report a critical modulatory role of TAAR 1 agonists in cocaine-induced behavioral plasticity, which may be indicative of its potential role for altering other long-lasting behavioral maladaptations of cocaine including drug addiction. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  6. Activation of Dopamine D1-D2 Receptor Complex Attenuates Cocaine Reward and Reinstatement of Cocaine-Seeking through Inhibition of DARPP-32, ERK, and ΔFosB

    Directory of Open Access Journals (Sweden)

    Ahmed Hasbi

    2018-01-01

    Full Text Available A significant subpopulation of neurons in rat nucleus accumbens (NAc coexpress dopamine D1 and D2 receptors, which can form a D1-D2 receptor complex, but their relevance in addiction is not known. The existence of the D1-D2 heteromer in the striatum of rat and monkey was established using in situ PLA, in situ FRET and co-immunoprecipitation. In rat, D1-D2 receptor heteromer activation led to place aversion and abolished cocaine CPP and locomotor sensitization, cocaine intravenous self-administration and reinstatement of cocaine seeking, as well as inhibited sucrose preference and abolished the motivation to seek palatable food. Selective disruption of this heteromer by a specific interfering peptide induced reward-like effects and enhanced the above cocaine-induced effects, including at a subthreshold dose of cocaine. The D1-D2 heteromer activated Cdk5/Thr75-DARPP-32 and attenuated cocaine-induced pERK and ΔFosB accumulation, together with inhibition of cocaine-enhanced local field potentials in NAc, blocking thus the signaling pathway activated by cocaine: D1R/cAMP/PKA/Thr34-DARPP-32/pERK with ΔFosB accumulation. In conclusion, our results show that the D1-D2 heteromer exerted tonic inhibitory control of basal natural and cocaine reward, and therefore initiates a fundamental physiologic function that limits the liability to develop cocaine addiction.

  7. 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

    (4-hydroxy-2-butynyl)-1-trimethylammonium-3-chlorocarbanilate chloride (McN-A-343), and the novel M(1)-selective agonist 1-(1-2-methylbenzyl)-1,4-bipiperidin-4-yl)-1H benzo[d]imidazol-2(3H)-one (TBPB) were tested as substitution and/or pretreatment to cocaine. Both muscarinic antagonists partially...... substituted for cocaine and enhanced its discriminative stimulus. Conversely, muscarinic agonists blunted cocaine discrimination and abolished cocaine self-administration with varying effects on food-maintained behavior. Specifically, increasing selectivity for the M(1) subtype (oxotremorine ... for cocaine addiction....

  8. The medial preoptic area modulates cocaine-induced locomotion in male rats.

    Science.gov (United States)

    Will, Ryan G; Martz, Julia R; Dominguez, Juan M

    2016-05-15

    Cocaine-induced locomotion is mediated by dopamine in the nucleus accumbens (NAc). Recent evidence indicates that the medial preoptic area (mPOA), a region in the rostral hypothalamus, modulates cocaine-induced dopamine in the NAc. Specifically, rats with lesions of the mPOA experienced a greater increase in dopamine following cocaine administration than rats with sham lesions. Whether the mPOA similarly influences cocaine-induced locomotion is not known. Here we examined whether radiofrequency or neurotoxic lesions of the mPOA in male rats influence changes in locomotion that follow cocaine administration. Locomotion was measured following cocaine administration in male rats with neurotoxic, radiofrequency, or sham lesions of the mPOA. Results indicate that bilateral lesions of the mPOA facilitated cocaine-induced locomotion. This facilitation was independent of lesion type, as increased locomotion was observed with either approach. These findings support a role for the mPOA as an integral region in the processing of cocaine-induced behavioral response, in this case locomotor activity. Published by Elsevier B.V.

  9. Cocaine-Induced Endocannabinoid Mobilization in the Ventral Tegmental Area

    Directory of Open Access Journals (Sweden)

    Huikun Wang

    2015-09-01

    Full Text Available Cocaine is a highly addictive drug that acts upon the brain’s reward circuitry via the inhibition of monoamine uptake. Endogenous cannabinoids (eCB are lipid molecules released from midbrain dopamine (DA neurons that modulate cocaine’s effects through poorly understood mechanisms. We find that cocaine stimulates release of the eCB, 2-arachidonoylglycerol (2-AG, in the rat ventral midbrain to suppress GABAergic inhibition of DA neurons, through activation of presynaptic cannabinoid CB1 receptors. Cocaine mobilizes 2-AG via inhibition of norepinephrine uptake and promotion of a cooperative interaction between Gq/11-coupled type-1 metabotropic glutamate and α1-adrenergic receptors to stimulate internal calcium stores and activate phospholipase C. The disinhibition of DA neurons by cocaine-mobilized 2-AG is also functionally relevant because it augments DA release in the nucleus accumbens in vivo. Our results identify a mechanism through which the eCB system can regulate the rewarding and addictive properties of cocaine.

  10. 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...

  11. 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...

  12. CaMKII Activity in the Ventral Tegmental Area Gates Cocaine-Induced Synaptic Plasticity in the Nucleus Accumbens

    Science.gov (United States)

    Liu, Xiaojie; Liu, Yong; Zhong, Peng; Wilkinson, Brianna; Qi, Jinshun; Olsen, Christopher M; Bayer, K Ulrich; Liu, Qing-song

    2014-01-01

    Addictive drugs such as cocaine induce synaptic plasticity in discrete regions of the reward circuit. The aim of the present study is to investigate whether cocaine-evoked synaptic plasticity in the ventral tegmental area (VTA) and nucleus accumbens (NAc) is causally linked. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a central regulator of long-term synaptic plasticity, learning, and drug addiction. We examined whether blocking CaMKII activity in the VTA affected cocaine conditioned place preference (CPP) and cocaine-evoked synaptic plasticity in its target brain region, the NAc. TatCN21 is a CaMKII inhibitory peptide that blocks both stimulated and autonomous CaMKII activity with high selectivity. We report that intra-VTA microinjections of tatCN21 before cocaine conditioning blocked the acquisition of cocaine CPP, whereas intra-VTA microinjections of tatCN21 before saline conditioning did not significantly affect cocaine CPP, suggesting that the CaMKII inhibitor blocks cocaine CPP through selective disruption of cocaine-cue-associated learning. Intra-VTA tatCN21 before cocaine conditioning blocked cocaine-evoked depression of excitatory synaptic transmission in the shell of the NAc slices ex vivo. In contrast, intra-VTA microinjection of tatCN21 just before the CPP test did not affect the expression of cocaine CPP and cocaine-induced synaptic plasticity in the NAc shell. These results suggest that CaMKII activity in the VTA governs cocaine-evoked synaptic plasticity in the NAc during the time window of cocaine conditioning. PMID:24154664

  13. Partial mGlu₅ Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects.

    Science.gov (United States)

    Gould, Robert W; Amato, Russell J; Bubser, Michael; Joffe, Max E; Nedelcovych, Michael T; Thompson, Analisa D; Nickols, Hilary H; Yuh, Johannes P; Zhan, Xiaoyan; Felts, Andrew S; Rodriguez, Alice L; Morrison, Ryan D; Byers, Frank W; Rook, Jerri M; Daniels, John S; Niswender, Colleen M; Conn, P Jeffrey; Emmitte, Kyle A; Lindsley, Craig W; Jones, Carrie K

    2016-03-01

    Cocaine abuse remains a public health concern for which pharmacotherapies are largely ineffective. Comorbidities between cocaine abuse, depression, and anxiety support the development of novel treatments targeting multiple symptom clusters. Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor 5 (mGlu5) subtype are currently in clinical trials for the treatment of multiple neuropsychiatric disorders and have shown promise in preclinical models of substance abuse. However, complete blockade or inverse agonist activity by some full mGlu5 NAM chemotypes demonstrated adverse effects, including psychosis in humans and psychotomimetic-like effects in animals, suggesting a narrow therapeutic window. Development of partial mGlu5 NAMs, characterized by their submaximal but saturable levels of blockade, may represent a novel approach to broaden the therapeutic window. To understand potential therapeutic vs adverse effects in preclinical behavioral assays, we examined the partial mGlu5 NAMs, M-5MPEP and Br-5MPEPy, in comparison with the full mGlu5 NAM MTEP across models of addiction and psychotomimetic-like activity. M-5MPEP, Br-5MPEPy, and MTEP dose-dependently decreased cocaine self-administration and attenuated the discriminative stimulus effects of cocaine. M-5MPEP and Br-5MPEPy also demonstrated antidepressant- and anxiolytic-like activity. Dose-dependent effects of partial and full mGlu5 NAMs in these assays corresponded with increasing in vivo mGlu5 occupancy, demonstrating an orderly occupancy-to-efficacy relationship. PCP-induced hyperlocomotion was potentiated by MTEP, but not by M-5MPEP and Br-5MPEPy. Further, MTEP, but not M-5MPEP, potentiated the discriminative-stimulus effects of PCP. The present data suggest that partial mGlu5 NAM activity is sufficient to produce therapeutic effects similar to full mGlu5 NAMs, but with a broader therapeutic index.

  14. AMN082, a metabotropic glutamate receptor 7 allosteric agonist, attenuates locomotor sensitization and cross-sensitization induced by cocaine and morphine in mice.

    Science.gov (United States)

    Jenda, M; Gawel, K; Marszalek, M; Komsta, L; Kotlinska, J H

    2015-03-03

    Previous studies have indicated that metabotropic glutamate receptors 7 (mGluR7s) are involved in drug addiction. However, the role of these receptors in drug-induced behavioral sensitization is unknown. The aim of the present study was to determine whether systemic injection of AMN082, a selective mGluR7 allosteric agonist, reduces the cocaine- and morphine-induced hyperactivity and the development and expression of locomotor sensitization, and also affects the reciprocal cross-sensitization to the stimulant effect of cocaine and morphine in mice. AMN082 (1.25-10.0 mg/kg, i.p.) did not have an impact on locomotion of naive mice and did not affect the acute cocaine- or morphine-induced hyperactivity, except the dose of 10 mg/kg that suppressed the locomotor effect of both drugs. Repeated exposure to cocaine or morphine (10 mg/kg, 5× every 3 days) gradually increased locomotion during induction of sensitization and after 4 (cocaine) or 7 day (morphine) withdrawal phase when challenged with cocaine (10 mg/kg, i.p.) or morphine (10 mg/kg, i.p.) on day 17 or 20, respectively. Pretreatment of animals with the lower doses of AMN082 (1.25-5.0 mg/kg, i.p.), 30 min before every cocaine or morphine injection during repeated drug administration or before cocaine or morphine challenge, dose-dependently attenuated the development, as well as the expression of cocaine or morphine locomotor sensitization. AMN082 also inhibited the reciprocal cross-sensitization between these drugs. Prior to administration of MMPIP (10 mg/kg, i.p.), a selective mGluR7 antagonist reversed the inhibitory effect of AMN082 on the development or expression of cocaine or morphine sensitization. These data indicate that AMN082 attenuated the development and expression of cocaine and morphine sensitization, and the reciprocal cross-sensitization via a mechanism that involves mGluR7s. Thus, AMN082 might have therapeutic implications not only in the treatment of cocaine or opioid addiction but also in the

  15. Attenuation of cocaine-induced locomotor activity in male and female mice by active immunization.

    Science.gov (United States)

    Kosten, Therese A; Shen, Xiaoyun Y; Kinsey, Berma M; Kosten, Thomas R; Orson, Frank M

    2014-01-01

    Immunotherapy for drug addiction is being investigated in several laboratories but most studies are conducted in animals of one sex. Yet, women show heightened immune responses and are more likely to develop autoimmune diseases than men. The purpose of this study was to compare the effects of an active anti-cocaine vaccine, succinyl-norcocaine conjugated to keyhole limpet hemocyanin, for its ability to elicit antibodies and alter cocaine-induced ambulatory activity in male versus female mice. Male and female BALB/c mice were vaccinated (n = 44) or served as non-vaccinated controls (n = 34). Three weeks after initial vaccination, a booster was given. Ambulatory activity induced by cocaine (20 mg/kg) was assessed at 7 weeks and plasma obtained at 8 weeks to assess antibody levels. High antibody titers were produced in mice of both sexes. The vaccine reduced ambulatory activity cocaine-induced but this effect was greater in female compared to male mice. The efficacy of this anti-cocaine vaccine is demonstrated in mice of both sexes but its functional consequences are greater in females than males. Results point to the importance of testing animals of both sexes in studies of immunotherapies for addiction. © American Academy of Addiction Psychiatry.

  16. Orexin-corticotropin-releasing factor receptor heteromers in the ventral tegmental area as targets for cocaine.

    Science.gov (United States)

    Navarro, Gemma; Quiroz, César; Moreno-Delgado, David; Sierakowiak, Adam; McDowell, Kimberly; Moreno, Estefanía; Rea, William; Cai, Ning-Sheng; Aguinaga, David; Howell, Lesley A; Hausch, Felix; Cortés, Antonio; Mallol, Josefa; Casadó, Vicent; Lluís, Carme; Canela, Enric I; Ferré, Sergi; McCormick, Peter J

    2015-04-29

    Release of the neuropeptides corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced cocaine-seeking behavior. We provide evidence for pharmacologically significant interactions between CRF and orexin-A that depend on oligomerization of CRF1 receptor (CRF1R) and orexin OX1 receptors (OX1R). CRF1R-OX1R heteromers are the conduits of a negative crosstalk between orexin-A and CRF as demonstrated in transfected cells and rat VTA, in which they significantly modulate dendritic dopamine release. The cocaine target σ1 receptor (σ1R) also associates with the CRF1R-OX1R heteromer. Cocaine binding to the σ1R-CRF1R-OX1R complex promotes a long-term disruption of the orexin-A-CRF negative crosstalk. Through this mechanism, cocaine sensitizes VTA cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces cocaine seeking. Copyright © 2015 the authors 0270-6474/15/356639-15$15.00/0.

  17. Orexin–Corticotropin-Releasing Factor Receptor Heteromers in the Ventral Tegmental Area as Targets for Cocaine

    Science.gov (United States)

    Navarro, Gemma; Quiroz, César; Moreno-Delgado, David; Sierakowiak, Adam; McDowell, Kimberly; Moreno, Estefanía; Rea, William; Cai, Ning-Sheng; Aguinaga, David; Howell, Lesley A.; Hausch, Felix; Cortés, Antonio; Mallol, Josefa; Casadó, Vicent; Lluís, Carme; Canela, Enric I.

    2015-01-01

    Release of the neuropeptides corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced cocaine-seeking behavior. We provide evidence for pharmacologically significant interactions between CRF and orexin-A that depend on oligomerization of CRF1 receptor (CRF1R) and orexin OX1 receptors (OX1R). CRF1R–OX1R heteromers are the conduits of a negative crosstalk between orexin-A and CRF as demonstrated in transfected cells and rat VTA, in which they significantly modulate dendritic dopamine release. The cocaine target σ1 receptor (σ1R) also associates with the CRF1R–OX1R heteromer. Cocaine binding to the σ1R–CRF1R–OX1R complex promotes a long-term disruption of the orexin-A–CRF negative crosstalk. Through this mechanism, cocaine sensitizes VTA cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces cocaine seeking. PMID:25926444

  18. Role of perineuronal nets in the anterior dorsal lateral hypothalamic area in the acquisition of cocaine-induced conditioned place preference and self-administration.

    Science.gov (United States)

    Blacktop, Jordan M; Todd, Ryan P; Sorg, Barbara A

    2017-05-15

    Addiction involves drug-induced neuroplasticity in the circuitry of motivated behavior, which includes the medial forebrain bundle and the lateral hypothalamic area. Emerging at the forefront of neuroplasticity regulation are specialized extracellular matrix (ECM) structures that form perineuronal nets (PNNs) around certain neurons, mainly parvalbumin positive (PV + ), fast-spiking interneurons (FSINs), making them a promising target for the regulation of drug-induced neuroplasticity. Despite the emerging significance of PNNs in drug-induced neuroplasticity and the well-established role of the lateral hypothalamic area (LHA) in reward, reinforcement, and motivation, very little is known about how PNN-expressing neurons control drug-seeking behavior. We found that a discrete region of the anterior dorsal LHA (LHAad) exhibited robust PNN and dense ECM expression. Approximately 87% of parvalbumin positive (PV + ) neurons co-expressed the PNN marker Wisteria floribunda agglutinin (WFA), while 62% of WFA positive (WFA + ) neurons co-expressed PV in the LHAad of drug naïve rats. Removal of PNNs within this brain region via chrondroitinase ABC (Ch-ABC) administration abolished acquisition of cocaine-induced CPP and significantly attenuated the acquisition of cocaine self-administration (SA). Removal of LHAad PNNs did not affect locomotor activity, sucrose intake, sucrose-induced CPP, or acquisition of sucrose SA in separate groups of cocaine naïve animals. These data suggest that PNN-dependent neuroplasticity within the LHAad is critical for the acquisition of both cocaine-induced CPP and SA but is not general to all rewards, and that PNN degradation may have utility for the management of drug-associated behavioral plasticity and memory in cocaine addicts. Published by Elsevier Ltd.

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

    Science.gov (United States)

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

    2016-04-27

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

  20. Exposure to cocaine regulates inhibitory synaptic transmission from the ventral tegmental area to the nucleus accumbens.

    Science.gov (United States)

    Ishikawa, Masago; Otaka, Mami; Neumann, Peter A; Wang, Zhijian; Cook, James M; Schlüter, Oliver M; Dong, Yan; Huang, Yanhua H

    2013-10-01

    Synaptic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) make up the backbone of the brain reward pathway, a neural circuit that mediates behavioural responses elicited by natural rewards as well as by cocaine and other drugs of abuse. In addition to the well-known modulatory dopaminergic projection, the VTA also provides fast excitatory and inhibitory synaptic input to the NAc, directly regulating NAc medium spiny neurons (MSNs). However, the cellular nature of VTA-to-NAc fast synaptic transmission and its roles in drug-induced adaptations are not well understood. Using viral-mediated in vivo expression of channelrhodopsin 2, the present study dissected fast excitatory and inhibitory synaptic transmission from the VTA to NAc MSNs in rats. Our results suggest that, following repeated exposure to cocaine (15 mg kg(-1) day(-1) × 5 days, i.p., 1 or 21 day withdrawal), a presynaptic enhancement of excitatory transmission and suppression of inhibitory transmission occurred at different withdrawal time points at VTA-to-NAc core synapses. In contrast, no postsynaptic alterations were detected at either type of synapse. These results suggest that changes in VTA-to-NAc fast excitatory and inhibitory synaptic transmissions may contribute to cocaine-induced alteration of the brain reward circuitry.

  1. Neuropeptide Y Y5 receptor antagonism causes faster extinction and attenuates reinstatement in cocaine-induced place preference

    DEFF Research Database (Denmark)

    Sørensen, Gunnar; Wörtwein, Gitta; Fink-Jensen, Anders

    2013-01-01

    Several studies have suggested a role for neuropeptide Y (NPY) in addiction to drugs of abuse, including cocaine. Recently, our group showed a role for the NPY Y5 receptor in the modulation of acute reinforcing effects of cocaine using self-administration and hyperlocomotion paradigms....... In the present study, we further explored potential anti-addiction-related effects of Y5 antagonism in another murine model of cocaine addiction-related behavior: conditioned place-preference (CPP). Using this model, it was tested whether blockade or deficiency of the NPY Y5 receptor could influence...... the induction, extinction or reinstatement of a conditioned cocaine response. We found that the Y5 antagonist L-152,804 causes faster extinction and reduced reinstatement of cocaine-induced CPP but did not reduce the ability of cocaine to induce CPP. Similarly, Y5-KO mice displayed faster extinction...

  2. 5-HT3 receptor antagonist MDL 72222 attenuates cocaine- and mazindol-, but not methylphenidate-induced neurochemical and behavioral effects in the rat.

    Science.gov (United States)

    Kankaanpää, Aino; Meririnne, Esa; Seppälä, Timo

    2002-02-01

    It has previously been demonstrated that the 5-HT(3) receptors located in the mesolimbic brain areas are able to modulate the dopaminergic effects of various abused drugs, including cocaine (COC). The present experiments investigated the role of 5-HT(3) receptors in the actions of selected monoamine uptake inhibitors. The ability of the 5-HT(3) receptor antagonist MDL 72222 (MDL; 0.1 and 1.0 mg/kg) to modify the neurochemical and behavioral changes induced by COC (20 mg/kg), mazindol (MAZ; 10 mg/kg), and methylphenidate (MP; 5.0 or 10, and 20 mg/kg) was assessed with an in vivo microdialysis technique, a conditioned place preference method, and motor activity measurements. MDL robustly attenuated the elevation of extracellular dopamine levels in the nucleus accumbens, acquisition of place preference, and motor activity induced by COC and MAZ, but not those induced by MP, the only drug with no significant effect on 5-HT. In contrast, expression of COC-induced place preference was not attenuated by MDL. These results show that COC- and MAZ-induced reward-related neurochemical and behavioral effects, preferentially those implicated in development of conditioned reward, are modified by the 5-HT(3) blockade. In contrast to COC and MAZ, the changes induced by MP, which has less effect on the serotonergic system, remain unchanged. Thus it appears that involvement of a serotonergic component in the mechanism of action of a drug could be a prerequisite for effective antagonism by 5-HT(3) receptor blockers.

  3. NMDA receptor glycine modulatory site in the ventral tegmental area regulates the acquisition, retrieval, and reconsolidation of cocaine reward memory.

    Science.gov (United States)

    Zhou, Shuang-jiang; Xue, Li-fen; Wang, Xue-yi; Jiang, Wen-gao; Xue, Yan-xue; Liu, Jian-feng; He, Yin-yin; Luo, Yi-xiao; Lu, Lin

    2012-05-01

    Accumulating clinical and preclinical studies have shown that the memories of the rewarding effects of drugs and their paired cues may contribute to relapse and persistent cocaine use. Glutaminergic actions in the ventral tegmental area (VTA) have been shown to regulate the rewarding effect of drugs and conditioned responses to drug-associated cues, but the role of the VTA in the acquisition, retrieval, and reconsolidation of cocaine cues is not yet known. In the present study, we used 7-chlorothiokynurenic acid (7-CTKA), an N-methyl-D-aspartate (NMDA) receptor glycine modulatory site antagonist with no rewarding effects, to examine the role of the NMDA receptor glycine modulatory site in the acquisition, retrieval, and reconsolidation of cocaine-related reward memory using the conditioned place preference (CPP) paradigm. Separate groups of Sprague-Dawley rats were trained to acquire cocaine-induced CPP. Vehicle or 7-CTKA was microinjected into the VTA or substantia nigra (SN) (5 μg/μl) at different time points: 10 min before each CPP training session (acquisition), 10 min before the reactivation of CPP (retrieval), and immediately after the reactivation of CPP (reconsolidation). Cocaine-induced CPP was retested 24 h and 1 and 2 weeks after 7-CTKA administration. 7-CTKA microinjected into the VTA, but not SN, significantly impaired the acquisition, retrieval, and reconsolidation of cocaine-induced CPP without affecting cocaine-induced locomotion. Our findings suggest that the NMDA receptor glycine modulatory site in the VTA plays a major role in cocaine reward memory, and NMDA receptor glycine site antagonists may be potential pharmacotherapies for the management of relapse.

  4. Effect of cocaine on ion channels and glutamatergic EPSCs in noradrenergic locus coeruleus neurons.

    Science.gov (United States)

    Liu, L N; Zhu, F P; Song, M Y; Kang, X J; Shang, S J; Zhang, X Y; Xu, H D; Teng, S S; Liu, B; Kuo, S T; Liu, W; Li, M L; Zhou, L; Jiao, R Y; Wang, C H; Wang, S R; Yang, H; Zhang, B; Zhou, Z; Xu, Z Q D

    2014-07-01

    The locus coeruleus (LC) is an important brainstem area involved in cocaine addiction. However, evidence to elucidate how cocaine modulates the activity of LC neurons remains incomplete. Here, we performed whole recordings in brain slices to evaluate the effects of cocaine on the sodium (Na(+)), potassium (K(+)), calcium (Ca(2+)) channels, and glutamatergic synaptic transmission in the locus coeruleus neurons. Local application of cocaine significantly and reversibly reduced the spontaneous firing rate but did not affect action potential amplitude, rising time, decay time, or half width of noradrenergic locus coeruleus neurons. Moreover, cocaine attenuated the sodium current but did not affect potassium and calcium currents. The N-methyl-D-aspartate receptor mediated excitatory postsynaptic currents were reduced by neuropeptide galanin but not cocaine. All those data demonstrate that cocaine has inhibitory effect on the spontaneous activities and sodium current in locus coeruleus neurons. Therefore, neuromodulation of sodium channel in locus coeruleus neurons may play an important role in drug addiction.

  5. The selective dopamine D₃ receptor antagonist SB-277011A attenuates drug- or food-deprivation reactivation of expression of conditioned place preference for cocaine in male Sprague-Dawley rats.

    Science.gov (United States)

    Ashby, Charles R; Rice, Onarae V; Heidbreder, Christian A; Gardner, Eliot L

    2015-06-01

    We determined the effect of the selective dopamine D3 receptor antagonist SB-277011A on reactivation of conditioned place preference (CPP) to cocaine elicited by priming injections of cocaine or exposure to food deprivation stress (21 h) in male Sprague-Dawley rats. Animals paired with the cocaine-associated chamber displayed a robust and consistent CPP response. This CPP was extinguished after repeated pairings of the conditioned stimuli (cocaine-paired chamber contextual cues) in the absence of the unconditioned stimulus (cocaine). Twenty-four hours later, the administration of 5 mg kg(-1) i.p. of cocaine (immediately before the test) or exposure to 21 h of food deprivation reactivated the expression of the cocaine-induced CPP. In contrast, administration of 1 ml kg(-1) i.p. of vehicle did not reactivate the CPP response. Administration of the selective dopamine D3 receptor antagonist SB-277011A (3-24 mg kg(-1) i.p.) 30 min before cocaine administration on the test day produced a significant attenuation of CPP reactivation. Reactivation of the CPP response produced by food deprivation was also significantly attenuated by SB-277011A (6 or 12 mg kg(-1) i.p.) given 30 min before the test session. SB-277011A (12 or 24 mg kg(-1) i.p.) did not itself produce reactivation of the CPP response. Overall, these results suggest that the reactivation of the incentive value of drug-associated cues by cocaine or food deprivation is attenuated by selective antagonism of D3 receptors. © 2015 Wiley Periodicals, Inc.

  6. Genetic overexpressing of GPx-1 attenuates cocaine-induced renal toxicity via induction of anti-apoptotic factors.

    Science.gov (United States)

    Mai, Huynh Nhu; Jeong, Ji Hoon; Kim, Dae-Joong; Chung, Yoon Hee; Shin, Eun-Joo; Nguyen, Lan Thuy Ty; Nam, Yunsung; Lee, Yu Jeung; Cho, Eun-Hee; Nah, Seung-Yeol; Jang, Choon-Gon; Lei, Xin Gen; Kim, Hyoung-Chun

    2016-04-01

    The present study investigates the role of the glutathione peroxidase (GPx)-1 gene in cocaine-induced renal damage in mice. Multiple doses of cocaine increased lipid peroxidation, protein oxidation, and glutathione oxidation in the kidney of the non-transgenic mice (non-TG mice). The enzymatic activities of GPx and glutathione reductase were significantly decreased in non-TG mice, whereas superoxide dismutase was increased in the early phase of cocaine exposure. Treatment with cocaine resulted in significant decreases in expression of Bcl-2 and Bcl-xl in the kidney of non-TG mice, which resulted in significant increases in Bax and cleaved-caspase 3. Consistently, cocaine-induced tubular epithelial vacuolization and focal tubular necrosis were mainly observed in the proximal tubules in the kidneys of non-TG mice. These renal pathologic changes were much less pronounced in GPx-1 TG than in non-TG mice. These results suggest that the GPx-1 gene is a protective factor against nephrotoxicity induced by cocaine via interactive modulations between antioxidant and cell survival signaling processes. © 2016 John Wiley & Sons Australia, Ltd.

  7. Sensing cocaine in saliva with attenuated total reflection infrared (ATR-IR) spectroscopy combined with a one-step extraction method

    Science.gov (United States)

    Hans, Kerstin M.-C.; Gianella, Michele; Sigrist, Markus W.

    2012-03-01

    On-site drug tests have gained importance, e.g., for protecting the society from impaired drivers. Since today's drug tests are majorly only positive/negative, there is a great need for a reliable, portable and preferentially quantitative drug test. In the project IrSens we aim to bridge this gap with the development of an optical sensor platform based on infrared spectroscopy and focus on cocaine detection in saliva. We combine a one-step extraction method, a sample drying technique and infrared attenuated total reflection (ATR) spectroscopy. As a first step we have developed an extraction technique that allows us to extract cocaine from saliva to an almost infrared-transparent solvent and to record ATR spectra with a commercially available Fourier Transform-infrared spectrometer. To the best of our knowledge this is the first time that such a simple and easy-to-use one-step extraction method is used to transfer cocaine from saliva into an organic solvent and detect it quantitatively. With this new method we are able to reach a current limit of detection around 10 μg/ml. This new extraction method could also be applied to waste water monitoring and controlling caffeine content in beverages.

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

    International Nuclear Information System (INIS)

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

    2006-01-01

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

  9. Dose-dependent effectiveness of wheel running to attenuate cocaine-seeking: impact of sex and estrous cycle in rats.

    Science.gov (United States)

    Peterson, Alexis B; Hivick, Daniel P; Lynch, Wendy J

    2014-07-01

    Exercise has shown promise as an intervention for drug addiction; however, little is known regarding the exercise conditions that most effectively reduce relapse vulnerability and whether these conditions differ by sex. Here, we examined sex differences in the dose-dependent effects of wheel running, an animal model of exercise, during abstinence on subsequent cocaine-seeking. Male and female rats self-administered cocaine (1.5 mg/kg/infusion) under extended access conditions (24 h/day, 4 discrete trials/h) for 10 days. Rats were then given voluntary access to either an unlocked or locked running wheel for 1, 2, 6, or 24 h/day during the 14-day abstinence period. Separate groups of rats were housed in polycarbonate cages during abstinence to control for physical activity that the wheel may provide. Subsequent cocaine-seeking was assessed under a within-session extinction/cue-induced reinstatement procedure. Estrous cycle was monitored in females to determine whether the effectiveness of wheel running varied by estrous cycle phase. Although females ran more than males, males were more sensitive to the effects of running and showed a dose-dependent decrease in cocaine-seeking with longer access resulting in greater suppression. The dose-effect relationship was less straightforward in females and access to both a locked and unlocked wheel decreased cocaine-seeking with effects dependent on estrous cycle phase. Notably, extended (6 and 24 h/day), but not limited (1 and 2 h/day) access to a wheel surmounted the heightened vulnerability observed in females during estrus. Taken together, our findings suggest that the effectiveness of wheel running is dose-, sex-, and estrous cycle-dependent.

  10. Preventive role of social interaction for cocaine conditioned place preference: correlation with FosB/DeltaFosB and pCREB expression in rat mesocorticolimbic areas

    Directory of Open Access Journals (Sweden)

    Rana eEl Rawas

    2012-03-01

    Full Text Available The worsening of drug abuse by drug-associated social interaction is a well-studied phenomenon. In contrast, the molecular mechanisms of the beneficial effect of social interaction, if offered as a mutually exclusive choice to drugs of abuse, are under-investigated. In a rat place preference conditioning (CPP paradigm, four 15 min episodes of social interaction with a gender- and weight matched male early-adult conspecific inhibited cocaine-induced reinstatement of cocaine CPP, a model of relapse. These protective effects of social interaction were paralleled by a reduced activation, as assessed by Zif268 expression in brain areas known to play pivotal roles in drug-seeking behavior. Here we show that social interaction during extinction of cocaine CPP also reduced cocaine-CPP-stimulated FosB expression in the nucleus accumbens shell and core. In addition, social interaction during cocaine CPP extinction increased pCREB (cAMP response element binding protein expression in the nucleus accumbens shell and the cingulate cortex area 1 (Cg1. Our results show that FosB and pCREB may be implicated in the protective effect of social interaction against cocaine-induced reinstatement of CPP. Thus, social interaction, if offered in a context that is clearly distinct from the previously drug-associated one, may profoundly inhibit relapse to cocaine addiction.

  11. Morphine and cocaine increase serum- and glucocorticoid-inducible kinase 1 activity in the ventral tegmental area.

    Science.gov (United States)

    Heller, Elizabeth A; Kaska, Sophia; Fallon, Barbara; Ferguson, Deveroux; Kennedy, Pamela J; Neve, Rachael L; Nestler, Eric J; Mazei-Robison, Michelle S

    2015-01-01

    Drugs of abuse modulate the function and activity of the mesolimbic dopamine circuit. To identify novel mediators of drug-induced neuroadaptations in the ventral tegmental area (VTA), we performed RNA sequencing analysis on VTA samples from mice administered repeated saline, morphine, or cocaine injections. One gene that was similarly up-regulated by both drugs was serum- and glucocorticoid-inducible kinase 1 (SGK1). SGK1 activity, as measured by phosphorylation of its substrate N-myc downstream regulated gene (NDRG), was also increased robustly by chronic drug treatment. Increased NDRG phosphorylation was evident 1 but not 24 h after the last drug injection. SGK1 phosphorylation itself was similarly modulated. To determine the role of increased SGK1 activity on drug-related behaviors, we over-expressed constitutively active (CA) SGK1 in the VTA. SGK1-CA expression reduced locomotor sensitization elicited by repeated cocaine, but surprisingly had the opposite effect and promoted locomotor sensitization to morphine, without affecting the initial locomotor responses to either drug. SGK1-CA expression did not significantly affect morphine or cocaine conditioned place preference, although there was a trend toward increased conditioned place preference with both drugs. Further characterizing the role of this kinase in drug-induced changes in VTA may lead to improved understanding of neuroadaptations critical to drug dependence and addiction. We find that repeated, but not acute, morphine or cocaine administration induces an increase in serum- and glucocorticoid-inducible kinase (SGK1) gene expression and activity in the ventral tegmental area (VTA). This increase in SGK1 activity may play a role in drug-dependent behaviors and suggests a novel signaling cascade for potential intervention in drug dependence and addiction. © 2014 International Society for Neurochemistry.

  12. d-Cycloserine enhanced extinction of cocaine-induced conditioned place preference is attenuated in serotonin transporter knockout rats.

    Science.gov (United States)

    Karel, Peter; Calabrese, Francesca; Riva, Marco; Brivio, Paola; Van der Veen, Bas; Reneman, Liesbeth; Verheij, Michel; Homberg, Judith

    2018-01-01

    d-Cycloserine (DCS), a partial NMDA receptor agonist, has been proposed as a cognitive enhancer to facilitate the extinction of drug-related memories. However, it is unknown whether there are individual differences in the efficacy of DCS. Here, we set out to investigate the influence of serotonin transporter (5-HTT) genotype on DCS treatment outcome and the underlying neural mechanism. To that end, we first determined the mRNA levels of several NMDA receptor subunits and observed a reduction in NR1/NR2C receptors in the ventromedial prefrontal cortex and nucleus accumbens of 5-HTT -/- compared with 5-HTT +/+ rats. Based on this finding, we hypothesized a lower sensitivity to DCS in the 5-HTT -/- rats. To test this, rats were trained in a cocaine-induced conditioned place preference (CPP) paradigm. A significant extinction of CPP was observed in 5-HTT +/+ rats receiving 1 mg/kg i.v. DCS, while a similar effect was found in the 5-HTT -/- rats only after 5 mg/kg. Following CPP, we tested if DCS were able to reduce FosB/∆FosB protein expression, a molecular switch for cocaine-seeking behaviour. We observed an overall lower number of FosB/∆FosB positive cells in 5-HTT -/- ventromedial prefrontal cortex and amygdala and an overall effect of DCS treatment on the number of positive cells in the nucleus accumbens. In conclusion, in this study, we show that the dosing of DCS to facilitate the extinction of cocaine-seeking behaviour is, at least partially, determined by 5-HTT genotype. © 2016 Society for the Study of Addiction.

  13. Norepinephrine regulates cocaine-primed reinstatement via α1-adrenergic receptors in the medial prefrontal cortex.

    Science.gov (United States)

    Schmidt, Karl T; Schroeder, Jason P; Foster, Stephanie L; Squires, Katherine; Smith, Brilee M; Pitts, Elizabeth G; Epstein, Michael P; Weinshenker, David

    2017-06-01

    Drug-primed reinstatement of cocaine seeking in rats is thought to reflect relapse-like behavior and is mediated by the integration of signals from mesocorticolimbic dopaminergic projections and corticostriatal glutamatergic innervation. Cocaine-primed reinstatement can also be attenuated by systemic administration of dopamine β-hydroxylase (DBH) inhibitors, which prevent norepinephrine (NE) synthesis, or by α1-adrenergic receptor (α1AR) antagonists, indicating functional modulation by the noradrenergic system. In the present study, we sought to further discern the role of NE in cocaine-seeking behavior by determining whether α1AR activation can induce reinstatement on its own or is sufficient to permit cocaine-primed reinstatement in the absence of all other AR signaling, and identifying the neuroanatomical substrate within the mesocorticolimbic reward system harboring the critical α1ARs. We found that while intracerebroventricular infusion of the α1AR agonist phenylephrine did not induce reinstatement on its own, it did overcome the blockade of cocaine-primed reinstatement by the DBH inhibitor nepicastat. Furthermore, administration of the α1AR antagonist terazosin in the medial prefrontal cortex (mPFC), but not the ventral tegmental area (VTA) or nucleus accumbens (NAc) shell, attenuated cocaine-primed reinstatement. Combined, these data indicate that α1AR activation in the mPFC is required for cocaine-primed reinstatement, and suggest that α1AR antagonists merit further investigation as pharmacotherapies for cocaine dependence. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    Leong, Kah-Chung; Zhou, Luyi; Ghee, Shannon M; See, Ronald E; Reichel, Carmela M

    2016-02-01

    Oxytocin has been shown to decrease cocaine taking and seeking in male rats, suggesting potential treatment efficacy for drug addiction. In the present study, we extended these findings to the assessment of cocaine seeking and taking in female rats. Further, we made direct comparisons of oxytocin's impact on cocaine induced locomotor activity in both males and females. In females, systemic oxytocin (0.3, 1.0, 3.0 mg/kg) attenuated lever pressing for cocaine during self-administration and oxytocin (1.0 mg/kg) attenuated cue-induced cocaine seeking following extinction. Cocaine increased baseline locomotor activity to a greater degree in females relative to males. Oxytocin (0.1, 0.3, 1.0, and 3.0 mg/kg) reduced cocaine-induced locomotor activity in females, but not significantly in males. These data illustrate sex similarities in oxytocin's attenuation of cocaine seeking, but sex differences in cocaine-induced locomotor effects. While reductions in cocaine seeking cannot be attributed to a reduction in locomotor activity in males, attenuation of locomotor function cannot be entirely ruled out as an explanation for a decrease in cocaine seeking in females suggesting that oxytocin's effect on cocaine seeking may be mediated by different mechanisms in male and females. PsycINFO Database Record (c) 2016 APA, all rights reserved.

  15. Attenuation of Cocaine-Induced Conditioned Place Preference and Motor Activity via Cannabinoid CB2 Receptor Agonism and CB1 Receptor Antagonism in Rats

    Science.gov (United States)

    Delis, Foteini; Polissidis, Alexia; Poulia, Nafsika; Justinova, Zuzana; Nomikos, George G.; Goldberg, Steven R.

    2017-01-01

    Abstract Background: Studies have shown the involvement of cannabinoid (CB) receptors in the behavioral and neurobiological effects of psychostimulants. Most of these studies have focused on the role of CB1 receptors in the psychostimulant effects of cocaine, while very few have investigated the respective role of CB2 receptors. Further studies are warranted to elucidate the extent of CB receptor involvement in the expression of cocaine-induced effects. Methods: The role of CB1 and CB2 receptors in the rewarding and motor properties of cocaine was assessed in conditioned place preference, conditioned motor activity, and open field activity in rats. Results: The CB1 receptor antagonist rimonabant (3 mg/kg) decreased the acquisition and the expression of conditioned place preference induced by cocaine (20 mg/kg). Rimonabant inhibited cocaine-elicited conditioned motor activity when administered during the expression of cocaine-induced conditioned place preference. Rimonabant decreased ambulatory and vertical activity induced by cocaine. The CB2 receptor agonist JWH-133 (10 mg/kg) decreased the acquisition and the expression of cocaine-induced conditioned place preference. JWH-133 inhibited cocaine-elicited conditioned motor activity when administered during the acquisition and the expression of cocaine-induced conditioned place preference. JWH-133 decreased ambulatory activity and abolished vertical activity induced by cocaine. The effects of JWH-133 on cocaine conditioned and stimulated responses were abolished when the CB2 receptor antagonist/inverse agonist AM630 (5 mg/kg) was preadministered. Conclusions: Cannabinoid CB1 and CB2 receptors modulate cocaine-induced rewarding behavior and appear to have opposite roles in the regulation of cocaine’s reinforcing and psychomotor effects. PMID:27994006

  16. Episodic Social Stress-Escalated Cocaine Self-Administration: Role of Phasic and Tonic Corticotropin Releasing Factor in the Anterior and Posterior Ventral Tegmental Area

    Science.gov (United States)

    Boyson, Christopher O.; Montagud-Romero, Sandra; Stein, Dirson J.; Gobrogge, Kyle L.; DeBold, Joseph F.; Miczek, Klaus A.

    2016-01-01

    Intermittent social defeat stress escalates later cocaine self-administration. Reward and stress both activate ventral tegmental area (VTA) dopamine neurons, increasing downstream extracellular dopamine concentration in the medial prefrontal cortex and nucleus accumbens. The stress neuropeptide corticotropin releasing factor (CRF) and its receptors (CRF-R1, CRF-R2) are located in the VTA and influence dopaminergic activity. These experiments explore how CRF release and the activation of its receptors within the VTA both during and after stress influence later cocaine self-administration in rats. In vivo microdialysis of CRF in the VTA demonstrated that CRF is phasically released in the posterior VTA (pVTA) during acute defeat, but, with repeated defeat, CRF is recruited into the anterior VTA (aVTA) and CRF tone is increased in both subregions. Intra-VTA antagonism of CRF-R1 in the pVTA and CRF-R2 in the aVTA during each social defeat prevented escalated cocaine self-administration in a 24 h “binge.” VTA CRF continues to influence cocaine seeking in stressed animals long after social defeat exposure. Unlike nonstressed controls, previously stressed rats show significant cocaine seeking after 15 d of forced abstinence. Previously stressed rats continue to express elevated CRF tone within the VTA and antagonism of pVTA CRF-R1 or aVTA CRF-R2 reverses cocaine seeking. In conclusion, these experiments demonstrate neuroadaptive changes in tonic and phasic CRF with repeated stress, that CRF release during stress may contribute to later escalated cocaine taking, and that persistently elevated CRF tone in the VTA may drive later cocaine seeking through increased activation of pVTA CRF-R1 and aVTA CRF-R2. SIGNIFICANCE STATEMENT Corticotropin releasing factor (CRF) within the ventral tegmental area (VTA) has emerged as a likely candidate molecule underlying the fundamental link between stress history and escalated drug self-administration. However, the nature of CRF

  17. 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.

  18. Attenuation and source properties at the Coso Geothermal area, California

    Science.gov (United States)

    Hough, S.E.; Lees, J.M.; Monastero, F.

    1999-01-01

    We use a multiple-empirical Green's function method to determine source properties of small (M -0.4 to 1.3) earthquakes and P- and S-wave attenuation at the Coso Geothermal Field, California. Source properties of a previously identified set of clustered events from the Coso geothermal region are first analyzed using an empirical Green's function (EGF) method. Stress-drop values of at least 0.5-1 MPa are inferred for all of the events; in many cases, the corner frequency is outside the usable bandwidth, and the stress drop can only be constrained as being higher than 3 MPa. P- and S-wave stress-drop estimates are identical to the resolution limits of the data. These results are indistinguishable from numerous EGF studies of M 2-5 earthquakes, suggesting a similarity in rupture processes that extends to events that are both tiny and induced, providing further support for Byerlee's Law. Whole-path Q estimates for P and S waves are determined using the multiple-empirical Green's function (MEGF) method of Hough (1997), whereby spectra from clusters of colocated events at a given station are inverted for a single attenuation parameter, ??, with source parameters constrained from EGF analysis. The ?? estimates, which we infer to be resolved to within 0.01 sec or better, exhibit almost as much scatter as a function of hypocentral distance as do values from previous single-spectrum studies for which much higher uncertainties in individual ?? estimates are expected. The variability in ?? estimates determined here therefore suggests real lateral variability in Q structure. Although the ray-path coverage is too sparse to yield a complete three-dimensional attenuation tomographic image, we invert the inferred ?? value for three-dimensional structure using a damped least-squares method, and the results do reveal significant lateral variability in Q structure. The inferred attenuation variability corresponds to the heat-flow variations within the geothermal region. A central low

  19. The Cardiovascular Effects of Cocaine.

    Science.gov (United States)

    Havakuk, Ofer; Rezkalla, Shereif H; Kloner, Robert A

    2017-07-04

    Cocaine is the leading cause for drug-abuse-related visits to emergency departments, most of which are due to cardiovascular complaints. Through its diverse pathophysiological mechanisms, cocaine exerts various adverse effects on the cardiovascular system, many times with grave results. Described here are the varied cardiovascular effects of cocaine, areas of controversy, and therapeutic options. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  20. Transcriptomic profiling of the ventral tegmental area and nucleus accumbens in rhesus macaques following long-term cocaine self-administration.

    Science.gov (United States)

    Vallender, Eric J; Goswami, Dharmendra B; Shinday, Nina M; Westmoreland, Susan V; Yao, Wei-Dong; Rowlett, James K

    2017-06-01

    The behavioral consequences associated with addiction are thought to arise from drug-induced neuroadaptation. The mesolimbic system plays an important initial role in this process, and while the dopaminergic system specifically has been strongly interrogated, a complete understanding of the broad transcriptomic effects associated with cocaine use remains elusive. Using next generation sequencing approaches, we performed a comprehensive evaluation of gene expression differences in the ventral tegmental area and nucleus accumbens of rhesus macaques that had self-administered cocaine for roughly 100days and saline-yoked controls. During self-administration, the monkeys increased daily consumption of cocaine until almost the maximum number of injections were taken within the first 15min of the one hour session for a total intake of 3mg/kg/day. We confirm the centrality of dopaminergic differences in the ventral tegmental area, but in the nucleus accumbens we see the strongest evidence for an inflammatory response and large scale chromatin remodeling. These findings suggest an expanded understanding of the pathology of cocaine addiction with the potential to lead to the development of alternative treatment strategies. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Contrasting the Role of xCT and GLT-1 Upregulation in the Ability of Ceftriaxone to Attenuate the Cue-Induced Reinstatement of Cocaine Seeking and Normalize AMPA Receptor Subunit Expression.

    Science.gov (United States)

    LaCrosse, Amber L; O'Donovan, Sinead M; Sepulveda-Orengo, Marian T; McCullumsmith, Robert E; Reissner, Kathryn J; Schwendt, Marek; Knackstedt, Lori A

    2017-06-14

    Long-term treatment with ceftriaxone attenuates the reinstatement of cocaine seeking while increasing the function of the glutamate transporter 1 (GLT-1) and system xC- (Sxc) in the nucleus accumbens core (NAc). Sxc contributes the majority of nonsynaptic extracellular glutamate in the NAc, while GLT-1 is responsible for the majority of glutamate uptake. Here we used antisense to decrease the expression of GLT-1 and xCT (a catalytic subunit of Sxc) to determine the relative importance of both proteins in mediating the ability of ceftriaxone to prevent cue-induced reinstatement of cocaine seeking and normalize glutamatergic proteins in the NAc of rats. Intra-NAc xCT knockdown prevented ceftriaxone from attenuating reinstatement and from upregulating GLT-1 and resulted in increased surface expression of AMPA receptor subunits GluA1 and GluA2. Intra-NAc GLT-1 knockdown also prevented ceftriaxone from attenuating reinstatement and from upregulating xCT expression, without affecting GluA1 and GluA2 expression. In the absence of cocaine or ceftriaxone treatment, xCT knockdown in the NAc increased the expression of both GluA1 and GluA2 without affecting GLT-1 expression while GLT-1 knockdown had no effect. PCR and immunoprecipitation of GLT-1 revealed that ceftriaxone does not upregulate GLT-1 and xCT through a transcriptional mechanism, and their coregulation by ceftriaxone is not mediated by physical interaction. These data support important and distinct roles for xCT and GLT-1 in the actions of ceftriaxone and add to a body of literature finding evidence for coregulation of these transporters. Our results also point to xCT expression and subsequent basal glutamate levels as being a key mediator of AMPA receptor expression in the NAc. SIGNIFICANCE STATEMENT Ceftriaxone attenuates the reinstatement of cocaine, alcohol, and heroin seeking. The mechanism of action of this behavioral effect has been attributed to glutamate transporter 1 (GLT-1) and xCT (a catalytic subunit

  2. Subsurface Contaminant Focus Area: Monitored Natural Attenuation (MNA)--Programmatic, Technical, and Regulatory Issues

    Energy Technology Data Exchange (ETDEWEB)

    Krupka, Kenneth M.; Martin, Wayne J.

    2001-07-23

    Natural attenuation processes are commonly used for remediation of contaminated sites. A variety of natural processes occur without human intervention at all sites to varying rates and degrees of effectiveness to attenuate (decrease) the mass, toxicity, mobility, volume, or concentration of organic and inorganic contaminants in soil, groundwater, and surface water systems. The objective of this review is to identify potential technical investments to be incorporated in the Subsurface Contaminant Focus Area Strategic Plan for monitored natural attenuation. When implemented, the technical investments will help evaluate and implement monitored natural attenuation as a remediation option at DOE sites. The outcome of this review is a set of conclusions and general recommendations regarding research needs, programmatic guidance, and stakeholder issues pertaining to monitored natural attenuation for the DOE complex.

  3. Assessment of Hexavalent Chromium Natural Attenuation for the Hanford Site 100 Area

    Energy Technology Data Exchange (ETDEWEB)

    Truex, Michael J. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Szecsody, James E. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Qafoku, Nikolla P. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Sahajpal, Rahul [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Zhong, Lirong [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Lawter, Amanda R. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Lee, Brady D. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

    2015-09-01

    Hexavalent chromium (Cr(VI)) plumes are present in the 100 Area at the Hanford Site. Remediation efforts are under way with objectives of restoring the groundwater to meet the drinking-water standard (48 µg/L) and protecting the Columbia River by ensuring that discharge of groundwater to the river is below the surface-water quality standard (10 µg/L). Current remedies include application of Pump-and-Treat (P&T) at the 100-D, 100-H, and 100-K Areas and Monitored Natural Attenuation (MNA) at the 100-F/IU Area. Remedy selection is still under way at the other 100 Areas. Additional information about the natural attenuation processes for Cr(VI) is important in all of these cases. In this study, laboratory experiments were conducted to demonstrate and quantify natural attenuation mechanisms using 100 Area sediments and groundwater conditions.

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

    Science.gov (United States)

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

    2017-05-01

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

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

    Science.gov (United States)

    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. Copyright © 2015 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    2017-09-01

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

  7. Cocaine (Coke, Crack) Facts

    Science.gov (United States)

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

  8. Drug smuggling using clothing impregnated with cocaine.

    Science.gov (United States)

    McDermott, Seán D; Power, John D

    2005-11-01

    A case study is presented where a woman travelling from South America to the Republic of Ireland was detained at Dublin Airport and articles of clothing she had in her luggage were found to be impregnated with cocaine. The study shows that the amount of powder recovered from the garments was approximately 14% of the total weight of the garments. The cocaine was in the form of cocaine hydrochloride and the purity was approximately 80%. An examination of the garments under filtered light highlighted the areas exposed to cocaine and indicated that the method of impregnation was by pouring liquid containing cocaine onto the clothing.

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

    OpenAIRE

    Leong, Kah-Chung; Zhou, Luyi; Ghee, Shannon M.; See, Ronald E.; Reichel, Carmela M.

    2016-01-01

    Oxytocin has been shown to decrease cocaine taking and seeking in male rats, suggesting potential treatment efficacy for drug addiction. In the present study, we extended these findings to the assessment of cocaine seeking and taking in female rats. Further, we made direct comparisons of oxytocin’s impact on cocaine induced locomotor activity in both males and females. In females, systemic oxytocin (0.3, 1.0, 3.0 mg/kg) attenuated lever pressing for cocaine during self-administration and oxyt...

  10. Elevated expression of serotonin 5-HT2A receptors in the rat ventral tegmental area enhances vulnerability to the behavioral effects of cocaine

    Directory of Open Access Journals (Sweden)

    David V. Herin

    2013-02-01

    Full Text Available The dopamine mesocorticoaccumbens pathway which originates in the ventral tegmental area (VTA and projects to the nucleus accumbens and prefrontal cortex is a circuit important in mediating the actions of psychostimulants. The function of this circuit is modulated by the actions of serotonin (5-HT at 5-HT2A receptors (5-HT2AR localized to the VTA. In the present study, we tested the hypothesis that virally-mediated overexpression of 5-HT2AR in the VTA would increase cocaine-evoked locomotor activity in the absence of alterations in basal locomotor activity. A plasmid containing the gene for the 5-HT2AR linked to a synthetic marker peptide (Flag was created and the construct was packaged in an adeno-associated virus vector (rAAV-5-HT2AR-Flag. This viral vector (2 µl; 109-10 transducing units/ml was unilaterally infused into the VTA of male rats, while control animals received an intra-VTA infusion of Ringer’s solution. Virus-pretreated rats exhibited normal spontaneous locomotor activity measured in a modified open-field apparatus at 7, 14, and 21 days following infusion. After an injection of cocaine (15 mg/kg, ip, both horizontal hyperactivity and rearing were significantly enhanced in virus-treated rats (p<0.05. Immunohistochemical analysis confirmed expression of Flag and overexpression of the 5-HT2AR protein. These data indicate that the vulnerability of adult male rats to hyperactivity induced by cocaine is enhanced following increased levels of expression of the 5-HT2AR in the VTA and suggest that the 5-HT2AR receptor in the VTA plays a role in regulation of responsiveness to cocaine.

  11. Ceftriaxone attenuates acquisition and facilitates extinction of cocaine-induced suppression of saccharin intake in C57BL/6J mice.

    Science.gov (United States)

    Freet, Christopher S; Lawrence, Antoneal L

    2015-10-01

    Growing evidence implicates glutamate homeostasis in a number of behaviors observed in addiction such as acquisition of drug taking, motivation, and reinstatement. To date, however, the role of glutamate homeostasis in the avoidance of natural rewards due to exposure to drugs of abuse has received little attention. The aim of the current study was to evaluate the beta-lactam antibiotic, ceftriaxone, which has been shown to normalize disrupted glutamate homeostasis associated with exposure to drugs of abuse, in cocaine-induced suppression of saccharin intake in C57BL/6J mice. Briefly, C57BL/6J mice received daily injections of either 200mg/kg ceftriaxone or saline. Mice were then given access to 0.15% saccharin for 1h and immediately injected intraperitoneally with either saline or 30 mg/kg cocaine; taste-drug pairings occurred every 24h for 5 trials followed by a final CS only trial. One week following taste-drug pairings, extinction was evaluated in a series of one- and two-bottle saccharin intake tests. Individual differences in cocaine-induced suppression were observed (i.e., low and high suppressors) with differential effects of ceftriaxone. Ceftriaxone delayed suppression of saccharin intake in high suppressors but prevented suppression in low suppressors. In addition, ceftriaxone history facilitated extinction in the high suppressors. These data suggest that changes in glutamate homeostasis may be involved in the formation and expression of cocaine-induced suppression of saccharin intake in mice. Copyright © 2015. Published by Elsevier Inc.

  12. Criminal justice involvement of crack cocaine users in the city of Rio de Janeiro and Greater Metropolitan Area: Implications for public health and the public security agenda.

    Science.gov (United States)

    Toledo, Lidiane; Cano, Ignácio; Bastos, Leonardo; Bertoni, Neilane; Bastos, Francisco Inacio

    2017-11-01

    The international literature has expressed different and sometimes contrasting perspectives when addressing criminal involvement by crack cocaine users, highlighting psychopharmacological aspects, the cycles of craving and pressing economic need, and the interplay with overall deprivation and structural violence. The current study aims to identify variables associated with the arrest and imprisonment of regular crack cocaine users. Interviewees were recruited from open drug scenes in the city of Rio de Janeiro and Greater Metropolitan Area from September 2011 to June 2013. Multilevel logistic regression models were fitted to the data. Most of the recruited crack cocaine users were male (78.2% [95%CI: 76.3-79.4]), 18-30 years old (64.7% [95%CI: 62.5-66.2]), non-white (92.9% [95%CI: 91.2-93.4]), single (68.9% [95%CI: 66.8-70.3]), and with 0-7 years of schooling (70.6% [95%CI: 68.5-71.9]). Factors independently associated with arrest were history of inpatient addiction treatment (adjOR 4.31 [95%CI: 1.70-11.32]); male gender (adjOR 2.05 [95%CI: 1.40-3.04); polydrug use (adjOR 1.82 [95%CI: 1.32-2.51]); and 0 to 7 years of schooling (adjOR 1.64 [95%CI: 1.17-2.32]). As for the outcome variable lifetime history of incarceration, the independently associated factors were: male gender (adjOR 2.47 [95%CI: 1.74-3.55]) and longer use of crack cocaine and related substances (e.g., free base and local varieties/denominations of coca products) (adjOR 1.05 [95%CI: 1.01-1.10]). The study's findings support the use of comprehensive multisector interventions, integrating health promotion and mental health rehabilitation, access to quality education, and management of combined/concomitant use of different substances to reduce and/or prevent criminal involvement by individuals that use crack cocaine and other substances, as well as to prevent/manage relapse. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

  13. High Attenuation Areas on Chest CT in Community-Dwelling Adults: The MESA Study

    Science.gov (United States)

    Podolanczuk, Anna J.; Oelsner, Elizabeth C.; Barr, R. Graham; Hoffman, Eric A.; Armstrong, Hilary F.; Austin, John H.M.; Basner, Robert C.; Bartels, Matthew N.; Christie, Jason D.; Enright, Paul L.; Gochuico, Bernadette R.; Stukovsky, Karen Hinckley; Kaufman, Joel D.; Nath, P. Hrudaya; Newell, John D.; Palmer, Scott M.; Rabinowitz, Dan; Raghu, Ganesh; Sell, Jessica L.; Sieren, Jered; Sonavane, Sushil K.; Tracy, Russell P.; Watts, Jubal R.; Williams, Kayleen; Kawut, Steven M.; Lederer, David J.

    2016-01-01

    Evidence suggests that lung injury, inflammation and extracellular matrix remodeling precede lung fibrosis in interstitial lung disease (ILD). We examined whether a quantitative measure of increased lung attenuation on computed tomography (CT) detects lung injury, inflammation and extracellular matrix remodeling in community-dwelling adults sampled without regard to respiratory symptoms or smoking. We measured high attenuation areas (HAA; percentage of lung voxels between -600 and -250 Hounsfield Units) on cardiac CT scans of adults enrolled in the Multi-Ethnic Study of Atherosclerosis. HAA was associated with higher serum matrix metalloproteinase-7 (mean adjusted difference 6.3% per HAA doubling, 95% CI 1.3 to 11.5), higher interleukin-6 (mean adjusted difference 8.8%, 95% CI 4.8 to 13.0), lower forced vital capacity (mean adjusted difference -82 mL, 95% CI -119 to -44), lower 6-minute walk distance (mean adjusted difference -40 m, 95% CI -1 to -80), higher odds of interstitial lung abnormalities at 9.5 years (adjusted OR 1.95, 95% CI 1.43 to 2.65), and higher all cause-mortality rate over 12.2 years (HR 1.58, 95% CI 1.39 to 1.79). High attenuation areas are associated with biomarkers of inflammation and extracellular matrix remodeling, reduced lung function, interstitial lung abnormalities, and a higher risk of death among community-dwelling adults. PMID:27471206

  14. High attenuation areas on chest computed tomography in community-dwelling adults: the MESA study.

    Science.gov (United States)

    Podolanczuk, Anna J; Oelsner, Elizabeth C; Barr, R Graham; Hoffman, Eric A; Armstrong, Hilary F; Austin, John H M; Basner, Robert C; Bartels, Matthew N; Christie, Jason D; Enright, Paul L; Gochuico, Bernadette R; Hinckley Stukovsky, Karen; Kaufman, Joel D; Hrudaya Nath, P; Newell, John D; Palmer, Scott M; Rabinowitz, Dan; Raghu, Ganesh; Sell, Jessica L; Sieren, Jered; Sonavane, Sushil K; Tracy, Russell P; Watts, Jubal R; Williams, Kayleen; Kawut, Steven M; Lederer, David J

    2016-11-01

    Evidence suggests that lung injury, inflammation and extracellular matrix remodelling precede lung fibrosis in interstitial lung disease (ILD). We examined whether a quantitative measure of increased lung attenuation on computed tomography (CT) detects lung injury, inflammation and extracellular matrix remodelling in community-dwelling adults sampled without regard to respiratory symptoms or smoking.We measured high attenuation areas (HAA; percentage of lung voxels between -600 and -250 Hounsfield Units) on cardiac CT scans of adults enrolled in the Multi-Ethnic Study of Atherosclerosis.HAA was associated with higher serum matrix metalloproteinase-7 (mean adjusted difference 6.3% per HAA doubling, 95% CI 1.3-11.5), higher interleukin-6 (mean adjusted difference 8.8%, 95% CI 4.8-13.0), lower forced vital capacity (FVC) (mean adjusted difference -82 mL, 95% CI -119--44), lower 6-min walk distance (mean adjusted difference -40 m, 95% CI -1--80), higher odds of interstitial lung abnormalities at 9.5 years (adjusted OR 1.95, 95% CI 1.43-2.65), and higher all cause-mortality rate over 12.2 years (HR 1.58, 95% CI 1.39-1.79).High attenuation areas are associated with biomarkers of inflammation and extracellular matrix remodelling, reduced lung function, interstitial lung abnormalities, and a higher risk of death among community-dwelling adults. Copyright ©ERS 2016.

  15. Multiple faces of BDNF in cocaine addiction.

    Science.gov (United States)

    Li, Xuan; Wolf, Marina E

    2015-02-15

    Brain-derived neurotrophic factor (BDNF) has been found to play roles in many types of plasticity including drug addiction. Here, we focus on rodent studies over the past two decades that have demonstrated diverse roles of BDNF in models of cocaine addiction. First, we will provide an overview of studies showing that cocaine exposure alters (and generally increases) BDNF levels in reward-related regions including the ventral tegmental area, nucleus accumbens, prefrontal cortex, and amygdala. Then we will review evidence that BDNF contributes to behavioral changes in animal models of cocaine addiction, focusing on conditioned place preference, behavioral sensitization, maintenance and reinstatement of self-administration, and incubation of cocaine craving. Last, we will review the role of BDNF in synaptic plasticity, particularly as it relates to plasticity of AMPA receptor transmission after cocaine exposure. We conclude that BDNF regulates cocaine-induced behaviors in a highly complex manner that varies depending on the brain region (and even among different cell types within the same brain region), the nature of cocaine exposure, and the "addiction phase" examined (e.g., acquisition vs maintenance; early vs late withdrawal). These complexities make BDNF a daunting therapeutic target for treating cocaine addiction. However, recent clinical evidence suggests that the serum BDNF level may serve as a biomarker in cocaine addicts to predict future relapse, providing an alternative direction for exploring BDNF's potential relevance to treating cocaine addiction. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Alpha 2A adrenergic receptor agonist, guanfacine, attenuates cocaine-related impairments of inhibitory response control and working memory in animal models

    OpenAIRE

    Terry, Alvin V.; Callahan, Patrick M.; Schade, Rosann; Kille, Nancy J.; Plagenhoef, Marc

    2014-01-01

    There is considerable evidence that centrally acting α2A adrenergic receptor agonists can attenuate impairments in executive function that result from dysfunction of the prefrontal cortex. Such positive effects resulted in the recent approval by the United States Food and Drug Administration (FDA) of the α2A agonists clonidine and guanfacine for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD), but also suggest that they could have beneficial effects in substance abuse disorde...

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

    Science.gov (United States)

    Reed, Stephanie Collins; Evans, Suzette M.

    2016-01-01

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

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

    Science.gov (United States)

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

    2013-02-01

    responses were attenuated by modafinil, mainly due to decreases in cue- reactivity in reward-related brain areas (VTA) and increases in cue reactivity in cognitive control areas (ACC). These modafinil-induced changes in brain activation in response to cocaine-related visual stimuli were associated with diminished self-reported craving. These findings imply that in cocaine dependent patients, modafinil, although mainly known as a cognitive enhancer, acts on both the motivational and the cognitive brain circuitry. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Cocaine and Psychiatric Symptoms.

    Science.gov (United States)

    Morton, W Alexander

    1999-08-01

    BACKGROUND: Cocaine is an addictive drug that produces numerous psychiatric symptoms, syndromes, and disorders. The symptoms include agitation, paranoia, hallucinations, delusions, violence, as well as suicidal and homicidal thinking. They can be primary to the drug's effect or secondary to exacerbation of comorbid psychiatric disorders. DATA SOURCES: A computerized literature search was conducted using MEDLINE to identify reports of psychiatric symptoms secondary to cocaine use. Additional reports were found via bibliographies of various published reports. DATA SYNTHESIS: The use of cocaine in the "crack" form is often associated with more frequent and intense symptoms. Paranoia occurs in 68% to 84% of patients using cocaine. Cocaine-related violent behaviors occur in as many as 55% of patients with cocaine-induced psychiatric symptoms. Homicide has also been associated with cocaine use in as many as 31% of homicide victims. In suicide, cocaine has been found to be present in as high as 18% to 22% of cases. Many patients with cocaine dependence have also been found to have a comorbid psychiatric disorder. CONCLUSION: Cocaine can produce a spectrum of psychiatric symptoms with which primary care practitioners need to be familiar. Comorbid psychiatric disorders are frequent in patients with cocaine use disorders and can worsen with cocaine use. Nonaddictive medication may be necessary to treat comorbid conditions such as anxiety and depressive disorders. Primary care practitioners need to be familiar with the treatment programs for patients with cocaine use disorders so appropriate referral can easily take place and follow-up care can be understood and maintained.

  20. Transcranial direct current stimulation of the frontal-parietal-temporal area attenuates smoking behavior.

    Science.gov (United States)

    Meng, Zhiqiang; Liu, Chang; Yu, Chengyang; Ma, Yuanye

    2014-07-01

    Many brain regions are involved in smoking addiction (e.g. insula, ventral tegmental area, prefrontal cortex and hippocampus), and the manipulation of the activity of these brain regions can show a modification of smoking behavior. Low current transcranial direct current stimulation (tDCS) is a noninvasive way to manipulate cortical excitability, and thus brain function and associated behaviors. In this study, we examined the effects of inhibiting the frontal-parietal-temporal association area (FPT) on attention bias to smoking-related cues and smoking behavior in tobacco users. This inhibition is induced by cathodal tDCS stimulation. We tested three stimulation conditions: 1) bilateral cathodal over both sides of FPT; 2) cathodal over right FPT; and 3) sham-tDCS. Visual attention bias to smoking-related cues was evaluated using an eye tracking system. The measurement for smoking behavior was the number of daily cigarettes consumed before and after tDCS treatment. We found that, after bilateral cathodal stimulation of the FPT area, while the attention to smoking-related cues showed a decreased trend, the effects were not significantly different from sham stimulation. The daily cigarette consumption was reduced to a significant level. These effects were not seen under single cathodal tDCS or sham-tDCS. Our results show that low current tDCS of FPT area attenuates smoking cue-related attention and smoking behavior. This non-invasive brain stimulation technique, targeted at FPT areas, might be a promising method for treating smoking behavior. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Oxytocin Reduces Cocaine Seeking and Reverses Chronic Cocaine-Induced Changes in Glutamate Receptor Function

    Science.gov (United States)

    Zhou, Luyi; Sun, Wei-Lun; Young, Amy B.; Lee, Kunhee; McGinty, Jacqueline F.

    2015-01-01

    Background: Oxytocin, a neurohypophyseal neuropeptide, is a potential mediator and regulator of drug addiction. However, the cellular mechanisms of oxytocin in drug seeking remain unknown. Methods: In the present study, we used a self-administration/reinstatement model to study the effects of oxytocin on cocaine seeking and its potential interaction with glutamate function at the receptor level. Results: Systemic oxytocin dose-dependently reduced cocaine self-administration during various schedules of reinforcement, including fixed ratio 1, fixed ratio 5, and progressive ratio. Oxytocin also attenuated reinstatement to cocaine seeking induced by cocaine prime or conditioned cues. Western-blot analysis indicated that oxytocin increased phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor GluA1 subunit at the Ser 845 site with or without accompanying increases in phosphorylation of extracellular signal-regulated kinase, in several brain regions, including the prefrontal cortex, bed nucleus of the stria terminalis, amygdala, and dorsal hippocampus. Immunoprecipitation of oxytocin receptor and GluA1 subunit receptors further demonstrated a physical interaction between these 2 receptors, although the interaction was not influenced by chronic cocaine or oxytocin treatment. Oxytocin also attenuated sucrose seeking in a GluA1- or extracellular-signal-regulated kinase-independent manner. Conclusions: These findings suggest that oxytocin mediates cocaine seeking through interacting with glutamate receptor systems via second messenger cascades in mesocorticolimbic regions. PMID:25539504

  2. Effects of Progesterone and Testosterone on Cocaine Self-Administration and Cocaine Discrimination by Female Rhesus Monkeys

    Science.gov (United States)

    Mello, Nancy K; Knudson, Inge M; Kelly, Maureen; Fivel, Peter A; Mendelson, Jack H

    2011-01-01

    The neuroactive steroid hormone progesterone attenuates cocaine's abuse-related effects in women and in rodents under some conditions, but the effects of testosterone are unknown. We compared the acute effects of progesterone (0.1, 0.2, and 0.3 mg/kg, intramuscularly (i.m.)), testosterone (0.001, 0.003, and 0.01 mg/kg, i.m.), and placebo on cocaine self-administration and cocaine discrimination dose–effect curves in female rhesus monkeys. Cocaine self-administration (0.03 mg/kg per inj.) was maintained on a fixed ratio 30 schedule of reinforcement, and monkeys had unlimited access to cocaine for 2 h each day. Cocaine doses were administered in an irregular order during each dose–effect curve determination, and the same dose order was used in each subject in all treatment conditions. Blood samples for hormone analysis were collected at the end of each test session. Banana-flavored food pellets (1 g) were also available in three 1-h daily sessions. In drug discrimination studies, the effects of pretreatment with progesterone (0.032–0.32 mg/kg, i.m.) and testosterone (0.001–0.01 mg/kg, i.m.) on the discriminative stimulus effects of cocaine (0.18 mg/kg, i.m.) were examined. Progesterone and testosterone did not alter cocaine discrimination, and did not substitute for cocaine. In contrast, progesterone and testosterone each significantly decreased cocaine self-administration, and produced a downward and rightward shift in the cocaine self-administration dose–effect curve. These findings are concordant with clinical reports that progesterone administration may decrease ratings of positive subjective effects of cocaine in women, and suggest the possible value of neuroactive steroid hormones for the treatment of cocaine abuse and reduction of risk for relapse. PMID:21796112

  3. 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.

  4. Prenatal Cocaine Exposure and Childhood Obesity at Nine Years

    Science.gov (United States)

    LaGasse, Linda L.; Gaskins, Ronnesia B.; Bada, Henrietta S.; Shankaran, Seetha; Liu, Jing; Lester, Barry M.; Bauer, Charles R.; Higgins, Rosemary D.; Das, Abhik; Roberts, Mary

    2010-01-01

    Little is known about the association between prenatal cocaine exposure and obesity. We tested whether prenatal cocaine exposure increases the likelihood of obesity in 561 9-year-old term children from the Maternal Lifestyle Study (MLS). Overall, 21.6% of children met criterion for obesity (body mass index [BMI] ≥ 95th percentile, age and sex-specific). While there was no overall cocaine effect on obesity, multivariate logistic analysis revealed that children exposed to cocaine but not alcohol were 4 times more likely to be obese (OR 4.11, CI 2.04–9.76) than children not exposed to either drug. No increase in obesity prevalence was found in children exposed to alcohol but not cocaine (OR 1.08, CI .59–1.93) or both (OR 1.21, CI 0.66–2.22). Alcohol exposure may attenuate the effect of cocaine exposure on obesity. Increased obesity associated with cocaine but not alcohol exposure was first observed at 7 years. BMI was also elevated from 3 to 9 years in children exposed to cocaine but not alcohol, due to increasing weight but normal height. Prenatal exposure to cocaine may alter the neuroendocrine system and metabolic processes resulting in increased weight gain and childhood obesity. PMID:21109003

  5. Involvement of reactive oxygen species in cocaine-taking behaviors in rats

    Science.gov (United States)

    Jang, Eun Young; Ryu, Yeon-Hee; Lee, Bong Hyo; Chang, Su-Chan; Yeo, Mi Jin; Kim, Sang Hyun; Folsom, Ryan J.; Schilaty, Nathan D.; Kim, Kwang Joong; Yang, Chae Ha; Steffensen, Scott C.; Kim, Hee Young

    2016-01-01

    Reactive oxygen species (ROS) have been implicated in the development of behavioral sensitization following repeated cocaine exposure. We hypothesized that increased ROS following cocaine exposure would act as signaling molecules in the mesolimbic dopamine (DA) system, which might play an important role in mediating the reinforcing effects of cocaine. The aim of this study was to evaluate cocaine enhancement of brain metabolic activity and the effects of ROS scavengers on cocaine self-administration behavior, cocaine-induced ROS production in the nucleus accumbens (NAc) and cocaine enhancement of DA release in the NAc. Metabolic neural activity monitored by temperature and oxidative stress were increased in NAc following cocaine exposure. Systemic administration of the ROS scavenger N-tert-butyl-α-phenylnitrone (PBN) or 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL), either pre- or post-treatment, significantly decreased cocaine self-administration without affecting food intake. Infusion of TEMPOL into the NAc inhibited cocaine self-administration. Increased oxidative stress was found mainly on neurons, but not astrocytes, microglia or oligodendrocytes, in NAc of rats self-administering cocaine. TEMPOL significantly attenuated cocaine-induced enhancement of DA release in the NAc, compared to saline controls. TEMPOL had no effect on the enhancement of DA release produced by the DA transporter inhibitor GBR12909. Taken together, these findings suggest that enhancement of ROS production in NAc neurons contributes to the reinforcing effect of cocaine. PMID:24975938

  6. Preventive role of social interaction for cocaine conditioned place preference: correlation with FosB/DeltaFosB and pCREB expression in rat mesocorticolimbic areas

    OpenAIRE

    El Rawas, Rana; Klement, Sabine; Salti, Ahmad; Fritz, Michael; Dechant, Georg; Saria, Alois; Zernig, Gerald

    2012-01-01

    The worsening of drug abuse by drug-associated social interaction is a well-studied phenomenon. In contrast, the molecular mechanisms of the beneficial effect of social interaction, if offered as a mutually exclusive choice to drugs of abuse, are under-investigated. In a rat place preference conditioning (CPP) paradigm, four 15 min episodes of social interaction with a gender- and weight-matched male early-adult conspecific inhibited cocaine-induced reinstatement of cocaine CPP, a model of re...

  7. Loss of the trpc4 gene is associated with a reduction in cocaine self-administration and reduced spontaneous ventral tegmental area dopamine neuronal activity, without deficits in learning for natural rewards.

    Science.gov (United States)

    Klipec, William D; Burrow, Kristin R; O'Neill, Casey; Cao, Jun-Li; Lawyer, Chloe R; Ostertag, Eric; Fowler, Melissa; Bachtell, Ryan K; Illig, Kurt R; Cooper, Donald C

    2016-06-01

    Among the canonical transient receptor potential (TRPC) channels, the TRPC4 non-selective cation channel is one of the most abundantly expressed subtypes within mammalian corticolimbic brain regions, but its functional and behavioral role is unknown. To identify a function for TRPC4 channels we compared the performance of rats with a genetic knockout of the trpc4 gene (trpc4 KO) to wild-type (WT) controls on the acquisition of simple and complex learning for natural rewards, and on cocaine self-administration (SA). Despite the abundant distribution of TRPC4 channels through the corticolimbic brain regions, we found trpc4 KO rats exhibited normal learning in Y-maze and complex reversal shift paradigms. However, a deficit was observed in cocaine SA in the trpc4 KO group, which infused significantly less cocaine than WT controls despite displaying normal sucrose SA. Given the important role of ventral tegmental area (VTA) dopamine neurons in cocaine SA, we hypothesized that TRPC4 channels may regulate basal dopamine neuron excitability. Double-immunolabeling showed a selective expression of TRPC4 channels in a subpopulation of putative dopamine neurons in the VTA. Ex vivo recordings of spontaneous VTA dopamine neuronal activity from acute brain slices revealed fewer cells with high-frequency firing rates in trpc4 KO rats compared to WT controls. Since deletion of the trpc4 gene does not impair learning involving natural rewards, but reduces cocaine SA, these data demonstrate a potentially novel role for TRPC4 channels in dopamine systems and may offer a new pharmacological target for more effective treatment of a variety of dopamine disorders. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Prediction Method for Rain Rate and Rain Propagation Attenuation for K-Band Satellite Communications Links in Tropical Areas

    Directory of Open Access Journals (Sweden)

    Baso Maruddani

    2015-01-01

    Full Text Available This paper deals with the prediction method using hidden Markov model (HMM for rain rate and rain propagation attenuation for K-band satellite communication link at tropical area. As is well known, the K-band frequency is susceptible of being affected by atmospheric condition, especially in rainy condition. The wavelength of K-band frequency which approaches to the size of rain droplet causes the signal strength is easily attenuated and absorbed by the rain droplet. In order to keep the quality of system performance for K-band satellite communication link, therefore a special attention has to be paid for rain rate and rain propagation attenuation. Thus, a prediction method for rain rate and rain propagation attenuation based on HMM is developed to process the measurement data. The measured and predicted data are then compared with the ITU-R recommendation. From the result, it is shown that the measured and predicted data show similarity with the model of ITU-R P.837-5 recommendation for rain rate and the model of ITU-R P.618-10 recommendation for rain propagation attenuation. Meanwhile, statistical data for measured and predicted data such as fade duration and interfade duration have insignificant discrepancy with the model of ITU-R P.1623-1 recommendation.

  9. MOVING BEYOND PUMP AND TREAT TOWARD ENHANCED ATTENUATION AND COMBINED REMEDIES T-AREA, SAVANNAH RIVER SITE

    Energy Technology Data Exchange (ETDEWEB)

    Looney, B; Brian Riha, B; Warren Hyde, W; Jay Noonkester, J; Gerald Blount, G

    2008-04-03

    Groundwater beneath T-Area, a former laboratory and semiworks operation at the Department of Energy (DOE) Savannah River Site, is contaminated by chlorinated solvents (cVOCs). Since the contamination was detected in the 1980s, the cVOCs at T-Area have been treated by a combination of soil vapor extraction and groundwater pump and treat. The site has received approval to discontinue the active treatments and implement a full scale test of enhanced attenuation--an engineering and regulatory strategy that has recently been developed by DOE and the Interstate Technology and Regulatory Council. Enhanced attenuation uses active engineering solutions to alter the target site in such a way that the contaminant plume will passively stabilize and shrink and to document that the action will be effective, timely, and sustainable. The paradigm recognizes that attenuation remedies are fundamentally based on a mass balance. Thus, long-term plume dynamics can be altered either by reducing the contaminant loading from the source or by increasing the rate of natural attenuation processes within all, or part of, the plume volume. The combination of technologies that emerged for T-Area included: (1) neat (pure) vegetable oil deployment in the deep vadose zone in the former source area, (2) emulsified vegetable oil deployment within the footprint of the groundwater plume, and (3) identification of attenuation mechanisms and rates for the distal portion of the plume. In the first part, neat oil spreads laterally forming a thin layer on the water table to intercept and reduce future cVOC loading (via partitioning) and reduce oxygen inputs (via biostimulation). In the second and third parts, emulsified oil forms active bioremediation reactor zones within the plume footprint to degrade existing groundwater contamination (via reductive dechlorination) and stimulates long-term attenuation capacity in the distal plume (via cometabolism). For T-Area, the enhanced attenuation development

  10. Obesity attenuates D2 autoreceptor-mediated inhibition of putative ventral tegmental area dopaminergic neurons.

    Science.gov (United States)

    Koyama, Susumu; Mori, Masayoshi; Kanamaru, Syohei; Sazawa, Takuya; Miyazaki, Ayano; Terai, Hiroki; Hirose, Shinichi

    2014-01-01

    Abstract The ventral tegmental area (VTA) in the midbrain is important for food reward. High-fat containing palatable foods have reinforcing effects and accelerate obesity. We have previously reported that diet-induced obesity selectively decreased the spontaneous activity of VTA GABA neurons, but not dopamine neurons. The spontaneous activity of VTA dopamine neurons is regulated by D2 autoreceptors. In this study, we hypothesized that obesity would affect the excitability of VTA dopamine neurons via D2 autoreceptors. To examine this hypothesis, we compared D2 receptor-mediated responses of VTA dopamine neurons between lean and obese mice. Mice fed on a high-fat (45%) diet and mice fed on a standard diet were used as obese and lean models, respectively. Brain slice preparations were made from these two groups. Spontaneous activity of VTA neurons was recorded by extracellular recording. Putative VTA dopamine neurons were identified by firing inhibition with a D2 receptor agonist quinpirole, and electrophysiological criteria (firing frequency 1.2 msec). Single-dose application of quinpirole (3-100 nmol/L) exhibited similar firing inhibition of putative VTA dopamine neurons between lean and obese mice. In stepwise application by increasing quinpirole concentrations of 3, 10, 30, and 100 nmol/L subsequently, quinpirole-induced inhibition of firing decreased in putative VTA dopamine neurons of obese mice compared with those of lean mice. In conclusion, high-fat diet-induced obesity attenuated D2 receptor-mediated inhibition of putative VTA dopamine neurons due to the acceleration of D2 receptor desensitization.

  11. Efficacy of an Adenovirus-based Anti-cocaine Vaccine to Reduce Cocaine Self-administration and Reacqusition using a Choice Procedure in Rhesus Macaques

    Science.gov (United States)

    Evans, Suzette M.; Foltin, Richard W.; Hicks, Martin J.; Rosenberg, Jonathan B.; De, Bishnu P.; Janda, Kim D.; Kaminsky, Stephen M.; Crystal, Ronald G.

    2016-01-01

    Immunopharmacotherapy offers an approach for treating cocaine abuse by specifically targeting the cocaine molecule and preventing its access to the CNS. dAd5GNE is a novel cocaine vaccine that attenuates the stimulant and the reinforcing effects of cocaine in rats. The goal of this study was to extend and validate dAd5GNE vaccine efficacy in non-human primates. Six experimentally naïve adult female rhesus monkeys (Macaca mulatta) were trained to self-administer 0.1 mg/kg/injection intravenous (i.v.) cocaine or receive candy; then 4 monkeys were administered the vaccine and 2 monkeys were administered vehicle intramuscularly, with additional vaccine boosts throughout the study. The reinforcing effects of cocaine were measured during self-administration, extinction, and reacquisition (relapse) phases. Serum antibody titers in the vaccinated monkeys remained high throughout the study. There was no change in the preference for cocaine over candy over a 20-week period in 5 of the 6 monkeys; only one of the 4 (25%) vaccinated monkeys showed a decrease in cocaine choice. All 6 monkeys extinguished responding for cocaine during saline extinction testing; vaccinated monkeys tended to take longer to extinguish responding than control monkeys (17.5 vs. 7.0 sessions). Vaccination substantially retarded reacquisition of cocaine self-administration; control monkeys resumed cocaine self-administration within 6–41 sessions and 1 vaccinated monkey resumed cocaine self-administration in 19 sessions. The other 3 vaccinated monkeys required between 57–94 sessions to resume cocaine self-administration even in the context of employing several manipulations to encourage cocaine reacquisition. These data suggest that the dAdGNE vaccine may have therapeutic potential for humans who achieve cocaine abstinence as part of a relapse prevention strategy. PMID:27697554

  12. Cocaine Addiction: Psychology and Neurophysiology.

    Science.gov (United States)

    Gawin, Frank H.

    1991-01-01

    The clinical characteristics of cocaine addiction, cocaine abstinence symptoms, and the short-term and long-term neurochemical actions of cocaine are discussed. The relative therapeutic value of various medications and treatment programs are discussed. (KR)

  13. Adolescent cocaine abuse. Addictive potential, behavioral and psychiatric effects.

    Science.gov (United States)

    Estroff, T W; Schwartz, R H; Hoffmann, N G

    1989-12-01

    Four hundred seventy-nine drug abusing adolescent patients enrolled in seven Straight, Inc. Adolescent Drug-Abuse Treatment Programs in five geographic regions across the United States were studied to determine the severity and patterns of cocaine abuse. Of these, 341 admitted to cocaine use and became part of this survey. Cocaine use was categorized as heavy, intermediate, or light. Areas examined were the addictive spectrum, psychosocial dysfunction, and psychiatric symptoms. Intermediate and heavy users of cocaine abused significantly less marijuana and inhalants than light cocaine abusers. Heavy and intermediate users were more likely to use cocaine intravenously and to use crack. They developed tachyphylaxis more frequently, progressed to weekly use in less than 3 months more frequently, and became preoccupied with obtaining and using cocaine significantly more frequently. They used more sedative hypnotics to calm themselves and engaged in more criminal behavior, such as stealing from parents and stores and passing bad checks. They had more arrests for possession of drugs, stole more cars, sold more drugs, and were more likely to trade sexual favors to obtain the drug. Heavy and intermediate users were significantly more psychiatrically disturbed than light users, becoming more suspicious, nervous, aggressive, and demonstrating increased symptoms of fatigue, sleeplessness, decreased appetite, and increasing cocaine dysphoria. All of these symptoms could be mistaken for psychiatric disorders. This study suggests that cocaine is as addictive in adolescents as in adults; possibly more so. It also causes psychosocial dysfunction and psychiatric symptoms. Further research into cocaine addiction among adolescents is indicated.

  14. Bioremediation (Natural Attenuation and Biostimulation) of Diesel-Oil-Contaminated Soil in an Alpine Glacier Skiing Area

    OpenAIRE

    Margesin, R.; Schinner, F.

    2001-01-01

    We investigated the feasibility of bioremediation as a treatment option for a chronically diesel-oil-polluted soil in an alpine glacier area at an altitude of 2,875 m above sea level. To examine the efficiencies of natural attenuation and biostimulation, we used field-incubated lysimeters (mesocosms) with unfertilized and fertilized (N-P-K) soil. For three summer seasons (July 1997 to September 1999), we monitored changes in hydrocarbon concentrations in soil and soil leachate and the accompa...

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

    Science.gov (United States)

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

    2013-09-01

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

  16. Intensity attenuation relation at Chamba–Garhwal area in north-west ...

    Indian Academy of Sciences (India)

    Seismic hazard assessment of any region depends on the attenuation relation which relates the seismo- logical data with ... northwest Himalayan region, isoseismal maps of previous earthquakes were the only source of informa- tion for computing the ..... 1999, in the Eastern Mediterranean and the Middle East;. Geophys.

  17. Coda attenuation analysis in the West Bohemia/Vogtland earthquake swarm area

    Czech Academy of Sciences Publication Activity Database

    Bachura, M.; Fischer, Tomáš

    2016-01-01

    Roč. 173, č. 2 (2016), s. 425-437 ISSN 0033-4553 R&D Projects: GA ČR GAP210/12/2336; GA MŠk LM2010008 Institutional support: RVO:67985530 Keywords : seismic coda * attenuation * Q quality factor Subject RIV: DC - Siesmology, Volcanology, Earth Structure Impact factor: 1.591, year: 2016

  18. Intensity attenuation relation at Chamba–Garhwal area in north-west ...

    Indian Academy of Sciences (India)

    Seismic hazard assessment of any region depends on the attenuation relation which relates the seismo- logical data with parameters of engineering interest. In the absence of sufficient strong motion data for northwest Himalayan region, isoseismal maps of previous earthquakes were the only source of informa-.

  19. Intensity attenuation relation at Chamba–Garhwal area in north-west ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Earth System Science; Volume 122; Issue 1 ... In the absence of sufficient strong motion data for northwest Himalayan region, isoseismal maps of previous earthquakes were the only source of information for ... With this information, attenuation relations of intensity with distance can be obtained.

  20. 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....

  1. Cannabis, Cocaine and Jobs

    NARCIS (Netherlands)

    van Ours, J.C.

    2005-01-01

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

  2. Mind Over Matter: Cocaine

    Science.gov (United States)

    ... Alcohol Facts Week® Enter Search Term(s): Teachers / NIDA Teaching Guide / Mind Over Matter Teaching Guide and Series / Cocaine Mind Over Matter: Cocaine ... of the source is appreciated, using the following language: Source: National Institute on Drug Abuse; National Institutes ...

  3. 21 CFR 862.3250 - Cocaine and cocaine metabolite test system.

    Science.gov (United States)

    2010-04-01

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

  4. [Complications of cocaine addiction].

    Science.gov (United States)

    Karila, Laurent; Lowenstein, William; Coscas, Sarah; Benyamina, Amine; Reynaud, Michel

    2009-06-20

    Addiction is a chronic relapsing disorder characterized by repetitive and compulsive drug-seeking behavior and drug abuse despite negative health or social consequences. Cocaine addiction is a significant worldwide public health problem, which has somatic, psychological, psychiatric, socio-economic and judicial complications. Some of the most frequent complications are cardiovascular effects (acute coronary syndrome, cardiac arrhythmias, increased blood pressure); respiratory effects (fibrosis, interstitial pneumonitis, pulmonary hypertension, alveolar haemorrhage, asthma exacerbation; emphysema), neurological effects (strokes, aneurysms, seizures, headaches); risk for contracting HIV/AIDS, hepatitis B and C, sexual transmitted disease and otolaryngologic effects. Other complications are not discussed here. The vast majority of studies indicate that there are cognitive deficits induced by cocaine addiction. Attention, visual and working memories, executive functioning are affected in cocaine users. Psychiatric complications found in clinical practice are major depressive disorders, cocaine-induced paranoia, cocaine-induced compulsive foraging and panic attacks.

  5. [Cocaine - Characteristics and addiction].

    Science.gov (United States)

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

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

  6. Cocaine cardiovascular effects and pharmacokinetics after treatment with the acetylcholinesterase inhibitor donepezil.

    Science.gov (United States)

    Grasing, Kenneth; Mathur, Deepan; DeSouza, Cherilyn; Newton, Thomas F; Moody, David E; Sturgill, Marc

    2016-08-01

    In rodents, cholinesterase inhibitors can cause sustained decreases in the reinforcing effects of cocaine. Nonetheless, cocaine is metabolized by butyrylcholinesterase (BuChE), raising concerns that cholinesterase inhibition could increase its peripheral concentrations, perhaps augmenting toxicity. Although donepezil is approved for use in patients and selective for inhibiting acetylcholinesterase over BuChE, no studies have reported cocaine bioavailability in human subjects receiving donepezil. Twelve cocaine-dependent veterans received three days of treatment with either oral placebo or 5 mg daily of donepezil, followed by cross-over to the opposite treatment. During both oral treatments, double-blind intravenous cocaine was administered at .0, .18, and .36 mg/kg in a laboratory setting, followed by determinations of heart rate, blood pressure, and plasma concentrations of cocaine and major metabolites. Intravenous cocaine produced dose-related increases in systolic blood pressure that were most pronounced over the initial 30 minutes after treatment. Oral donepezil attenuated drug-induced elevations of systolic blood pressure following low-dose cocaine (.18 mg/kg). No significant difference in blood pressure following treatment with placebo or donepezil after high-dose cocaine (.36 mg/kg). Peak values of blood pressure and heart rate were unaffected by donepezil. Plasma concentrations of cocaine and metabolites did not differ in donepezil- and placebo-treated participants. We conclude that donepezil can attenuate drug-induced increases in systolic blood pressure following low-dose cocaine, but does not otherwise modify the cardiovascular effects of intravenous cocaine. Clinically significant changes in cocaine bioavailability and cardiovascular effects do not occur following this dose of donepezil. (Am J Addict 2016;25:392-399). © 2016 American Academy of Addiction Psychiatry.

  7. TREATABILITY STUDY FOR EDIBLE OIL DEPLOYMENT FOR ENHANCED CVOC ATTENUATION FOR T-AREA, SAVANNAH RIVER SITE

    Energy Technology Data Exchange (ETDEWEB)

    Riha, B.; Looney, B.; Noonkester, J.; Hyde, W.; Walker, R.

    2012-05-15

    Groundwater beneath T-Area, a former laboratory and semiworks operation at the Department of Energy (DOE) Savannah River Site (SRS), is contaminated by chlorinated solvents (cVOCs). Since the contamination was detected in the 1980s, the cVOCs at T-Area have been treated by a combination of soil vapor extraction and groundwater pump and treat. The site received approval to temporarily discontinue the active groundwater treatment and implement a treatability study of enhanced attenuation - an engineering and regulatory strategy that has recently been developed by DOE and the Interstate Technology and Regulatory Council (ITRC 2007). Enhanced attenuation uses active engineering solutions to alter the target site in such a way that the contaminant plume will passively stabilize and shrink and to document that the action will be effective, timely, and sustainable. The paradigm recognizes that attenuation remedies are fundamentally based on a mass balance. Thus, long-term plume dynamics can be altered either by reducing the contaminant loading from the source or by increasing the rate of natural attenuation processes within all, or part of, the plume volume. The combination of technologies that emerged for T-Area included: (1) neat (pure) vegetable oil deployment in the deep vadose zone in the former source area, (2) emulsified vegetable oil deployment within the footprint of the groundwater plume, and (3) identification of attenuation mechanisms and rates for the distal portion of the plume. In the first part, neat oil spreads laterally forming a thin layer on the water table to intercept and reduce future cVOC loading (via partitioning) and reduce oxygen inputs (via biostimulation). In the second and third parts, emulsified oil forms active bioremediation reactor zones within the plume footprint to degrade existing groundwater contamination (via reductive dechlorination and/or cometabolism) and stimulates long-term attenuation capacity in the distal plume (via

  8. Characteristics of freebase cocaine psychosis.

    Science.gov (United States)

    Manschreck, T. C.; Laughery, J. A.; Weisstein, C. C.; Allen, D.; Humblestone, B.; Neville, M.; Podlewski, H.; Mitra, N.

    1988-01-01

    Psychosis was present in 29 percent of cocaine-disordered patients hospitalized in 1985 during an epidemic of freebase cocaine abuse in the Bahamas. Record reviews revealed that a variety of psychotic phenomenologic patterns were present. Prior major mental disorders and increased dosage of cocaine were more common among psychotic than non-psychotic patients. Violent behavior was common among cocaine patients, especially those with psychosis. We conclude that freebase cocaine psychosis is neither rare nor benign. PMID:3407210

  9. Characteristics of freebase cocaine psychosis.

    OpenAIRE

    Manschreck, T. C.; Laughery, J. A.; Weisstein, C. C.; Allen, D.; Humblestone, B.; Neville, M.; Podlewski, H.; Mitra, N.

    1988-01-01

    Psychosis was present in 29 percent of cocaine-disordered patients hospitalized in 1985 during an epidemic of freebase cocaine abuse in the Bahamas. Record reviews revealed that a variety of psychotic phenomenologic patterns were present. Prior major mental disorders and increased dosage of cocaine were more common among psychotic than non-psychotic patients. Violent behavior was common among cocaine patients, especially those with psychosis. We conclude that freebase cocaine psychosis is nei...

  10. Effects of an acute cannabidiol treatment on cocaine self-administration and cue-induced cocaine seeking in male rats.

    Science.gov (United States)

    Mahmud, Ashraf; Gallant, Stephanie; Sedki, Firas; D'Cunha, Tracey; Shalev, Uri

    2017-01-01

    Cannabidiol is a non-psychoactive compound that is the second most abundant component of cannabis. It has been shown to have a potential therapeutic value for a wide range of disorders, including anxiety, psychosis, and depression. Recently, it was suggested that cannabidiol might be a potential treatment for heroin craving and relapse. Here we investigated the effects of an acute treatment with cannabidiol on cocaine self-administration and cue-induced cocaine seeking in rats. Rats were trained to press a lever to self-administer cocaine (0.5 mg/kg/infusion), first under a fixed interval 20 s (FI-20 s) and then under a progressive ratio (PR) schedule of reinforcement. Cocaine self-administration under a PR schedule of reinforcement was not attenuated by cannabidiol injections (5.0 mg/kg and 10.0 mg/kg; i.p.) when tested 30 min and 24 h after treatment. Cannabidiol treatment (5.0 mg/kg or 10.0 mg/kg) also did not attenuate cue-induced cocaine seeking in rats after a withdrawal period of 14 days. In contrast, treatment with cannabidiol (10.0 mg/kg; i.p.) resulted in a statistically significant anxiolytic effect in the elevated plus-maze. Our findings suggest that, under the conditions described here, an acute cannabidiol treatment has a minimal effect on a rat model of cocaine intake and relapse.

  11. 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.

  12. Cocaine-induced psychosis.

    Science.gov (United States)

    Brady, K T; Lydiard, R B; Malcolm, R; Ballenger, J C

    1991-12-01

    Chronic stimulant use can produce a paranoid psychosis that is similar to acute paranoid schizophrenia. While this phenomenon has been systematically explored in amphetamine abusers, it has been relatively unexplored in a systematic fashion in cocaine abusers. The experience of cocaine-induced psychosis was evaluated in 55 individuals consecutively admitted for treatment of DSM-III-R cocaine dependence. Each subject was interviewed about their experiences of psychosis while intoxicated by means of a standardized, semistructured interview. Fifty-three percent (29/55) of those interviewed reported experiencing transient cocaine-induced psychosis. There was no significant difference in lifetime amount of cocaine use or amount of cocaine use in the month before admission between those who experienced psychosis and those who did not. The psychosis-positive group used significantly more cocaine in the year prior to admission (p less than or equal to .02) and had a longer duration of use (p less than or equal to .01). Males were significantly (p less than or equal to .05) more likely than females to develop psychosis. Ninety percent (26/29) developed paranoid delusions directly related to drug use. Ninety-six percent (28/29) of the subjects experienced hallucinations: 83% (24/29), auditory hallucinations; 38% (11/29), visual hallucinations; and 21% (6/29), tactile hallucinations. Twenty-seven percent (15/55) of subjects developed transient behavioral stereotypies. Cocaine-induced paranoia is a common experience among chronic users. Amount and duration of use are related to its development. Implications for a kindling model of cocaine-induced psychosis will be discussed.

  13. Gentamicin-attenuated Leishmania infantum vaccine: protection of dogs against canine visceral leishmaniosis in endemic area of southeast of Iran.

    Science.gov (United States)

    Daneshvar, Hamid; Namazi, Mohammad Javad; Kamiabi, Hossein; Burchmore, Richard; Cleaveland, Sarah; Phillips, Stephen

    2014-04-01

    An attenuated line of Leishmania infantum (L. infantum H-line) has been established by culturing promastigotes in vitro under gentamicin pressure. A vaccine trial was conducted using 103 naive dogs from a leishmaniosis non-endemic area (55 vaccinated and 48 unvaccinated) brought into an endemic area of southeast Iran. No local and/or general indications of disease were observed in the vaccinated dogs immediately after vaccination. The efficacy of the vaccine was evaluated after 24 months (4 sandfly transmission seasons) by serological, parasitological analyses and clinical examination. In western blot analysis of antibodies to L. infantum antigens, sera from 10 out of 31 (32.2%) unvaccinated dogs, but none of the sera from vaccinated dogs which were seropositive at >100, recognized the 21 kDa antigen of L. infantum wild-type (WT). Nine out of 31 (29%) unvaccinated dogs, but none of vaccinated dogs, were positive for the presence of Leishmania DNA. One out of 46 (2.2%) vaccinated dogs and 9 out of 31 (29%) unvaccinated dogs developed clinical signs of disease. These results suggest that gentamicin-attenuated L. infantum induced a significant and strong protective effect against canine visceral leishmaniosis in the endemic area.

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

    OpenAIRE

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

    2013-01-01

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

  15. HMG-CoA synthase 2 drives brain metabolic reprogramming in cocaine exposure.

    Science.gov (United States)

    Shao, Xue; Tang, Yunxuan; Long, Hailei; Gu, Hui; Zhang, Jie; Deng, Pengchi; Zhao, Yinglan; Cen, Xiaobo

    2017-10-04

    The brain is a high energy-consuming organ that typically utilizes glucose as the main energy source for cerebral activity. When glucose becomes scarce under conditions of stress, ketone bodies, such as β-hydroxybutyrate, acetoacetate and acetone, become extremely important. Alterations in brain energy metabolism have been observed in psychostimulant abusers; however, the mode of brain metabolic programming in cocaine dependence remains largely unknown. Here, we profiled the metabolites and metabolic enzymes from brain nucleus accumbens (NAc) of mice exposed to cocaine. We found that cocaine modified energy metabolism and markedly activated ketogenesis pathway in the NAc. The expression of HMG-CoA synthase 2 (HMGCS2), a critical rate-limiting ketogenesis enzyme, was markedly up-regulated. After switching metabolic pathways from ketogenesis to glycolysis through activation of glucokinase, cocaine-evoked metabolic reprogramming regained homeostasis, and the cocaine effect was attenuated. Importantly, both the pharmacological and genetic inhibition of HMGCS2 significantly suppressed cocaine-induced ketogenesis and behavior. In conclusion, cocaine induces a remarkable energy reprogramming in the NAc, which is characterized by HMGCS2-driven ketogenesis. Such effect may facilitate adaptations to cocaine-induced energy stress in the brain. Our findings establish an important link between drug-induced energy reprogramming and cocaine effect, and may have implication in the treatment of cocaine addiction. Copyright © 2017. Published by Elsevier Ltd.

  16. Epigenetic Readers of Lysine Acetylation Regulate Cocaine-Induced Plasticity

    Science.gov (United States)

    Sartor, Gregory C.; Powell, Samuel K.; Brothers, Shaun P.

    2015-01-01

    Epigenetic processes that regulate histone acetylation play an essential role in behavioral and molecular responses to cocaine. To date, however, only a small fraction of the mechanisms involved in the addiction-associated acetylome have been investigated. Members of the bromodomain and extraterminal (BET) family of epigenetic “reader” proteins (BRD2, BRD3, BRD4, and BRDT) bind acetylated histones and serve as a scaffold for the recruitment of macromolecular complexes to modify chromatin accessibility and transcriptional activity. The role of BET proteins in cocaine-induced plasticity, however, remains elusive. Here, we used behavioral, pharmacological, and molecular techniques to examine the involvement of BET bromodomains in cocaine reward. Of the BET proteins, BRD4, but not BRD2 or BRD3, was significantly elevated in the nucleus accumbens (NAc) of mice and rats following repeated cocaine injections and self-administration. Systemic and intra-accumbal inhibition of BRD4 with the BET inhibitor, JQ1, attenuated the rewarding effects of cocaine in a conditioned place preference procedure but did not affect conditioned place aversion, nor did JQ1 alone induce conditioned aversion or preference. Investigating the underlying mechanisms, we found that repeated cocaine injections enhanced the binding of BRD4, but not BRD3, to the promoter region of Bdnf in the NAc, whereas systemic injection of JQ1 attenuated cocaine-induced expression of Bdnf in the NAc. JQ1 and siRNA-mediated knockdown of BRD4 in vitro also reduced expression of Bdnf. These findings indicate that disrupting the interaction between BET proteins and their acetylated lysine substrates may provide a new therapeutic avenue for the treatment of drug addiction. SIGNIFICANCE STATEMENT Proteins involved in the “readout” of lysine acetylation marks, referred to as BET bromodomain proteins (including BRD2, BRD3, BRD4, and BRDT), have been shown to be key regulators of chromatin dynamics and disease, and

  17. Epigenetic Readers of Lysine Acetylation Regulate Cocaine-Induced Plasticity.

    Science.gov (United States)

    Sartor, Gregory C; Powell, Samuel K; Brothers, Shaun P; Wahlestedt, Claes

    2015-11-11

    Epigenetic processes that regulate histone acetylation play an essential role in behavioral and molecular responses to cocaine. To date, however, only a small fraction of the mechanisms involved in the addiction-associated acetylome have been investigated. Members of the bromodomain and extraterminal (BET) family of epigenetic "reader" proteins (BRD2, BRD3, BRD4, and BRDT) bind acetylated histones and serve as a scaffold for the recruitment of macromolecular complexes to modify chromatin accessibility and transcriptional activity. The role of BET proteins in cocaine-induced plasticity, however, remains elusive. Here, we used behavioral, pharmacological, and molecular techniques to examine the involvement of BET bromodomains in cocaine reward. Of the BET proteins, BRD4, but not BRD2 or BRD3, was significantly elevated in the nucleus accumbens (NAc) of mice and rats following repeated cocaine injections and self-administration. Systemic and intra-accumbal inhibition of BRD4 with the BET inhibitor, JQ1, attenuated the rewarding effects of cocaine in a conditioned place preference procedure but did not affect conditioned place aversion, nor did JQ1 alone induce conditioned aversion or preference. Investigating the underlying mechanisms, we found that repeated cocaine injections enhanced the binding of BRD4, but not BRD3, to the promoter region of Bdnf in the NAc, whereas systemic injection of JQ1 attenuated cocaine-induced expression of Bdnf in the NAc. JQ1 and siRNA-mediated knockdown of BRD4 in vitro also reduced expression of Bdnf. These findings indicate that disrupting the interaction between BET proteins and their acetylated lysine substrates may provide a new therapeutic avenue for the treatment of drug addiction. Proteins involved in the "readout" of lysine acetylation marks, referred to as BET bromodomain proteins (including BRD2, BRD3, BRD4, and BRDT), have been shown to be key regulators of chromatin dynamics and disease, and BET inhibitors are currently

  18. Natural attenuation of chlorinated solvents at Area 6, Dover Air Force Base: characterization of microbial community structure

    Science.gov (United States)

    Davis, John W.; Odom, J. Martin; DeWeerd, Kim A.; Stahl, David A.; Fishbain, Susan S.; West, Robert J.; Klecka, Gary M.; DeCarolis, John G.

    2002-07-01

    A polyphasic approach based on cultivation and direct recovery of 16S rRNA gene sequences was utilized for microbial characterization of an aquifer contaminated with chlorinated ethenes. This work was conducted in order to support the evaluation of natural attenuation of chlorinated ethenes in groundwater at Area 6 at Dover Air Force Base (Dover, DE). Results from these studies demonstrated the aquifer contained relatively low biomass (e.g. direct microscopic counts of bacteria/g of sediment) comprised of a physiologically diverse group of microorganisms including iron reducers, acetogens, sulfate reducers, denitrifiers, aerobic and anaerobic heterotrophs. Laboratory microcosms prepared with authentic sediment and groundwater provided direct microbiological evidence that the mineralization of vinyl chloride and cis-dichloroethene as well as each step in the complete reductive dechlorination of tetracloroethene to ethene can occur in the Area 6 aquifer. Enrichment cultures capable of the oxidative degradation of cis-1,2-dichloroethene ( cis-DCE) and vinyl chloride (VC) were obtained from groundwater across the aquifer demonstrating the possible importance of direct, non-cometabolic oxidation of cis-DCE and VC in natural attenuation. Culture-independent analyses based upon recovery of 16S rRNA gene sequences revealed the presence of anaerobic organisms distributed primarily between two major bacterial divisions: the delta subdivision of the Proteobacteria and low-G+C gram positive. Recovery of sequences affiliated with phylogenetic groups containing known anaerobic-halorespiring organisms such as Desulfitobacterium, Dehalobacter, and certain groups of iron reducers provided qualitative support for a role of reductive dechlorination processes in the aquifer. This molecular data is suggestive of a functional linkage between the microbiology of the site and the apparent natural attenuation process. The presence and distribution of microorganisms were found to be

  19. Chronic treatment with Tempol during acquisition or withdrawal from CPP abolishes the expression of cocaine reward and diminishes oxidative damage

    OpenAIRE

    Beiser, Tehila; Numa, Ran; Kohen, Ron; Yaka, Rami

    2017-01-01

    In previous studies, we reported that pretreatment with the antioxidant Tempol attenuated the development and expression of cocaine-induced psychomotor sensitization in rats and diminished cocaine-induced oxidative stress (OS) in the prefrontal cortex (PFC) and nucleus accumbens (NAc), suggesting a potential role for Tempol in interfering with cocaine-related psychomotor sensitization. The aim of the current study was to examine the role of Tempol in reward and reinforcement using the conditi...

  20. Cocaine contamination of banknotes: a review.

    Science.gov (United States)

    Troiano, Gianmarco; Mercurio, Isabella; Golfera, Marco; Nante, Nicola; Melai, Paola; Lancia, Massimo; Bacci, Mauro

    2017-12-01

    The analysis of drug traces on banknotes with different validated techniques can provide important information about the types of substances that are used in a geographical region. The aim of our review was to investigate banknotes' contamination by cocaine, by its metabolite, but also by other drugs. A systematic literature search (English written literature) was conducted in MEDLINE, and Scopus, collecting studies from 1974 till 2017. The Key search terms included: 'banknote AND drug'; 'banknote AND cocaine'. The literature search yielded 88 publications; 9 were included in our review. In six studies that showed banknotes' positivity to cocaine, the percentage ranged from 2.5% to 100%. The concentration of cocaine ranged from 0.09 ng/note to 889 µg/note. Benzoylecgonine was indentified only in three studies with a range from 0.71 to 130 ng/note. Other indentified drugs were: amphetamine derivatives, opiates, benzodiazepines. Circulating banknotes could be used to indicate substances used in a population, and those recently introduced in a geographical macro-area. The identification of very high amounts of cocaine can provide important information for the identification of banknotes used in illegal trafficking. © The Author 2017. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.

  1. Cocaine-induced psychotic symptoms in French cocaine addicts.

    Science.gov (United States)

    Vorspan, Florence; Brousse, Georges; Bloch, Vanessa; Bellais, Laetitia; Romo, Lucia; Guillem, Eric; Coeuru, Philippe; Lépine, Jean-Pierre

    2012-12-30

    Cocaine use is known to induce transient psychotic symptoms. We evaluated retrospectively the lifetime prevalence of cocaine-induced psychotic symptoms in 105 cocaine addicts with the French version of the Scale for Assessment of Positive Symptoms-Cocaine Induced Psychosis (SAPS-CIP) in a clinical setting. Most patients (86.5%) described such symptoms. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  2. Mirtazapine prevents induction and expression of cocaine-induced behavioral sensitization in rats.

    Science.gov (United States)

    Salazar-Juárez, Alberto; Barbosa-Méndez, Susana; Jurado, Noe; Hernández-Miramontes, Ricardo; Leff, Philippe; Antón, Benito

    2016-07-04

    Cocaine abuse is a major health problem worldwide. Treatment based on both 5-HT2A/C and 5-HT3 receptor antagonists attenuate not only the effects of cocaine abuse but also the incentive/motivational effect related to cocaine-paired cues. Mirtazapine, an antagonist of postsynaptic α2-adrenergic, 5-HT2A/C and 5HT3 receptors and inverse agonist of the 5-HT2C receptor, has been shown to effectively modify, at the preclinical and clinical levels, various behavioral alterations induced by drugs abuse. Therefore, it is important to assess whether chronic dosing of mirtazapine alters locomotor effects of cocaine as well as induction and expression of cocaine sensitization. Our results reveal that a daily mirtazapine regimen administered for 30days effectively induces a significant attenuation of cocaine-dependent locomotor activity and as well as the induction and expression of behavioral sensitization. These results suggest that mirtazapine may be used as a potentially effective therapy to attenuate induction and expression of cocaine-induced locomotor sensitization. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. [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.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-08-01

    attenuates cocaine neurotoxicity. • This effect is mediated by the cannabinoid CB1 receptor/PI3K pathway.

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

    International Nuclear Information System (INIS)

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

    2015-01-01

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

  6. The development of a preference for cocaine over food identifies individual rats with addiction-like behaviors.

    Science.gov (United States)

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

    2013-01-01

    Cocaine dependence is characterized by compulsive drug taking that supercedes other recreational, occupational or social pursuits. We hypothesized that rats vulnerable to addiction could be identified within the larger population based on their preference for cocaine over palatable food rewards. To validate the choice self-administration paradigm as a preclinical model of addiction, we examined changes in motivation for cocaine and recidivism to drug seeking in cocaine-preferring and pellet-preferring rats. We also examined behavior in males and females to identify sex differences in this "addicted" phenotype. Preferences were identified during self-administration on a fixed-ratio schedule with cocaine-only, pellet-only and choice sessions. Motivation for each reward was probed early and late during self-administration using a progressive-ratio schedule. Reinstatement of cocaine- and pellet-seeking was examined following exposure to their cues and non-contingent delivery of each reward. Cocaine preferring rats increased their drug intake at the expense of pellets, displayed increased motivation for cocaine, attenuated motivation for pellets and greater cocaine and cue-induced reinstatement of drug seeking. Females were more likely to develop cocaine preferences and recidivism of cocaine- and pellet-seeking was sexually dimorphic. The choice self-administration paradigm is a valid preclinical model of addiction. The unbiased selection criteria also revealed sex-specific vulnerability factors that could be differentiated from generalized sex differences in behavior, which has implications for the neurobiology of addiction and effective treatments in each sex.

  7. Cocaine-induced vasculitis with cutaneous manifestation: A recurrent episode after 2 years

    Directory of Open Access Journals (Sweden)

    Thein Swe

    2016-01-01

    Full Text Available Cocaine is a popular recreational drug in the United States, and up to 70% of the seized cocaine contains levamisole which is an antihelminthic that can cause cutaneous vasculitis with necrosis and positive antineutrophil cytoplasmic antibodies (ANCAs. Here, we report a unique case of recurrent cocaine-induced vasculitis in a patient who smokes cocaine for more than 20 years. A 38-year-old woman complained of painful erythematous rash in her right arm and right thigh which appeared some hours after smoking cocaine. Physical examination revealed tender, erythematous base, retiform purpura with necrosis and bullae. Serological test showed high atypical perinuclear ANCA titer of 1:320 and antimyeloperoxidase antibody level of 20.4 U/mL. Cocaine-induced vasculitis should be one of the differential diagnoses in cocaine abusers who present with painful rash and areas of necrosis. Early diagnosis is important since it is an emerging public health concern.

  8. Sensing cocaine in saliva with infrared laser spectroscopy

    Science.gov (United States)

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

    2013-02-01

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

  9. Lateral Habenula Involvement in Impulsive Cocaine Seeking.

    Science.gov (United States)

    Zapata, Agustin; Hwang, Eun-Kyung; Lupica, Carl R

    2017-04-01

    The lateral habenula (LHb) is a brain structure receiving inputs from limbic forebrain areas and innervating major midbrain monoaminergic nuclei. Evidence indicates LHb involvement in sleep control, reward-based decision making, avoidance of punishment, and responses to stress. Additional work has established that the LHb mediates negative feedback in response to aversive events. As a hallmark of drug addiction is the inability to limit drug use despite negative consequences, we hypothesize that LHb dysfunction may have a role in the lack of control over drug seeking. Here we examine the effects of LHb inactivation in control over drug seeking in several cocaine self-administration (SA) paradigms in rats. We find that inhibition of the LHb with GABAergic agonists did not alter cocaine SA under progressive ratio or seeking/taking chained reinforcement schedules, or during punishment-induced suppression of cocaine-reinforced responding. In contrast, LHb inhibition increased cocaine seeking when the drug was not available in rats trained to discriminate its presence using an environmental cue. This effect of LHb inhibition was selective for cocaine, as it did not impair responding for sucrose reinforcement. The effect of LHb injection of GABA agonists was mimicked by intra-LHb muscarinic cholinergic (mACh) antagonist injection, and activation of mACh receptors excited a majority of LHb neurons in in vitro electrophysiology experiments. These results indicate that the LHb participates in the suppression of impulsive responding for cocaine through the activation of a cholinergic circuit, and they suggest that LHb dysfunction may contribute to impaired impulse control associated with drug addiction.

  10. The circadian system is a target and modulator of prenatal cocaine effects.

    Directory of Open Access Journals (Sweden)

    Eva H Shang

    2007-07-01

    Full Text Available Prenatal exposure to cocaine can be deleterious to embryonic brain development, but the results in humans remain controversial, the mechanisms involved are not well understood and effective therapies are yet to be designed. We hypothesize that some of the prenatal effects of cocaine might be related to dysregulation of physiological rhythms due to alterations in the integrating circadian clock function.Here we introduce a new high-throughput genetically well-characterized diurnal vertebrate model for studying the mechanisms of prenatal cocaine effects by demonstrating reduced viability and alterations in the pattern of neuronal development following repeated cocaine exposure in zebrafish embryos. This effect is associated with acute cocaine-induced changes in the expression of genes affecting growth (growth hormone, zGH and neurotransmission (dopamine transporter, zDAT. Analysis of circadian gene expression, using quantitative real-time RT-PCR (QPCR, demonstrates that cocaine acutely and dose-dependently changes the expression of the circadian genes (zPer-3, zBmal-1 and genes encoding melatonin receptors (zMelR that mediate the circadian message to the entire organism. Moreover, the effects of prenatal cocaine depend on the time of treatment, being more robust during the day, independent of whether the embryos are raised under the light-dark cycle or in constant light. The latter suggests involvement of the inherited circadian factors. The principal circadian hormone, melatonin, counteracts the effects of cocaine on neuronal development and gene expression, acting via specific melatonin receptors.These findings demonstrate that, in a diurnal vertebrate, prenatal cocaine can acutely dysregulate the expression of circadian genes and those affecting melatonin signaling, growth and neurotransmission, while repeated cocaine exposure can alter neuronal development. Daily variation in these effects of cocaine and their attenuation by melatonin suggest

  11. Subsecond dopamine release promotes cocaine seeking.

    Science.gov (United States)

    Phillips, Paul E M; Stuber, Garret D; Heien, Michael L A V; Wightman, R Mark; Carelli, Regina M

    2003-04-10

    The dopamine-containing projection from the ventral tegmental area of the midbrain to the nucleus accumbens is critically involved in mediating the reinforcing properties of cocaine. Although neurons in this area respond to rewards on a subsecond timescale, neurochemical studies have only addressed the role of dopamine in drug addiction by examining changes in the tonic (minute-to-minute) levels of extracellular dopamine. To investigate the role of phasic (subsecond) dopamine signalling, we measured dopamine every 100 ms in the nucleus accumbens using electrochemical technology. Rapid changes in extracellular dopamine concentration were observed at key aspects of drug-taking behaviour in rats. Before lever presses for cocaine, there was an increase in dopamine that coincided with the initiation of drug-seeking behaviours. Notably, these behaviours could be reproduced by electrically evoking dopamine release on this timescale. After lever presses, there were further increases in dopamine concentration at the concurrent presentation of cocaine-related cues. These cues alone also elicited similar, rapid dopamine signalling, but only in animals where they had previously been paired to cocaine delivery. These findings reveal an unprecedented role for dopamine in the regulation of drug taking in real time.

  12. Geochemistry of acid mine drainage from a coal mining area and processes controlling metal attenuation in stream waters, southern Brazil

    Directory of Open Access Journals (Sweden)

    VERIDIANA P. CAMPANER

    2014-06-01

    Full Text Available Acid drainage influence on the water and sediment quality was investigated in a coal mining area (southern Brazil. Mine drainage showed pH between 3.2 and 4.6 and elevated concentrations of sulfate, As and metals, of which, Fe, Mn and Zn exceeded the limits for the emission of effluents stated in the Brazilian legislation. Arsenic also exceeded the limit, but only slightly. Groundwater monitoring wells from active mines and tailings piles showed pH interval and chemical concentrations similar to those of mine drainage. However, the river and ground water samples of municipal public water supplies revealed a pH range from 7.2 to 7.5 and low chemical concentrations, although Cd concentration slightly exceeded the limit adopted by Brazilian legislation for groundwater. In general, surface waters showed large pH range (6 to 10.8, and changes caused by acid drainage in the chemical composition of these waters were not very significant. Locally, acid drainage seemed to have dissolved carbonate rocks present in the local stratigraphic sequence, attenuating the dispersion of metals and As. Stream sediments presented anomalies of these elements, which were strongly dependent on the proximity of tailings piles and abandoned mines. We found that precipitation processes in sediments and the dilution of dissolved phases were responsible for the attenuation of the concentrations of the metals and As in the acid drainage and river water mixing zone. In general, a larger influence of mining activities on the chemical composition of the surface waters and sediments was observed when enrichment factors in relation to regional background levels were used.

  13. Vascular disease in cocaine addiction.

    Science.gov (United States)

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

    2017-07-01

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

  14. Cocaine detection using piezoresistive microcantilevers

    Science.gov (United States)

    Srijanto, Bernadeta; Cheney, Christine P.; Hedden, David L.; Gehl, Anthony; Ferrell, Thomas L.

    2008-03-01

    Sensitive and inexpensive sensors play a significant role in the analysis of drugs and drug metabolites. Specifically, reliable in vivo detection of cocaine and cocaine metabolites serves as a useful tool in research of the body's reaction to the drug and in the treatment of the drug addiction. We present here a promising cocaine biosensor to be used in the human body. The sensor's active element consists of piezoresistive microcantilevers coated with an oligonucleotide-based aptamer as the cocaine binder. In vitro cocaine detection was carried out by flowing a cocaine solution over the microcantilevers. Advantages of this device are its low power consumption, its high sensitivity, and its potential for miniaturization into an implantable capsule. The limit of detection for cocaine in distilled water was found to be 1 ng/ml.

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

    Science.gov (United States)

    Bruner, Natalie R; Johnson, Matthew W

    2014-03-01

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

  16. Demand Curves for Hypothetical Cocaine in Cocaine-Dependent Individuals

    Science.gov (United States)

    Bruner, Natalie R.; Johnson, Matthew W.

    2013-01-01

    Rationale Drug purchasing tasks have been successfully used to examine demand for hypothetical consumption of abused drugs including heroin, nicotine, and alcohol. In these tasks drug users make hypothetical choices whether to buy drugs, and if so, at what quantity, at various potential prices. These tasks allow for behavioral economic assessment of that drug's intensity of demand (preferred level of consumption at extremely low prices) and demand elasticity (sensitivity of consumption to price), among other metrics. However, a purchasing task for cocaine in cocaine-dependent individuals has not been investigated. Objectives This study examined a novel Cocaine Purchasing Task and the relation between resulting demand metrics and self-reported cocaine use data. Methods Participants completed a questionnaire assessing hypothetical purchases of cocaine units at prices ranging from $0.01 to $1,000. Demand curves were generated from responses on the Cocaine Purchasing Task. Correlations compared metrics from the demand curve to measures of real-world cocaine use. Results Group and individual data were well modeled by a demand curve function. The validity of the Cocaine Purchasing Task was supported by a significant correlation between the demand curve metrics of demand intensity and Omax (determined from Cocaine Purchasing Task data) and self-reported measures of cocaine use. Partial correlations revealed that after controlling for demand intensity, demand elasticity and the related measure, Pmax, were significantly correlated with real-world cocaine use. Conclusions Results indicate that the Cocaine Purchasing Task produces orderly demand curve data, and that these data relate to real-world measures of cocaine use. PMID:24217899

  17. 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. Copyright © 2014 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    2017-11-01

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

  19. Cocaine and Pregnancy

    Science.gov (United States)

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

  20. Cocaine and Psychiatric Symptoms

    OpenAIRE

    Morton, W. Alexander

    1999-01-01

    Background: Cocaine is an addictive drug that produces numerous psychiatric symptoms, syndromes, and disorders. The symptoms include agitation, paranoia, hallucinations, delusions, violence, as well as suicidal and homicidal thinking. They can be primary to the drug's effect or secondary to exacerbation of comorbid psychiatric disorders.

  1. PRELIMINARY DATA REPORT: HUMATE INJECTION AS AN ENHANCED ATTENUATION METHOD AT THE F-AREA SEEPAGE BASINS, SAVANNAH RIVER SITE

    Energy Technology Data Exchange (ETDEWEB)

    Millings, M.

    2013-09-16

    A field test of a humate technology for uranium and I-129 remediation was conducted at the F-Area Field Research Site as part of the Attenuation-Based Remedies for the Subsurface Applied Field Research Initiative (ABRS AFRI) funded by the DOE Office of Soil and Groundwater Remediation. Previous studies have shown that humic acid sorbed to sediments strongly binds uranium at mildly acidic pH and potentially binds iodine-129 (I-129). Use of humate could be applicable for contaminant stabilization at a wide variety of DOE sites however pilot field-scale tests and optimization of this technology are required to move this technical approach from basic science to actual field deployment and regulatory acceptance. The groundwater plume at the F-Area Field Research Site contains a large number of contaminants, the most important from a risk perspective being strontium-90 (Sr-90), uranium isotopes, I-129, tritium, and nitrate. Groundwater remains acidic, with pH as low as 3.2 near the basins and increasing to the background pH of approximately 5at the plume fringes. The field test was conducted in monitoring well FOB 16D, which historically has shown low pH and elevated concentrations of Sr-90, uranium, I-129 and tritium. The field test included three months of baseline monitoring followed by injection of a potassium humate solution and approximately four and half months of post monitoring. Samples were collected and analyzed for numerous constituents but the focus was on attenuation of uranium, Sr-90, and I-129. This report provides background information, methodology, and preliminary field results for a humate field test. Results from the field monitoring show that most of the excess humate (i.e., humate that did not sorb to the sediments) has flushed through the surrounding formation. Furthermore, the data indicate that the test was successful in loading a band of sediment surrounding the injection point to a point where pH could return to near normal during the study

  2. Combined cocaine hydrolase gene transfer and anti-cocaine vaccine synergistically block cocaine-induced locomotion.

    Directory of Open Access Journals (Sweden)

    Marilyn E Carroll

    Full Text Available Mice and rats were tested for reduced sensitivity to cocaine-induced hyper-locomotion after pretreatment with anti-cocaine antibody or cocaine hydrolase (CocH derived from human butyrylcholinesterase (BChE. In Balb/c mice, direct i.p. injection of CocH protein (1 mg/kg had no effect on spontaneous locomotion, but it suppressed responses to i.p. cocaine up to 80 mg/kg. When CocH was injected i.p. along with a murine cocaine antiserum that also did not affect spontaneous locomotion, there was no response to any cocaine dose. This suppression of locomotor activity required active enzyme, as it was lost after pretreatment with iso-OMPA, a selective BChE inhibitor. Comparable results were obtained in rats that developed high levels of CocH by gene transfer with helper-dependent adenoviral vector, and/or high levels of anti-cocaine antibody by vaccination with norcocaine hapten conjugated to keyhole limpet hemocyanin (KLH. After these treatments, rats were subjected to a locomotor sensitization paradigm involving a "training phase" with an initial i.p. saline injection on day 1 followed by 8 days of repeated cocaine injections (10 mg/kg, i.p.. A 15-day rest period then ensued, followed by a final "challenge" cocaine injection. As in mice, the individual treatment interventions reduced cocaine-stimulated hyperactivity to a modest extent, while combined treatment produced a greater reduction during all phases of testing compared to control rats (with only saline pretreatment. Overall, the present results strongly support the view that anti-cocaine vaccine and cocaine hydrolase vector treatments together provide enhanced protection against the stimulatory actions of cocaine in rodents. A similar combination therapy in human cocaine users might provide a robust therapy to help maintain abstinence.

  3. Combined Cocaine Hydrolase Gene Transfer and Anti-Cocaine Vaccine Synergistically Block Cocaine-Induced Locomotion

    Science.gov (United States)

    Carroll, Marilyn E.; Zlebnik, Natalie E.; Anker, Justin J.; Kosten, Thomas R.; Orson, Frank M.; Shen, Xiaoyun; Kinsey, Berma; Parks, Robin J.; Gao, Yang; Brimijoin, Stephen

    2012-01-01

    Mice and rats were tested for reduced sensitivity to cocaine-induced hyper-locomotion after pretreatment with anti-cocaine antibody or cocaine hydrolase (CocH) derived from human butyrylcholinesterase (BChE). In Balb/c mice, direct i.p. injection of CocH protein (1 mg/kg) had no effect on spontaneous locomotion, but it suppressed responses to i.p. cocaine up to 80 mg/kg. When CocH was injected i.p. along with a murine cocaine antiserum that also did not affect spontaneous locomotion, there was no response to any cocaine dose. This suppression of locomotor activity required active enzyme, as it was lost after pretreatment with iso-OMPA, a selective BChE inhibitor. Comparable results were obtained in rats that developed high levels of CocH by gene transfer with helper-dependent adenoviral vector, and/or high levels of anti-cocaine antibody by vaccination with norcocaine hapten conjugated to keyhole limpet hemocyanin (KLH). After these treatments, rats were subjected to a locomotor sensitization paradigm involving a “training phase" with an initial i.p. saline injection on day 1 followed by 8 days of repeated cocaine injections (10 mg/kg, i.p.). A 15-day rest period then ensued, followed by a final “challenge" cocaine injection. As in mice, the individual treatment interventions reduced cocaine-stimulated hyperactivity to a modest extent, while combined treatment produced a greater reduction during all phases of testing compared to control rats (with only saline pretreatment). Overall, the present results strongly support the view that anti-cocaine vaccine and cocaine hydrolase vector treatments together provide enhanced protection against the stimulatory actions of cocaine in rodents. A similar combination therapy in human cocaine users might provide a robust therapy to help maintain abstinence. PMID:22912888

  4. Fingertip and nasal tip thermal burn in crack cocaine user*

    Science.gov (United States)

    Bernardes, Fred; da Silva, Ystannyslau Bernardes; Martins, Luiz Gustavo; Sasso, Letícia Soares; de Abreu, Marilda Aparecida Milanez Morgado

    2013-01-01

    Crack cocaine addiction is a public health problem in Brazil. It is an endemic disease that affects rural and urban areas. The Ministry of Health has launched emergency programs for the treatment of dependents and to combat drug trafficking. Recognition of dermatological signs of this disease is important because through them the diagnosis can be suspected and early treatment of patients with crack cocaine addiction be provided. PMID:24173204

  5. Enhanced Choice for Viewing Cocaine Pictures in Cocaine Addiction

    International Nuclear Information System (INIS)

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

    2009-01-01

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

  6. 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.

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

    Science.gov (United States)

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

    2015-12-01

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

  8. Prenatal and postnatal cocaine exposure predict teen cocaine use

    Science.gov (United States)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2011-01-01

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

  10. Role of the agranular insular cortex in contextual control over cocaine-seeking behavior in rats.

    Science.gov (United States)

    Arguello, Amy A; Wang, Rong; Lyons, Carey M; Higginbotham, Jessica A; Hodges, Matthew A; Fuchs, Rita A

    2017-08-01

    Environmental stimulus control over drug relapse requires the retrieval of context-response-cocaine associations, maintained in long-term memory through active reconsolidation processes. Identifying the neural substrates of these phenomena is important from a drug addiction treatment perspective. The present study evaluated whether the agranular insular cortex (AI) plays a role in drug context-induced cocaine-seeking behavior and cocaine memory reconsolidation. Rats were trained to lever press for cocaine infusions in a distinctive context, followed by extinction training in a different context. Rats in experiment 1 received bilateral microinfusions of vehicle or a GABA agonist cocktail (baclofen and muscimol (BM)) into the AI or the overlying somatosensory cortex (SSJ, anatomical control region) immediately before a test of drug-seeking behavior (i.e., non-reinforced lever presses) in the previously cocaine-paired context. The effects of these manipulations on locomotor activity were also assessed in a novel context. Rats in experiment 2 received vehicle or BM into the AI after a 15-min reexposure to the cocaine-paired context, intended to reactivate context-response-cocaine memories and initiate their reconsolidation. The effects of these manipulations on drug context-induced cocaine-seeking behavior were assessed 72 h later. BM-induced pharmacological inactivation of the AI, but not the SSJ, attenuated drug context-induced reinstatement of cocaine-seeking behavior without altering locomotor activity. Conversely, AI inactivation after memory reactivation failed to impair subsequent drug-seeking behavior and thus cocaine memory reconsolidation. These findings suggest that the AI is a critical element of the neural circuitry that mediates contextual control over cocaine-seeking behavior.

  11. Anti-cocaine antibody and butyrylcholinesterase-derived cocaine hydrolase exert cooperative effects on cocaine pharmacokinetics and cocaine-induced locomotor activity in mice

    OpenAIRE

    Brimijoin, Stephen; Orson, Frank; Kosten, Tom; Kinsey, Berma; Shen, Xiao Yun; White, Sarah J.; Gao, Yang

    2012-01-01

    We are investigating treatments for cocaine abuse based on viral gene transfer of a cocaine hydrolase (CocH) derived from human butyrylcholinesterase, which can reduce cocaine-stimulated locomotion and cocaine-primed reinstatement of drug-seeking behavior in rats for many months. Here, in mice, we explored the possibility that anti-cocaine antibodies can complement the actions of CocH to reduce cocaine uptake in brain and block centrally-evoked locomotor stimulation. Direct injections of test...

  12. Cocaine-, caffeine-, and stress-evoked cocaine reinstatement in high vs. low impulsive rats: treatment with allopregnanolone.

    Science.gov (United States)

    Regier, Paul S; Claxton, Alexander B; Zlebnik, Natalie E; Carroll, Marilyn E

    2014-10-01

    Previous research indicates that individual differences in traits such as impulsivity, avidity for sweets, and novelty reactivity are predictors of several aspects of drug addiction. Specifically, rats that rank high on these behavioral measures are more likely than their low drug-seeking counterparts to exhibit several characteristics of drug-seeking behavior. In contrast, initial work suggests that the low drug-seeking animals are more reactive to negative events (e.g., punishment and anxiogenic stimuli). The goal of this study was to compare high and low impulsive rats on reinstatement of cocaine-seeking behavior elicited by cocaine (COC) and by negative stimuli such as the stress-inducing agent yohimbine (YOH) or a high dose of caffeine (CAFF). An additional goal was to determine whether treatment with allopregnanolone (ALLO) would reduce reinstatement (or relapse) of cocaine-seeking behavior under these priming conditions. Female rats were selected as high (HiI) or low (LoI) impulsive using a delay-discounting task. After selection, they were allowed to self-administer cocaine for 12 days. Cocaine was then replaced with saline, and rats extinguished lever responding over 16 days. Subsequently, rats were pretreated with either vehicle control or ALLO, and cocaine seeking was reinstated by injections of COC, CAFF, or YOH. While there were no phenotype differences in maintenance and extinction of cocaine self-administration or reinstatement under control treatment conditions, ALLO attenuated COC- and CAFF-primed reinstatement in LoI but not HiI rats. Overall, the present findings suggest that individual differences in impulsive behavior may influence efficacy of interventions aimed to reduce drug-seeking behavior. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  13. Recurrent Thrombotic Vasculopathy in a Former Cocaine User

    Directory of Open Access Journals (Sweden)

    Preeti Jadhav

    2015-01-01

    Full Text Available We report a case of a 35-year-old female who presented to the emergency room (ER complaining of a pruritic rash involving multiple areas of the body. She had a significant history of cocaine use in the past. She had first developed a similar rash in 2013 when she was diagnosed with cocaine-induced vasculitis. Her urine toxicology had been positive for cocaine in the past until July 2013. She was incarcerated and attended a drug rehabilitation program after which she quit cocaine use, which was consistent with negative urine toxicology on subsequent admissions. Further workup did not reveal any other, autoimmune or infectious, etiology of this clinical presentation. The patient underwent biopsy of the skin lesion that was consistent with thrombotic vasculopathy likely secondary to levamisole.

  14. Generation of a Four-Class Attenuation Map for MRI-Based Attenuation Correction of PET Data in the Head Area Using a Novel Combination of STE/Dixon-MRI and FCM Clustering.

    Science.gov (United States)

    Khateri, Parisa; Saligheh Rad, Hamidreza; Jafari, Amir Homayoun; Fathi Kazerooni, Anahita; Akbarzadeh, Afshin; Shojae Moghadam, Mohsen; Aryan, Arvin; Ghafarian, Pardis; Ay, Mohammad Reza

    2015-12-01

    The aim of this study is to generate a four-class magnetic resonance imaging (MRI)-based attenuation map (μ-map) for attenuation correction of positron emission tomography (PET) data of the head area using a novel combination of short echo time (STE)/Dixon-MRI and a dedicated image segmentation method. MR images of the head area were acquired using STE and two-point Dixon sequences. μ-maps were derived from MRI images based on a fuzzy C-means (FCM) clustering method along with morphologic operations. Quantitative assessment was performed to evaluate generated MRI-based μ-maps compared to X-ray computed tomography (CT)-based μ-maps. The voxel-by-voxel comparison of MR-based and CT-based segmentation results yielded an average of more than 95 % for accuracy and specificity in the cortical bone, soft tissue, and air region. MRI-based μ-maps show a high correlation with those derived from CT scans (R (2) > 0.95). Results indicate that STE/Dixon-MRI data in combination with FCM-based segmentation yields precise MR-based μ-maps for PET attenuation correction in hybrid PET/MRI systems.

  15. Topiramate increases the rewarding properties of cocaine in young-adult mice limiting its clinical usefulness.

    Science.gov (United States)

    Arenas, M C; Mateos-García, A; Manzanedo, C; Rodríguez-Arias, M; Aguilar, M A; Navarrete, F; Gutiérrez, M S García; Manzanares, J; Miñarro, J

    2016-12-01

    Topiramate is an anticonvulsant drug which has been evaluated as a therapeutic option for the treatment of cocaine addiction during the last decade. The purpose of this study was to evaluate the effects of topiramate on the reinforcing actions of cocaine. To this aim, the topiramate-mediated regulation of acquisition and extinction phases of the cocaine conditioned place preference (CPP) was assessed in young-adult mice using three experimental designs. Topiramate (50 mg/kg, p.o.) was given as follows: (1) during cocaine (1 and 25 mg/kg, i.p.) conditioning sessions (4 days) and cocaine (25 mg/kg) post-conditioning session; (2) 2 weeks before and during cocaine conditioning (25 mg/kg); and (3) during extinction of CPP induced by cocaine (25 mg/kg). In the first experimental design, changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) gene expressions were measured in the ventral tegmental area (VTA). Topiramate significantly increased cocaine-induced CPP and delayed or failed to produce extinction after the first cocaine reinstatement extinction in the first and second experiments. Furthermore, treatment with topiramate after place conditioning blocked the extinction of cocaine-induced CPP. TH and DAT gene expression in the VTA was significantly lower both with topiramate alone and in combination with cocaine compared with animals receiving only cocaine. These findings suggest that topiramate increases the rewarding properties of cocaine, at least in part, by regulating dopaminergic signaling in the mesolimbic circuit. Consequently, the results of this study do not support the use of topiramate for the treatment of problems related to cocaine dependence. • Topiramate increases the rewarding properties of cocaine in CPP • Topiramate alters dopaminergic signaling in the mesolimbic circuit • Topiramate delays the extinction of cocaine-induced CPP • TH and DAT gene expression in the VTA decreases with topiramate and/or with cocaine

  16. 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...

  17. Sample Differentiation: Cocaine Example.

    Science.gov (United States)

    Baugh, L D; Liu, R H

    1991-12-01

    Since the analyses of drug samples in crime laboratories are often associated with investigations, potential differentiations of test samples are frequently requested and explored. Cocaine sample differentiation requires the determination of synthetic or natural origin. Synthetic samples are characterized by the presence of optical isomers, certain diastereoisomers and other by-products, and chemical residues used in synthesis. Samples derived from a natural origin (coca leaves) are characterized by the presence of certain natural products or their derivatives that are carried through the overall process and by residual chemicals reflecting the treatment procedures. Various approaches and analytical data available in the literature concerning the differentiation of cocaine samples are reviewed. Each sample must carry its own "signature"; however, true sample "individualization" cannot be accomplished using the technologies commonly available and used in crime laboratories, and is not usually needed. Alternatively, "classifying" cocaine samples in certain categories or groups can be accomplished routinely and often provides adequate information for investigatory purposes. Copyright © 1991 Central Police University.

  18. Intracellular mechanisms of cocaine-memory reconsolidation in the basolateral amygdala and dorsal hippocampus

    Science.gov (United States)

    Wells, Audrey Marie

    0126 was administered after exposure to an unpaired context), suggesting that ERK in the BLA plays a critical role in restabilizing contextual cocaine-related memories. Next, Experiment 2 evaluated the hypothesis that the transcription factor (TF) nuclear factor-kappaB (NF-kappaB) would also critically mediate instrumental cocaine-memory reconsolidation in the BLA. Remarkably, the NF-kappaB inhibitor, sulfasalazine (SSZ), administered bilaterally into the BLA following cocaine-memory reactivation, did not significantly alter subsequent cocaine-seeking behavior, relative to VEH, despite producing an observable trend for an enhancement in this behavior. Future studies will be needed to further examine this relationship, but the present findings may suggest that NF-kappaB TFs acts as negative regulators of cocaine-memory reconsolidation. Finally, Experiment 3 tested the hypothesis that members of the Src family of tyrosine kinases (SFKs) are obligatory for instrumental cocaine-memory reconsolidation. Consistent with our hypothesis, PP2, a nonspecific inhibitor of SFKs, administered bilaterally into the DH after cocaine-memory reactivation, attenuated subsequent drug-context induced motivation for cocaine, relative to VEH, in a memory reactivation-dependent manner. This effect was associated with a preferential disruption of SFK-mediated phosphorylation of the NR2a N-methyl-D-aspartate receptor (NMDAR) subunit. Together, these findings begin to illuminate how the BLA and DH may subserve the long-term stability of maladaptive cocaine-related memories that underlie contextual stimulus control over cocaine-seeking behavior.

  19. Groundwater contamination in coastal urban areas: Anthropogenic pressure and natural attenuation processes. Example of Recife (PE State, NE Brazil).

    Science.gov (United States)

    Bertrand, G; Hirata, R; Pauwels, H; Cary, L; Petelet-Giraud, E; Chatton, E; Aquilina, L; Labasque, T; Martins, V; Montenegro, S; Batista, J; Aurouet, A; Santos, J; Bertolo, R; Picot, G; Franzen, M; Hochreutener, R; Braibant, G

    2016-09-01

    In a context of increasing land use pressure (over-exploitation, surface-water contamination) and repeated droughts, identifying the processes affecting groundwater quality in coastal megacities of the tropical and arid countries will condition their long-term social and environmental sustainability. The present study focuses on the Brazilian Recife Metropolitan Region (RMR), which is a highly urbanized area (3,743,854 inhabitants in 2010) on the Atlantic coast located next to an estuarial zone and overlying a multi-layered sedimentary system featured by a variable sediment texture and organic content. It investigates the contamination and redox status patterns conditioning potential attenuation within the shallow aquifers that constitute the interface between the city and the strategic deeper semi-confined aquifers. These latter are increasingly exploited, leading to high drawdown in potenciometric levels of 20-30m and up to 70m in some high well density places, and potentially connected to the surface through leakage. From a multi-tracer approach (major ions, major gases, δ(11)B, δ(18)O-SO4, δ(34)S-SO4) carried out during two field campaigns in September 2012 and March 2013 (sampling of 19 wells and 3 surface waters), it has been possible to assess the contamination sources and the redox processes. The increasing trend for mineralization from inland to coastal and estuarial wells (from 119 to around 10,000μS/cm) is at first attributed to water-rock interactions combined with natural and human-induced potentiometric gradients. Secondly, along with this trend, one finds an environmental pressure gradient related to sewage and/or surface-channel network impacts (typically depleted δ(11)B within the range of 10-15‰) that are purveyors of chloride, nitrate, ammonium and sulfate. Nitrate, ammonium and sulfate (ranging from 0 to 1.70mmol/L, from 0 to 0,65mmol/L, from 0.03 to 3.91mmol/L respectively are also potentially produced or consumed through various redox

  20. Field-scale model for the natural attenuation of uranium at the Hanford 300 area using high performance computing

    Energy Technology Data Exchange (ETDEWEB)

    Lichtner, Peter C [Los Alamos National Laboratory; Hammond, Glenn E [PNNL

    2009-01-01

    Three-dimensional reactive flow and transport simulations are carried out to better understand the persistence of uranium [U(VI)] at the Hanford 300 Area bordering the Columbia River. The massively parallel code PFLOTRAN developed under a DOE SciDAC-2 project is employed in the simulations. The calculations were carried out on 4096 processor cores on ORNL's Jaguar XT4 & 5 Cray supercomputers with run times on the order of 6 hours, equivalent to several years if performed on a single processor with sufficient memory. A new conceptual model is presented for understanding present-day and future attenuation rates of U(VI) at the 300 Area site. Unique to the conceptual model is the recognition of three distinct phases in the evolution of the site corresponding to: (I) initial emplacement of waste; (II) present-day conditions of slow leaching of U(VI) from the Hanford sediments; and (III) the complete removal of non-labile U(VI) from the source region. This work focuses on Phase II. Both labile and non-labile forms of U(VI) are included in the model as sorbed and mineralized forms of U(VI), respectively. The non-labile form plays an important role in providing a long-term source of U(VI) as it slowly leaches out of the Hanford sediment. Rapid fluctuations in the Columbia River stage on hourly, weekly and seasonal time scales are found to' playa major role in determining the migration behavior of U(VI). The calculations demonstrate that U(VI) is released into the Columbia River at a highly fluctuating rate in a ratchet-like behavior with nonzero U(VI) flux occurring only during flow from contaminated sediment into the river. The cumulative flux, however, is found to increase approximately linearly with time. The flow rate and U(VI) flux into the Columbia River predicted by the model is highly sensitive to the value used in the conductance boundary condition at the river-sediment interface. By fitting the conductance to the measured piezometric head at well 399

  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 craving during protracted withdrawal requires PKCε priming within vmPFC.

    Science.gov (United States)

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

    2017-05-01

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

  3. The mPer2 clock gene modulates cocaine actions in the mouse circadian system.

    Science.gov (United States)

    Brager, Allison J; Stowie, Adam C; Prosser, Rebecca A; Glass, J David

    2013-04-15

    Cocaine is a potent disruptor of photic and non-photic pathways for circadian entrainment of the master circadian clock of the suprachiasmatic nucleus (SCN). These actions of cocaine likely involve its modulation of molecular (clock gene) components for SCN clock timekeeping. At present, however, the physiological basis of such an interaction is unclear. To address this question, we compared photic and non-photic phase-resetting responses between wild-type (WT) and Per2 mutant mice expressing nonfunctional PER2 protein to systemic and intra-SCN cocaine administrations. In the systemic trials, cocaine was administered i.p. (20 mg/kg) either at midday or prior to a light pulse in the early night to assess its non-photic and photic behavioral phase-resetting actions, respectively. In the intra-SCN trial, cocaine was administered by reverse microdialysis at midday to determine if the SCN is a direct target for its non-photic phase-resetting action. Non-photic phase-advancing responses to i.p. cocaine at midday were significantly (∼3.5-fold) greater in Per2 mutants than WTs. However, the phase-advancing action of intra-SCN cocaine perfusion at midday did not differ between genotypes. In the light pulse trial, Per2 mutants exhibited larger photic phase-delays than did WTs, and the attenuating action of cocaine on this response was proportionately larger than in WTs. These data indicate that the Per2 clock gene is a potent modulator of cocaine's actions in the circadian system. With regard to non-photic phase-resetting, the SCN is confirmed as a direct target of cocaine action; however, Per2 modulation of this effect likely occurs outside of the SCN. Copyright © 2013 Elsevier B.V. All rights reserved.

  4. Dose- and time-dependent effects of mirtazapine on the expression of cocaine-induced behavioral sensitization in rats.

    Science.gov (United States)

    Barbosa-Méndez, Susana; Matus-Ortega, Maura; Flores-Zamora, Anabel; Jurado, Noe; Salazar-Juárez, Alberto

    2017-08-01

    Relapse to cocaine use is a major problem in the clinical treatment of cocaine dependence. Antidepressant medications have been studied as potential therapeutic drugs to relieve a cocaine dependence disorder. Mirtazapine is an antidepressant implicated in reducing behavioral alterations induced by drugs of abuse. We have reported elsewhere that 30mg/kg mirtazapine administered for 30 days during cocaine extinction significantly attenuated the induction and expression of cocaine-induced locomotor sensitization and decreased the duration of the cocaine-induced locomotor effect. This study focused on exploring whether different mirtazapine dosing regimens could optimize and/or improve the effect of 30mg/kg mirtazapine administered for 30 days on cocaine-induced locomotor activity during the expression phase of behavioral sensitization. Our study revealed that the daily dosing regimen with a fixed dose of mirtazapine (30mg/kg ip) over 60 days improved the decrease in cocaine-induced locomotor activity and behavioral sensitization obtained by dosing of 30mg mirtazapine for 30 days. In addition, it showed that a dosing regimen of 30mg/Kg mirtazapine for 30 days managed to reduce cocaine toxicity. These results suggested that dosage of mirtazapine for 30 consecutive days may be an effective therapy. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  5. Cocaine/Crack: The Big Lie.

    Science.gov (United States)

    National Inst. on Drug Abuse (DHHS/PHS), Rockville, MD.

    This pamphlet focuses on cocaine and crack use and the addictive nature of cocaine/crack. It contains a set of 21 questions about crack and cocaine, each accompanied by a clear and complete response. Interspersed throughout the booklet are photographs and quotes from former cocaine or crack users/addicts. Questions and answers focus on what…

  6. 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

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

    Science.gov (United States)

    Joseph, Lauren; Thomsen, Morgane

    2017-06-30

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

  8. Pancreatitis Induced by Cocaine

    Directory of Open Access Journals (Sweden)

    Sebastián Pablo Chapela

    2017-04-01

    Full Text Available Pancreatitis is one of the commonest diseases of the gastrointestinal tract, characterized by epigastric pain of moderate to severe intensity, which radiates to the back, elevation of pancreatic lipase and amylase enzymes, and changes in pancreatic parenchyma in imaging methods. The most common etiologies vary, generally the most frequent being biliary lithiasis and alcohol, followed by hypertriglyceridemia. Among the less frequent causes is drug-induced pancreatitis. We report a case of acute pancreatitis caused by cocaine, rarely described in literature.

  9. Reward and Toxicity of Cocaine Metabolites Generated by Cocaine Hydrolase.

    Science.gov (United States)

    Murthy, Vishakantha; Geng, Liyi; Gao, Yang; Zhang, Bin; Miller, Jordan D; Reyes, Santiago; Brimijoin, Stephen

    2015-08-01

    Butyrylcholinesterase (BChE) gene therapy is emerging as a promising concept for treatment of cocaine addiction. BChE levels after gene transfer can rise 1000-fold above those in untreated mice, making this enzyme the second most abundant plasma protein. For months or years, gene transfer of a BChE mutated into a cocaine hydrolase (CocH) can maintain enzyme levels that destroy cocaine within seconds after appearance in the blood stream, allowing little to reach the brain. Rapid enzyme action causes a sharp rise in plasma levels of two cocaine metabolites, benzoic acid (BA) and ecgonine methyl ester (EME), a smooth muscle relaxant that is mildly hypotensive and, at best, only weakly rewarding. The present study, utilizing Balb/c mice, tested reward effects and cardiovascular effects of administering EME and BA together at molar levels equivalent to those generated by a given dose of cocaine. Reward was evaluated by conditioned place preference. In this paradigm, cocaine (20 mg/kg) induced a robust positive response but the equivalent combined dose of EME + BA failed to induce either place preference or aversion. Likewise, mice that had undergone gene transfer with mouse CocH (mCocH) showed no place preference or aversion after repeated treatments with a near-lethal 80 mg/kg cocaine dose. Furthermore, a single administration of that same high cocaine dose failed to affect blood pressure as measured using the noninvasive tail-cuff method. These observations confirm that the drug metabolites generated after CocH gene transfer therapy are safe even after a dose of cocaine that would ordinarily be lethal.

  10. Cocaine self-administration in Wistar-Kyoto rats: a behavioral and biochemical analysis.

    Science.gov (United States)

    Jastrzębska, Joanna; Frankowska, Małgorzata; Szumiec, Łukasz; Sadakierska-Chudy, Anna; Haduch, Anna; Smaga, Irena; Bystrowska, Beata; Daniel, Wladyslawa A; Filip, Małgorzata

    2015-10-15

    Depression and cocaine abuse disorders are common concurrent diagnoses. In the present study, we employed Wistar-Kyoto (WKY) rats that showed a depressive-like phenotype to study intravenous cocaine self-administration and extinction/reinstatement procedures. We also investigated the basal tissue level of neurotransmitters, their metabolites and plasma corticosterone (CORT) concentrations in WKY rats, bulbectomized (OBX) rats, and control rats. The WKY rats exhibited an attenuation of the cocaine-associated lever presses and cocaine intake during the acquisition/maintenance of cocaine self-administration only under specific conditions. Active lever presses exhibited by the WKY rats and control animals did not differ during the extinction training and cocaine-seeking behaviors. The WKY rats demonstrated alterations in the basal levels of dopamine, norepinephrine, and serotonin in selected brain structures involved in depression and drug addiction. The changes in the level of neurotransmitters in these animals refer not only to the control (Wistar) rats but also to bulbectomized animals, which represent another depression model. Furthermore, we identified unchanged levels of CORT in the WKY and OBX rats during the light phase and free-stress conditions. This finding suggests that WKY rats should not be used to investigate the co-occurrence of depression and cocaine addiction, as this rat strain does not show an enhanced risk of relapse. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. Counter-attack on cocaine trafficking: the strategy of drug law enforcement.

    Science.gov (United States)

    Caffrey, R J

    1984-01-01

    In the past cocaine was abused by the affluent and the famous members of society while at present it is widely abused by people in all social strata. Both abuse and availability of cocaine are increasing in the United States of America. Cocaine traffickers possess enormous assets, financial resources and means of transport that enable them to remain in operation. The incidence of violent activities, including homicides, is higher among cocaine traffickers than among traffickers in other drugs. Certain cocaine-related criminal groups are routinely engaged in wanton violence. Cocaine trafficking is closely connected with various sorts of crime, corruption and subversive activities. Suppression of cocaine traffic is among the most important priorities of the Drug Enforcement Administration (DEA). Coca plant eradication is regarded as the most effective weapon against cocaine trafficking. DEA special agents, in co-operation with their counterparts from concerned countries, are conducting intelligence exchange, international cocaine investigations and training programmes in cocaine source areas. The United States Government has focused on coordination of efforts of various concerned agencies at the federal, state and local levels to combat drug abuse and trafficking. The Department of Justice has mandated the establishment of law enforcement coordinating councils throughout the United States to ensure appropriate utilization of prosecution resources and to co-ordinate criminal investigative efforts. Task forces against organized crime are established in 12 key areas of the country. Control of precursors and essential chemicals that are used clandestine drug manufacturing is one among other measures currently being undertaken by the Government to suppress trafficking in cocaine and other drugs.

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

    Science.gov (United States)

    Siciliano, Cody A.; Fordahl, Steve C.

    2016-01-01

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

  13. Chronic treatment with Tempol during acquisition or withdrawal from CPP abolishes the expression of cocaine reward and diminishes oxidative damage.

    Science.gov (United States)

    Beiser, Tehila; Numa, Ran; Kohen, Ron; Yaka, Rami

    2017-09-11

    In previous studies, we reported that pretreatment with the antioxidant Tempol attenuated the development and expression of cocaine-induced psychomotor sensitization in rats and diminished cocaine-induced oxidative stress (OS) in the prefrontal cortex (PFC) and nucleus accumbens (NAc), suggesting a potential role for Tempol in interfering with cocaine-related psychomotor sensitization. The aim of the current study was to examine the role of Tempol in reward and reinforcement using the conditioned place preference (CPP) paradigm. We found that administration of Tempol during the conditioning session abolished the expression of cocaine-induced CPP. We also found that OS was significantly elevated following the establishment of CPP, and that cocaine-induced OS was significantly diminished by pretreatment with Tempol during conditioning. Furthermore, we found that repeated, but not single, administration of Tempol for seven days during withdrawal from CPP resulted in significant attenuation in the expression of CPP. Moreover, Tempol did not affect the expression of food reward. Taken together, these findings provide evidence for the involvement of Tempol in regulating cocaine rewarding properties without affecting natural rewards. Since Tempol was found to be effective in reducing OS and expression of CPP following withdrawal, it may be a potential treatment for cocaine addiction.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-10-15

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

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

    International Nuclear Information System (INIS)

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

    2013-01-01

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

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

    Science.gov (United States)

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

    2017-01-01

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

  17. Influence of the dopaminergic system, CREB, and transcription factor-B on cocaine neurotoxicity

    Directory of Open Access Journals (Sweden)

    C.S. Planeta

    2013-11-01

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

  18. Cocaine – Characteristics and addiction

    OpenAIRE

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

    2016-01-01

    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 N...

  19. Trace Amines and Cocaine Abuse

    OpenAIRE

    Li, Jun-Xu

    2014-01-01

    Cocaine addiction remains a clinical challenge with no effective pharmacotherapy available. Trace amine associated receptor (TAAR) 1 represents a promising drug target for the modulation of dopaminergic system and stimulant abuse. This Viewpoint discusses the emerging data which strongly suggest that TAAR 1 functions as a molecular “brake” that controls the addiction-related effects of cocaine and could be a novel drug target for the development of efficacious pharmacothe...

  20. Post-transcriptional regulation of dopamine D1 receptor expression in caudate-putamen of cocaine-sensitized mice.

    Science.gov (United States)

    Tobón, Krishna E; Catuzzi, Jennifer E; Cote, Samantha R; Sonaike, Adenike; Kuzhikandathil, Eldo V

    2015-07-01

    The dopamine D1 receptor is centrally involved in mediating the effects of cocaine and is essential for cocaine-induced locomotor sensitization. Changes in D1 receptor expression have been reported in various models of cocaine addiction; however, the mechanisms that mediate these changes in D1 receptor expression are not well understood. Using preadolescent drd1a-EGFP mice and a binge cocaine treatment protocol we demonstrate that the D1 receptor is post-transcriptionally regulated in the caudate-putamen of cocaine-sensitized animal. While cocaine-sensitized mice express high levels of steady-state D1 receptor mRNA, the expression of D1 receptor protein is not elevated. We determined that the post-transcriptional regulation of D1 receptor mRNA is rapidly attenuated and D1 receptor protein levels increase within 30 min when the sensitized mice are challenged with cocaine. The rapid increase in D1 receptor protein levels requires de novo protein synthesis and correlates with the cocaine-induced hyperlocomotor activity in the cocaine-sensitized mice. The increase in D1 receptor protein levels in the caudate-putamen inversely correlated with the levels of microRNA 142-3p and 382, both of which regulate D1 receptor protein expression. The levels of these two microRNAs decreased significantly within 5 min of cocaine challenge in sensitized mice. The results provide novel insights into the previously unknown rapid kinetics of D1 receptor protein expression which occurs in a time scale that is comparable to the expression of immediate early genes. Furthermore, the results suggest a potential novel role for inherently labile microRNAs in regulating the rapid expression of D1 receptor protein in cocaine-sensitized animals. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  1. Cocaine induces cell death and activates the transcription nuclear factor kappa-b in pc12 cells

    Directory of Open Access Journals (Sweden)

    Lepsch Lucilia B

    2009-02-01

    Full Text Available Abstract Cocaine is a worldwide used drug and its abuse is associated with physical, psychiatric and social problems. The mechanism by which cocaine causes neurological damage is very complex and involves several neurotransmitter systems. For example, cocaine increases extracellular levels of dopamine and free radicals, and modulates several transcription factors. NF-κB is a transcription factor that regulates gene expression involved in cellular death. Our aim was to investigate the toxicity and modulation of NF-κB activity by cocaine in PC 12 cells. Treatment with cocaine (1 mM for 24 hours induced DNA fragmentation, cellular membrane rupture and reduction of mitochondrial activity. A decrease in Bcl-2 protein and mRNA levels, and an increase in caspase 3 activity and cleavage were also observed. In addition, cocaine (after 6 hours treatment activated the p50/p65 subunit of NF-κB complex and the pretreatment of the cells with SCH 23390, a D1 receptor antagonist, attenuated the NF-κB activation. Inhibition of NF-κB activity by using PDTC and Sodium Salicilate increased cell death caused by cocaine. These results suggest that cocaine induces cell death (apoptosis and necrosis and activates NF-κB in PC12 cells. This activation occurs, at least partially, due to activation of D1 receptors and seems to have an anti-apoptotic effect on these cells.

  2. Decreased Cocaine Motor Sensitization and Self-Administration in Mice Overexpressing Cannabinoid CB2 Receptors

    Science.gov (United States)

    Aracil-Fernández, Auxiliadora; Trigo, José M; García-Gutiérrez, María S; Ortega-Álvaro, Antonio; Ternianov, Alexander; Navarro, Daniela; Robledo, Patricia; Berbel, Pere; Maldonado, Rafael; Manzanares, Jorge

    2012-01-01

    The potential involvement of the cannabinoid CB2 receptors (CB2r) in the adaptive responses induced by cocaine was studied in transgenic mice overexpressing the CB2r (CB2xP) and in wild-type (WT) littermates. For this purpose, the acute and sensitized locomotor responses to cocaine, conditioned place preference, and cocaine intravenous self-administration were evaluated. In addition, we assessed whether CB2r were localized in neurons and/or astrocytes, and whether they colocalized with dopamine D1 and D2 receptors (D1Dr and D2Dr). Dopamine (DA) extracellular levels in the nucleus accumbens (NAcc), and gene expression of tyrosine hydroxylase (TH) and DA transporter (DAT) in the ventral tegmental area (VTA), and μ-opioid and cannabinoid CB1 receptors in the NAcc were also studied in both genotypes. CB2xP mice showed decreased motor response to acute administration of cocaine (10–20 mg/kg) and cocaine-induced motor sensitization compared with WT mice. CB2xP mice presented cocaine-induced conditioned place aversion and self-administered less cocaine than WT mice. CB2r were found in neurons and astrocytes and colocalized with D2Dr in the VTA and NAcc. No significant differences in extracellular DA levels in the NAcc were observed between genotypes after cocaine administration. Under baseline conditions, TH and DAT gene expression was higher and μ-opioid receptor gene expression was lower in CB2xP than in WT mice. However, both genotypes showed similar changes in TH and μ-opioid receptor gene expression after cocaine challenge independently of the pretreatment received. Importantly, the cocaine challenge decreased DAT gene expression to a lesser extent in cocaine-pretreated CB2xP than in cocaine-pretreated WT mice. These results revealed that CB2r are involved in cocaine motor responses and cocaine self-administration, suggesting that this receptor could represent a promising target to develop novel treatments for cocaine addiction. PMID:22414816

  3. Response contingency directs long-term cocaine-induced neuroplasticity in prefrontal and striatal dopamine terminals.

    Science.gov (United States)

    Wiskerke, Joost; Schoffelmeer, Anton N M; De Vries, Taco J

    2016-10-01

    Exposure to addictive substances such as cocaine is well-known to alter brain organisation. Cocaine-induced neuroadaptations depend on several factors, including drug administration paradigm. To date, studies addressing the consequences of cocaine exposure on dopamine transmission have either not been designed to investigate the role of response contingency or focused only on short-term neuroplasticity. We demonstrate a key role of response contingency in directing long-term cocaine-induced neuroplasticity throughout projection areas of the mesocorticolimbic dopamine system. We found enhanced electrically-evoked [(3)H]dopamine release from superfused brain slices of nucleus accumbens shell and core, dorsal striatum and medial prefrontal cortex three weeks after cessation of cocaine self-administration. In yoked cocaine rats receiving the same amount of cocaine passively, sensitised dopamine terminal reactivity was only observed in the nucleus accumbens core. Control sucrose self-administration experiments demonstrated that the observed neuroadaptations were not the result of instrumental learning per se. Thus, long-term withdrawal from cocaine self-administration is associated with widespread sensitisation of dopamine terminals throughout frontostriatal circuitries. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  4. Effects of cocaine alone and in combination with mazindol in human cocaine abusers.

    Science.gov (United States)

    Preston, K L; Sullivan, J T; Berger, P; Bigelow, G E

    1993-10-01

    Mazindol is a catecholamine reuptake inhibitor that blocks binding of cocaine at the dopamine reuptake site. This study was conducted to determine whether the acute administration of mazindol modulates the pharmacological effects of intravenous cocaine in humans. In a crossover study, twelve acute drug conditions were tested in randomized order under double-blind, double-dummy conditions in eight cocaine abusers. Cocaine (0, 12.5, 25 and 50 mg, i.v.) was administered in combination with mazindol (0, 1 and 2 mg given orally 2 hr before the cocaine injection). Physiological and subject- and observer-rated responses were measured. Cocaine and mazindol alone both significantly increased heart rate and blood pressure. Cocaine increased ratings on stimulant-like subjective effect measures, including desire for cocaine; mazindol had mild, stimulant-like subjective effects. There were significant interactions between the effects of cocaine and mazindol on heart rate and blood pressure, with combinations producing significantly large and more sustained increases compared with cocaine alone. There was no evidence that mazindol substantially altered the magnitude or profile of the subjective effects of cocaine, including cocaine-induced craving for cocaine. These results do not support the utility of acute administration of mazindol in the treatment of cocaine abusers through a mechanism of modulation of cocaine's subjective effects. Furthermore, mazindol treatment may increase the cardiovascular risks of cocaine.

  5. 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.

  6. Pyrolysis and volatilization of cocaine

    International Nuclear Information System (INIS)

    Martin, B.R.; Lue, L.P.; Boni, J.P.

    1989-01-01

    The increasing popularity of inhaling cocaine vapor prompted the present study, to determine cocaine's fate during this process. The free base of [3H]cocaine (1 microCi/50 mg) was added to a glass pipe, which was then heated in a furnace to simulate freebasing. Negative pressure was used to draw the vapor through a series of glass wool, ethanol, acidic, and basic traps. Air flow rate and temperature were found to have profound effects on the volatilization and pyrolysis of cocaine. At a temperature of 260 degrees C and a flow rate of 400 mL/min, 37% of the radioactivity remained in the pipe, 39% was found in the glass wool trap, and less than 1% in the remainder of the volatilization apparatus after a 10-min volatilization. Reducing the air flow rate to 100 mL/min reduced the amount of radioactivity collected in the glass wool trap to less than 10% of the starting material and increased the amount that remained in the pipe to 58%. GC/MS analysis of the contents of the glass wool trap after volatilization at 260 degrees C and a flow rate of 400 mL/min revealed that 60% of the cocaine remained intact, while approximately 6 and 2% of the starting material was recovered as benzoic acid and methylecgonidine, respectively. As the temperature was increased to 650 degrees C, benzoic acid and methylecgonidine accounted for 83 and 89% of the starting material, respectively, whereas only 2% of the cocaine remained intact. Quantitation of cocaine in the vapor during the course of volatilization revealed high concentrations during the first two min and low concentrations for the remaining time

  7. Effects of Varying RedoxConditions on Natural Attenuation of Inorganic Contaminants from the D-Area Coal Pile Runoff Basin (U)

    Energy Technology Data Exchange (ETDEWEB)

    Kaplan, D

    2004-05-30

    The objective of this study was to provide geochemical parameters to characterize the D-Area Coal Pile Runoff Basin (DCPRB) sediment as a potential source term. It is anticipated that the measured values will be used in risk calculations and will provide additional technical support for imposing Monitored Natural Attenuation at D-Area. This study provides a detailed evaluation of the DCPRB sediment and is part of another study that quantified the Monitored Natural Attenuation of inorganic contaminants more broadly at the D-Area Expanded Operable Unit, which includes the DCPRB (Powell et al. 2004). Distribution coefficients (K{sub d} values; a solid to liquid contaminant concentration ratio) and the Potentially Leachable Fraction (the percent of the total contaminant concentration in the sediment that can likely contribute to a contaminant plume) were measured in a DCPRB sediment as a function of redox conditions. Redox conditions at the DCPRB are expected to vary greatly as the system undergoes varying drying and flooding conditions. Conservative values; K{sub d} values that err on the side of being too low and Potentially Leachable Fraction values that err on the side of being too high, are presented. The K{sub d} values are high compared to conservative literature values, and underscores the importance of measuring site-specific values to provide estimates of sediments natural attenuation/sorption capacities. The Potentially Leachable Fraction indicates that as little as 27% of the As, but all of the Cu and Tl will be part of the source term. In the case of the As, the remaining 83% will likely never leach out of the sediment, thereby providing a form of natural attenuation. Importantly, Be, Cr, Cu, Ni, and V concentrations in the sediment were less-than twice background levels, indicating this sediment was not a potential source for these contaminants. K{sub d} values generally increased significantly (As, Cd, Co, Cr, Cu, Ni, Se, and Tl) when the sediment was

  8. Clinical diagnostic considerations on cocaine abuse.

    Science.gov (United States)

    Palermo, G B; Palermo, M T

    1990-01-01

    Following a review of the research literature on the psychophysiological effects of cocaine, a study is described of a group of 120 cocaine addicts. Of the 120 patients, 10 (8.33%) exhibited fleeting, unformed, organic delusions and hallucinations. Case reports of the 10 cases are presented. The quality of the adverse subjective effects of cocaine is emphasized, and the differential diagnosis between Cocaine Delusional Disorder and Paranoid Schizophrenia is discussed. Guidelines for a more accurate differential diagnosis are provided.

  9. Treatment with modafinil and escitalopram, alone and in combination, on cocaine-induced effects: a randomized, double blind, placebo-controlled human laboratory study.

    Science.gov (United States)

    Verrico, Christopher D; Haile, Colin N; Mahoney, James J; Thompson-Lake, Daisy G Y; Newton, Thomas F; De La Garza, Richard

    2014-08-01

    Concurrent administration of dopamine and serotonin reuptake inhibitors reduces cocaine self-administration in monkeys. Consonant with this, clinical trials assessing modafinil and selective serotonin reuptake inhibitors alone show some efficacy as potential pharmacotherapies for cocaine dependence. We hypothesized that combining modafinil with escitalopram would attenuate the euphoric effects of cocaine to a greater degree than modafinil alone. In a randomized, double blind, parallel groups design participants received either placebo (0mg/day; n=16), modafinil (200mg/day; n=16), escitalopram (20mg/day; n=17), or modafinil+escitalopram (200+20mg/day; n=15) for 5 days. On day 5, during separate sessions participants received an intravenous sample of cocaine (0 or 20mg; randomized) and five $1 bills. Participants rated the subjective effects of the infusions and subsequently made choices to either return $1 and receive another infusion or keep $1 and receive no infusion. Compared to saline, cocaine (20mg) significantly (p≤0.008) increased most ratings, including "good effects", "stimulated", and "high". Relative to placebo, modafinil significantly (p≤0.007) attenuated subject-rated increases of "any drug effect", "high", "good effects", and "stimulated" produced by cocaine. Compared to saline, participants chose cocaine infusions significantly more; however, no treatment significantly reduced choices for cocaine infusions. Escitalopram did not enhance the efficacy of modafinil to reduce any measure. Modafinil attenuated many positive subjective effects produced by cocaine; however, escitalopram combined with modafinil did not enhance the efficacy of modafinil to reduce cocaine effects. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  10. Cocaine Conditioned Behavior: A Cocaine Memory Trace or an Anti-Habituation Effect

    OpenAIRE

    Carey, Robert J.; Damianopoulos, Ernest N.; Shanahan, Arielle B.

    2008-01-01

    Whether cocaine locomotor conditioning represents a cocaine positive effect; i.e., a Pavlovian cocaine conditioned response; or, a cocaine negative effect; i.e., interference with habituation to the test environment, is a subject of some controversy. Three separate experiments were conducted to compare the behavior (locomotion and grooming) of separate groups of rats given 1, 9 or 14 cocaine (10 mg/kg) treatments paired/unpaired with placement into an open-field arena. The behavior of the coc...

  11. Acute Brain Metabolic Effects of Cocaine in Rhesus Monkeys with a History of Cocaine Use

    OpenAIRE

    Henry, Porche’Kirkland; Murnane, Kevin; Votaw, John R.; Howell, Leonard L.

    2010-01-01

    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 i.v. drug self-administration. PET imaging with F-18 labeled fluorodeoxyglucose (FDG) was used to measure acute i.m. cocaine-induced changes in brain metabol...

  12. Lack of Cocaine Self-Administration in Mice Expressing a Cocaine-Insensitive Dopamine Transporter

    OpenAIRE

    Thomsen, Morgane; Han, Dawn D.; Gu, Howard H.; Caine, S. Barak

    2009-01-01

    Cocaine addiction is a worldwide public health problem for which there are no established treatments. The dopamine transporter (DAT) is suspected as the primary target mediating cocaine's abuse-related effects based on numerous pharmacological studies. However, in a previous study, DAT knockout mice were reported to self-administer cocaine, generating much debate regarding the importance of the DAT in cocaine's abuse-related effects. Here, we show that mice expressing a “knockin” of a cocaine...

  13. Recent developments in the abuse of cocaine.

    Science.gov (United States)

    Cohen, S

    1984-01-01

    Cocaine is a powerful euphoriant and it relieves, though only transiently, depression, dread and dysphoria. New patterns of cocaine abuse, such as the inhalation of vaporized cocaine base, the intravenous injection of cocaine hydrochloride and the smoking of coca paste, produce a brief elation that quickly gives way either to a return to the baseline mood or to displeasure, resulting in a strong desire to return to the momentary ecstatic experience, a cycle that leads to compulsive use. The enormous profits made from illicit traffic in cocaine lead to corruption, violence and political destabilization. The individual costs of cocaine abuse include loss of personal fortunes, jobs and families. The safety of cocaine use is a myth. There are a number of ways in which cocaine can be lethal. The high doses of cocaine abused today induce physical dependence, but this is less a contributory factor than the intense psychological craving to perpetuate cocaine use. There is no specific way to treat dysfunctional cocaine use; instead the treatment plan must deal with the individual's specific situation. Except for a reduction of cocaine supply at the source, preventive measures are only feasible in the context of abstinence from all abusable drugs.

  14. Prenatal Cocaine Exposure and Infant Cortisol Reactivity

    Science.gov (United States)

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

    2009-01-01

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

  15. Cerebral vasculitis associated with cocaine abuse

    International Nuclear Information System (INIS)

    Kaye, B.R.; Fainstat, M.

    1987-01-01

    A case of cerebral vasculitis in a previously healthy 22-year-old man with a history of cocaine abuse is described. Cerebral angiograms showed evidence of vasculitis. A search for possible causes other than cocaine produced no results. The authors include cocaine with methamphetamines, heroin, and ephedrine as illicit drugs that can cause cerebral vasculitis

  16. 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

  17. Cocaine use in pregnancy in Amsterdam

    NARCIS (Netherlands)

    Smit, B. J.; Boer, K.; van Huis, A. M.; Lie-A-Ling, I. S.; Schmidt, S. C.

    1994-01-01

    To study the effects of cocaine use in pregnancy in Amsterdam, clinical data on cocaine-using pregnant women (n = 21) and their offspring (n = 23) were obtained retrospectively (1987-1994) at the Academic Medical Center, Amsterdam. Infants exposed to cocaine had a median gestational age of 39 weeks

  18. α2δ-1 signaling in nucleus accumbens is necessary for cocaine-induced relapse.

    Science.gov (United States)

    Spencer, Sade; Brown, Robyn M; Quintero, Gabriel C; Kupchik, Yonatan M; Thomas, Charles A; Reissner, Kathryn J; Kalivas, Peter W

    2014-06-18

    Relapse to cocaine seeking is associated with potentiated excitatory synapses in nucleus accumbens. α2δ-1 is an auxiliary subunit of voltage-gated calcium channels that affects calcium-channel trafficking and kinetics, initiates extracellular signaling cascades, and promotes excitatory synaptogenesis. Previous data demonstrate that repeated exposure to alcohol, nicotine, methamphetamine, and morphine upregulates α2δ-1 in reward-related brain regions, but it was unclear whether this alteration generalized to cocaine. Here, we show that α2δ-1 protein was increased in nucleus accumbens after cocaine self-administration and extinction compared with saline controls. Furthermore, the endogenous ligand thrombospondin-1, responsible for the synaptogenic properties of the α2δ-1 receptor, was likewise elevated. Using whole-cell patch-clamp recordings of EPSCs in nucleus accumbens, we demonstrated that gabapentin, a specific α2δ-1 antagonist, preferentially reduced the amplitude and increased the paired-pulse ratio of EPSCs evoked by electrical stimulation in slices from cocaine-experienced rats compared with controls. In vivo, gabapentin microinjected in the nucleus accumbens core attenuated cocaine-primed but not cue-induced reinstatement. Importantly, gabapentin's effects on drug seeking were not due to a general depression of spontaneous or cocaine-induced locomotor activity. Moreover, gabapentin had no effect on reinstatement of sucrose seeking. These data indicate that α2δ-1 contributes specifically to cocaine-reinstated drug seeking, and identifies this protein as a target for the development of cocaine relapse medications. These results also inform ongoing discussion in the literature regarding efficacy of gabapentin as a candidate addiction therapy. Copyright © 2014 the authors 0270-6474/14/338605-07$15.00/0.

  19. Cocaine exposure modulates dopamine and adenosine signaling in the fetal brain

    Science.gov (United States)

    Kubrusly, Regina C. C.; Bhide, Pradeep G.

    2009-01-01

    Exposure to cocaine during the fetal period can produce significant lasting changes in the structure and function of the brain. Cocaine exerts its effects on the developing brain by blocking monoamine transporters and impairing monoamine receptor signaling. Dopamine is a major central target of cocaine. In a mouse model, we show that cocaine exposure from embryonic day 8 (E8) to E14 produces significant reduction in dopamine transporter activity, attenuation of dopamine D1-receptor function and upregulation of dopamine D2-receptor function. Cocaine’s effects on the D1-receptor are at the level of protein expression as well as activity. The cocaine exposure also produces significant increases in basal cAMP levels in the striatum and cerebral cortex. The increase in the basal cAMP levels was independent of dopamine receptor activity. In contrast, blocking the adenosine A2a receptor downregulated of the basal cAMP levels in the cocaine-exposed brain to physiological levels, suggesting the involvement of adenosine receptors in mediating cocaine’s effects on the embryonic brain. In support of this suggestion, we found that the cocaine exposure downregulated adenosine transporter function. We also found that dopamine D2- and adenosine A2a-receptors antagonize each other’s function in the embryonic brain in a manner consistent with their interactions in the mature brain. Thus, our data show that prenatal cocaine exposure produces direct effects on both the dopamine and adenosine systems. Furthermore, the dopamine D2 and adenosine A2a receptor interactions in the embryonic brain discovered in this study unveil a novel substrate for cocaine’s effects on the developing brain. PMID:19765599

  20. Prenatal and acute cocaine exposure affects neural responses and habituation to visual stimuli

    Directory of Open Access Journals (Sweden)

    Elizabeth Brooke Riley

    2015-08-01

    Full Text Available Psychostimulants have many effects on visual function, from adverse, following acute and prenatal exposure to therapeutic, on attention deficit. To determine the impact of prenatal and acute cocaine exposure on visual processing, we studied neuronal responses to visual stimuli in two brain regions of a transgenic larval zebrafish expressing the calcium indicator GCaMP-HS. We found that both red light (LF and dark (DF flashes elicited similar responses in the optic tectum neuropil (TOn, while the dorsal telencephalon (dTe responded only to LF. Acute cocaine (0.5 μM reduced neuronal responses to LF in both brain regions but did not affect responses to DF. Repeated stimulus presentation led to habituation of dTe neurons to LF. Acute cocaine prevented habituation. TOn habituated to DF, but not LF, and DF habituation was not modified by cocaine. Remarkably, prenatal cocaine exposure prevented the effects of acute cocaine on LF response amplitude and habituation later in development in both brain regions, but did not affect DF responses. We discovered that, in spite of similar neural responses to LF and DF in the TO (superior colliculus in mammals, responses to LF are more complex, involving dTe (homologous to the cerebral cortex, and are more vulnerable to cocaine. Our results demonstrate that acute cocaine exposure affects visual processing differentially by brain region, and that prenatal cocaine exposure modifies zebrafish visual processing in multiple structures in a stimulus-dependent manner. These findings are in accordance with the major role that the optic tectum and cerebral cortex play in sustaining visual attention, and support the hypothesis that modification of these areas by prenatal cocaine exposure may be responsible for visual deficits noted in humans. This model offers new methodological approaches for studying the adverse and therapeutic effects of psychostimulants on attention, and for the development of new pharmacological

  1. Effect of Herbal-Acupuncture on Repeated Cocaine-induced Behavioral Sensitization in the Rat

    Directory of Open Access Journals (Sweden)

    B.B. Lee

    2004-02-01

    Full Text Available Substantial evidence suggests that behavioral and reinforcing effects of cocaine can be mediated by the mesolimbic dopaminergic system. It has been shown that repeated injections of cocaine produce increase in locomotor activity, expression of the immediate-early gene, c-fos in the nucleus accumbens (NAc, which was one of the main dopaminergic terminal areas. Herbal-acupuncture as a therapeutic intervention has been widely used for the treatment of many functional disorders such as drug abuse. Coptidis Rhizoma (CR and its main component, berberine (BER were selected as herbal medicine of herbal-acupuncture. Both medicines have been known to have the therapeutic effect on the central nervous system. In order to investigate the effects of CR and BER herbal-acupuncture at shenmen (HT7 point (CR/H and BER/H on the cocaine-induced behavioral sensitization, the influence of CR/H and BER/H on repeated cocaine-induced locomotor activity, the change of c-Fos expression in the brain by immunohistochemistry were examined. Male SD rats were given CR/H (0.4 mg/kg and BER/H (0.1 mg/kg 30 min before daily injections of cocaine hydrochloride (15 mg/kg, i.p. 10 days. After 3 days withdrawal, rats received a challenge injection of cocaine (15 mg/kg, i.p.. Systemic challenge with cocaine produced much larger increased locomotor activity, accumbal Fos-like immunoreactivity in the NAc. Pretreatment with CR/H and BER/H significantly inhibited cocaine-induced locomotor activity, the change of c-Fos expression in the rats. Our data demonstrated that the inhibitory effects of cocaine-induced behavioral sensitization by CR/H and BER/H were closely associated with the reduction of presynaptic dopamine release in the NAc. These results suggest that CR/H and BER/H can be effectively applied to cocaine addiction.

  2. Antidepressants for cocaine dependence and problematic cocaine use.

    Science.gov (United States)

    Pani, Pier Paolo; Trogu, Emanuela; Vecchi, Simona; Amato, Laura

    2011-12-07

    Cocaine dependence is a disorder for which no pharmacological treatment of proven efficacy exists, advances in the neurobiology could guide future medication development. To investigate the efficacy and acceptability of antidepressants alone or in combination with any psychosocial intervention for the treatment of cocaine dependence and problematic cocaine use. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE and CINAHL in July 2011 and researchers for unpublished trials. Randomised clinical trials comparing antidepressants alone or associated with psychosocial intervention with placebo, no treatment, other pharmacological or psychosocial interventions. Two authors independently assessed trial quality and extracted data. 37 studies were included in the review (3551 participants).Antidepressants versus placebo: results for dropouts did not show evidence of difference, 31 studies, 2819 participants, RR 1.03 (Cl 95% 0.93 to 1.14). Looking at Abstinence from cocaine use, even though not statistically significant, the difference shown by the analysis in the three-weeks abstinence rate was in favour of antidepressants (eight studies, 942 participants, RR 1.22 (Cl 95% 0.99 to 1.51)). Considering only studies involving tricyclics, five studies, 367 participants, or only desipramine, four studies, 254 participants, the evidence was in favour of antidepressants. However, selecting only studies with operationally defined diagnostic criteria, statistical significance favouring antidepressants, as well as the trend for significance shown by the full sample, disappeared. Looking at safety issues, the results did not show evidence of differences (number of patients withdrawn for medical reasons, thirteen studies, 1396 participants, RR 1.39 (Cl 95% 0.91 to 2.12)). Subgroup analysis considering length of the trial, associated opioid dependence or associated psychosocial interventions as confounding factors, failed in showing consistent and

  3. Effects of continuous nicotine treatment and subsequent termination on cocaine versus food choice in male rhesus monkeys.

    Science.gov (United States)

    Schwienteck, Kathryn L; Negus, S Stevens; Poklis, Justin L; Banks, Matthew L

    2015-10-01

    One complicating factor in cocaine addiction may be concurrent exposure and potential dependence on nicotine. The aim of the present study was to determine the effects of continuous nicotine treatment and subsequent termination on cocaine versus food choice in rhesus monkeys (Macaca mulatta). For comparison, we also determined effects of the nicotinic receptor antagonist mecamylamine on cocaine versus food choice during continuous saline and nicotine treatment. Rhesus monkeys (N = 3) responded under a concurrent schedule of food pellet (1 g) and intravenous cocaine (0-0.1 mg/kg/injection) availability. Saline and ascending nicotine doses (0.1-1.0 mg/kg/hr, intravenous) were continuously infused for 7-day treatment periods and separated by 24-hr saline treatment periods. Acute effects of mecamylamine (0.32-1.8 mg/kg, intramuscular, 15 min pretreatment) were determined during continuous saline and 0.32-mg/kg/hr nicotine treatments. During saline treatment, cocaine maintained a dose-dependent increase in cocaine choice. Nicotine treatment did not alter cocaine versus food choice. In contrast, preference of 0.032 mg/kg/injection cocaine was attenuated 24 hr following termination of 0.32-mg/kg/hr nicotine treatment, despite no somatic abstinence signs being observed. Acute mecamylamine enhanced cocaine choice during saline treatment and mainly suppressed rates of behavior during nicotine treatment. Overall, continuous nicotine exposure, up to 1 mg/kg/hr, does not enhance cocaine choice and does not produce nicotine dependence, as demonstrated by the lack of abstinence signs. (c) 2015 APA, all rights reserved).

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

    Science.gov (United States)

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

    2017-07-15

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

  5. Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope.

    Science.gov (United States)

    Tsai, Shang-Yi A; Chuang, Jian-Ying; Tsai, Meng-Shan; Wang, Xiao-Fei; Xi, Zheng-Xiong; Hung, Jan-Jong; Chang, Wen-Chang; Bonci, Antonello; Su, Tsung-Ping

    2015-11-24

    The sigma-1 receptor (Sig-1R) chaperone at the endoplasmic reticulum (ER) plays important roles in cellular regulation. Here we found a new function of Sig-1R, in that it translocates from the ER to the nuclear envelope (NE) to recruit chromatin-remodeling molecules and regulate the gene transcription thereof. Sig-1Rs mainly reside at the ER-mitochondrion interface. However, on stimulation by agonists such as cocaine, Sig-1Rs translocate from ER to the NE, where Sig-1Rs bind NE protein emerin and recruit chromatin-remodeling molecules, including lamin A/C, barrier-to-autointegration factor (BAF), and histone deacetylase (HDAC), to form a complex with the gene repressor specific protein 3 (Sp3). Knockdown of Sig-1Rs attenuates the complex formation. Cocaine was found to suppress the gene expression of monoamine oxidase B (MAOB) in the brain of wild-type but not Sig-1R knockout mouse. A single dose of cocaine (20 mg/kg) in rats suppresses the level of MAOB at nuclear accumbens without affecting the level of dopamine transporter. Daily injections of cocaine in rats caused behavioral sensitization. Withdrawal from cocaine in cocaine-sensitized rats induced an apparent time-dependent rebound of the MAOB protein level to about 200% over control on day 14 after withdrawal. Treatment of cocaine-withdrawn rats with the MAOB inhibitor deprenyl completely alleviated the behavioral sensitization to cocaine. Our results demonstrate a role of Sig-1R in transcriptional regulation and suggest cocaine may work through this newly discovered genomic action to achieve its addictive action. Results also suggest the MAOB inhibitor deprenyl as a therapeutic agent to block certain actions of cocaine during withdrawal.

  6. An allosteric enhancer of M(4) muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine

    DEFF Research Database (Denmark)

    Nielsen, Ditte Dencker; Weikop, Pia; Sørensen, Gunnar

    2012-01-01

    The mesostriatal dopamine system plays a key role in mediating the reinforcing effects of psychostimulant drugs like cocaine. The muscarinic M(4) acetylcholine receptor subtype is centrally involved in the regulation of dopamine release in striatal areas. Consequently, striatal M(4) receptors could...... be a novel target for modulating psychostimulant effects of cocaine....

  7. Dopamine D1 and D3 receptors mediate reconsolidation of cocaine memories in mouse models of drug self-administration.

    Science.gov (United States)

    Yan, Y; Newman, A H; Xu, M

    2014-10-10

    Memories of drug experience and drug-associated environmental cues can elicit drug-seeking and taking behaviors in humans. Disruption of reconsolidation of drug memories dampens previous memories and therefore may provide a useful way to treat drug abuse. We and others previously demonstrated that dopamine D1 and D3 receptors play differential roles in acquiring cocaine-induced behaviors. Moreover, D3 receptors contribute to the reconsolidation of cocaine-induced conditioned place preference. In the present study, we examined effects of manipulating D1 or D3 receptors on reconsolidation of cocaine memories in mouse models of drug self-administration. We found that pharmacological blockade of D1 receptors or a genetic mutation of the D3 receptor gene attenuated reconsolidation that lasted for at least 1week after the memory retrieval. In contrast, with no memory retrieval, pharmacological antagonism of D1 receptors or the D3 receptor gene mutation did not significantly affect reconsolidation of cocaine memories. Pharmacological blockade of D3 receptors also attenuated reconsolidation in wild-type mice that lasted for at least 1week after the memory retrieval. These results suggest that D1 and D3 receptors and related signaling mechanisms play key roles in reconsolidation of cocaine memories in mice, and that these receptors may serve as novel targets for the treatment of cocaine abuse in humans. Copyright © 2014 IBRO. All rights reserved.

  8. 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.

  9. Early postpartum pup preference is altered by gestational cocaine treatment: associations with infant cues and oxytocin expression in the MPOA.

    Science.gov (United States)

    Lippard, E T Cox; Jarrett, T M; McMurray, M S; Zeskind, P S; Garber, K A; Zoghby, C R; Glaze, K; Tate, W; Johns, J M

    2015-02-01

    Cross-fostering studies suggest cocaine-induced deficits in maternal behavior could be associated with altered behavior of offspring following prenatal cocaine-exposure. Neonatal vocalizations are an important offspring cue facilitating early interactions between dam and rodent pup offspring and have been shown to be altered following prenatal cocaine-exposure. It is unclear how variations in acoustic parameters of USVs impact maternal behavior and the mechanism(s) underlying these processes. The present study examined differences in cocaine-exposed and control rodent dam maternal preference of cocaine-exposed or untreated pups in a dual choice apparatus. Relationship of preference-like behavior with pup USVs and dam oxytocin expression was explored. Gestational cocaine-exposure interfered with preference-like behavior of dams on postpartum day 1 with cocaine-exposure associated with decreased time spent on the cocaine-exposed pup side compared to the control pup side, and decreases in preference-like behavior associated in part with decreased number of USVs being emitted by cocaine-exposed pups. On postpartum day 5, decreased oxytocin expression in the medial preoptic area was associated with altered preference-like behavior in cocaine-exposed dams, including frequency and latency to touch/sniff pups. Results indicate cocaine's effects on the mother-infant relationship is likely synergistic, in that cocaine influences mother and offspring both independently and concertedly and that variations within pup vocalizations and the oxytocin system may be potential mechanism(s) underlying this synergistic relationship during the postpartum period. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. The effect of persistence of cocaine use on 12-month outcomes for the treatment of heroin dependence.

    Science.gov (United States)

    Williamson, Anna; Darke, Shane; Ross, Joanne; Teesson, Maree

    2006-02-28

    To determine the effects of cocaine use across the study period on outcomes of treatment for heroin dependence 12 months post-treatment entry. Longitudinal cohort (12 months). Interviews were conducted at baseline, 3 and 12 months. Sydney, Australia. Four hundred ninety-five heroin users recruited for the Australian Treatment Outcome Study and re-interviewed at 12-month follow-up. Cocaine was widely used among treatment entrants in NSW, with almost all having a lifetime history of cocaine use and almost half having used in the month preceding baseline. While there was an overall decline in cocaine use across the study period, individual use patterns varied widely. Approximately half of the cohort did not report cocaine use at any data point, with the remainder reporting having used at one (29%), two (12%), or at all three (5%) points. Cocaine use across the study period was an independent predictor of most major treatment outcomes, with more cocaine use points predicting poorer outcome. Persistent cocaine use predicted a higher prevalence of homelessness, heroin use, daily injecting, needle sharing and injection-related health problems at 12 months as well as more extensive recent polydrug use. Cocaine use was common among individuals seeking treatment for primary heroin dependence in NSW. Any cocaine use over the study period was associated with poorer outcomes in virtually all areas. Persistent cocaine use over the study period, however, appeared particularly detrimental. Cocaine use among clients should evidently be a cause for concern amongst treatment providers and may warrant being specifically targeted during treatment.

  11. Lobeline Attenuates the Locomotor-Activating Properties of ...

    African Journals Online (AJOL)

    Erah

    studies in rats, lobeline (0.3 – 3 mg/kg) attenuated cocaine- and nicotine induced hyperactivity after acute and repeated (12 days) stimulant treatment [11,14]. Recently, our laboratory demonstrated that lobeline diminishes the effects of µ opiate receptor agonists, possibly via an interaction with µ opiate receptors in brain [15].

  12. Effect of experimenter-delivered and self-administered cocaine on extracellular beta-endorphin levels in the nucleus accumbens.

    Science.gov (United States)

    Roth-Deri, I; Zangen, A; Aleli, M; Goelman, R G; Pelled, G; Nakash, R; Gispan-Herman, I; Green, T; Shaham, Y; Yadid, G

    2003-03-01

    Beta-endorphin is an endogenous opioid peptide that has been hypothesized to be involved in the behavioral effects of drugs of abuse including psychostimulants. Using microdialysis, we studied the effect of cocaine on extracellular levels of beta-endorphin in the nucleus accumbens, a brain region involved in the reinforcing effects of psychostimulant drugs. Experimenter-delivered cocaine (2 mg/kg, i.v.) increased extracellular beta-endorphin immunoreactive levels in the nucleus accumbens, an effect attenuated by 6-hydroxy-dopamine lesions or systemic administration of the D1-like receptor antagonist, SCH-23390 (0.25 mg/kg, i.p.). The effect of cocaine on beta-endorphin release in the nucleus accumbens was mimicked by a local perfusion of dopamine (5 microm) and was blocked by coadministration of SCH-23390 (10 microm). Self-administered cocaine (1 mg/kg/infusion, i.v.) also increased extracellular beta-endorphin levels in the nucleus accumbens. In addition, using functional magnetic resonance imaging, we found that cocaine (1 mg/kg, i.v.) increases regional brain activity in the nucleus accumbens and arcuate nucleus. We demonstrate an increase in beta-endorphin release in the nucleus accumbens following experimenter-delivered and self-administered cocaine mediated by the local dopaminergic system. These findings suggest that activation of the beta-endorphin neurons within the arcuate nucleus-nucleus accumbens pathway may be important in the neurobiological mechanisms underlying the behavioral effects of cocaine.

  13. 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

  14. One month of cocaine abstinence potentiates rapid dopamine signaling in the nucleus accumbens core.

    Science.gov (United States)

    Cameron, Courtney M; Wightman, R Mark; Carelli, Regina M

    2016-12-01

    Cocaine addiction is a chronic relapsing disorder that is difficult to treat in part because addicts relapse even after extended periods of abstinence. Given the importance of the mesolimbic dopamine (DA) system in drug addiction, we sought to characterize cocaine abstinence induced changes in rapid DA signaling in the nucleus accumbens (NAc). Here, rats were trained to self-administer cocaine for 14 consecutive days, then divided into two groups. Day 1 rats (D1; n = 7) underwent 24 h of abstinence; Day 30 rats (D30; n = 7) underwent one month of abstinence. After abstinence, all rats underwent a single extinction session. Immediately after, rats were deeply anesthetized and fast scan cyclic voltammetry (FSCV) was used to measure DA release and uptake dynamics in the NAc core before and following a single cocaine injection. We show that one month of cocaine abstinence potentiates the peak concentration of electrically evoked DA in the NAc core following an acute injection of cocaine. This potentiation is not related to alterations in DA uptake parameters, which are unchanged following abstinence, but may reflect alterations in release. These results further support the abundance of literature showing that cocaine abstinence induces neuroplasticity in brain areas implicated in drug reward and relapse. The present findings also demonstrate critical differences between abstinence-induced neuroadaptations in DA signaling and those caused by drug exposure itself. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Arginine Methyltransferase 1 in the Nucleus Accumbens Regulates Behavioral Effects of Cocaine.

    Science.gov (United States)

    Li, Yan; Zhu, Ruiming; Wang, Wenjing; Fu, Dengqi; Hou, Jing; Ji, Sen; Chen, Bo; Hu, Zhengtao; Shao, Xue; Yu, Xuri; Zhao, Qian; Zhang, Baolai; Du, Changman; Bu, Qian; Hu, Chunyan; Tang, Yun; Zhong, Lei; Yang, Shengyong; Zhao, Yinglan; Cen, Xiaobo

    2015-09-16

    downregulation of PRMT1 in NAc also attenuated cocaine-caused CPP and locomotion activity, which was associated with decreased expression of histone H4 arginine 3 asymmetric demethylation (H4R3me2a) and hypoacetylation of histone H3 lysine 9 and 14 (acH3K9/K14). This study also showed that H4R3me2a controlled transcriptions of Cdk5 and CaMKII, and that PRMT1 negatively affected the ability of cocaine to induce CaMKII and Cdk5 in NAc. Notably, increased H4R3me2a by repeated cocaine injection was relatively long-lived as increased expression was observed up to 7 d after withdrawal from cocaine. Together, this study suggests that PRMT1 inhibition may serve as a potential therapeutic strategy for cocaine addiction. Copyright © 2015 the authors 0270-6474/15/3512891-13$15.00/0.

  16. The First American Cocaine Epidemic.

    Science.gov (United States)

    Courtwright, David T.

    1991-01-01

    Discusses the wave of cocaine abuse that followed the drug's recommendation by the late nineteenth-century medical community as a cure all. Details drug addiction among ethnic and social groups at the turn of the century. Warns that drug epidemics have important social and legal consequences. Suggests legal pressure may alter the form of drug…

  17. Acupuncture attenuates cognitive deficits and increases pyramidal neuron number in hippocampal CA1 area of vascular dementia rats.

    Science.gov (United States)

    Li, Fang; Yan, Chao-Qun; Lin, Li-Ting; Li, Hui; Zeng, Xiang-Hong; Liu, Yi; Du, Si-Qi; Zhu, Wen; Liu, Cun-Zhi

    2015-04-28

    Decreased cognition is recognized as one of the most severe and consistent behavioral impairments in dementia. Experimental studies have reported that acupuncture may improve cognitive deficits, relieve vascular dementia (VD) symptoms, and increase cerebral perfusion and electrical activity. Multi-infarction dementia was modeled in rats with 3% microemboli saline suspension. Two weeks after acupuncture at Zusanli (ST36), all rats were subjected to a hidden platform trial to test their 3-day spatial memory using the Morris water maze test. To estimate the numbers of pyramidal neuron, astrocytes, and synaptic boutons in hippocampal CA1 area, we adopted an unbiased stereology method to accurately sample and measure the size of cells. We found that acupuncture at ST36 significantly decreased the escape latency of VD rats. In addition, acupuncture significantly increased the pyramidal neuron number in hippocampal CA1 area (P 0.05). These findings suggest that acupuncture may improve cognitive deficits and increase pyramidal neuron number of hippocampal CA1 area in VD rats.

  18. Psychostimulant drugs for cocaine dependence.

    Science.gov (United States)

    Castells, Xavier; Cunill, Ruth; Pérez-Mañá, Clara; Vidal, Xavier; Capellà, Dolors

    2016-09-27

    Cocaine dependence is a severe disorder for which no medication has been approved. Like opioids for heroin dependence, replacement therapy with psychostimulants could be an effective therapy for treatment. To assess the effects of psychostimulants for cocaine abuse and dependence. Specific outcomes include sustained cocaine abstinence and retention in treatment. We also studied the influence of type of drug and comorbid disorders on psychostimulant efficacy. This is an update of the review previously published in 2010. For this updated review, we searched the Cochrane Drugs and Alcohol Group Trials Register, CENTRAL, MEDLINE, Embase and PsycINFO up to 15 February 2016. We handsearched references of obtained articles and consulted experts in the field. We included randomised parallel group controlled clinical trials comparing the efficacy of a psychostimulant drug versus placebo. We used standard methodological procedures expected by Cochrane. We included 26 studies involving 2366 participants. The included studies assessed nine drugs: bupropion, dexamphetamine, lisdexamfetamine, methylphenidate, modafinil, mazindol, methamphetamine, mixed amphetamine salts and selegiline. We did not consider any study to be at low risk of bias for all domains included in the Cochrane 'Risk of bias' tool. Attrition bias was the most frequently suspected potential source of bias of the included studies. We found very low quality evidence that psychostimulants improved sustained cocaine abstinence (risk ratio (RR) 1.36, 95% confidence interval (CI) 1.05 to 1.77, P = 0.02), but they did not reduce cocaine use (standardised mean difference (SMD) 0.16, 95% CI -0.02 to 0.33) among participants who continued to use it. Furthermore, we found moderate quality evidence that psychostimulants did not improve retention in treatment (RR 1.00, 95% CI 0.93 to 1.06). The proportion of adverse event-induced dropouts and cardiovascular adverse event-induced dropouts was similar for psychostimulants

  19. Treatment of cocaine dependence and depression.

    Science.gov (United States)

    Rounsaville, Bruce J

    2004-11-15

    In common with all other classes of substance use disorders, cocaine dependence has been shown to be strongly associated with depression by community and clinical surveys. Diagnosing depression in cocaine abusers can be challenging because it is difficult to distinguish transient symptoms caused by cocaine from enduring depression syndromes. Nonetheless, both "substance-induced" and "independent" depression syndromes require clinical attention, especially when symptoms have been persistent and severe before entering treatment. Use of antidepressant medications for combined cocaine dependence and depression is supported by a preponderance of evidence from 4 randomized clinical trials (RCTs) that prospectively targeted both depression and cocaine dependence and 7 RCTs in which a post hoc analyses demonstrated efficacy in the subgroup of cocaine abusers with comorbid depression. Notably, most negative studies have evaluated SSRIs while positive studies have used agents such as desipramine or buproprion. A substantial clinical trials literature supports the efficacy of behavioral treatments for general populations of cocaine abusers and of patients with depression but few studies have addressed patients with both disorders. Treatment development and research are needed on models of care that truly integrate strategies for addressing both cocaine use and depression. Recent advances have paved the way for a new generation of research. These include validation of efficacious cocaine treatments, improved diagnostic methods, organization of the Clinical Trials Network and development of guidelines for managing methodological challenges posed by high rates of current medication use and polysubstance abuse in treatment entering cocaine abusers.

  20. Metabolic Enzymes of Cocaine Metabolite Benzoylecgonine.

    Science.gov (United States)

    Chen, Xiabin; Zheng, Xirong; Zhan, Max; Zhou, Ziyuan; Zhan, Chang-Guo; Zheng, Fang

    2016-08-19

    Cocaine is one of the most addictive drugs without a U.S. Food and Drug Administration (FDA)-approved medication. Enzyme therapy using an efficient cocaine-metabolizing enzyme is recognized as the most promising approach to cocaine overdose treatment. The actual enzyme, known as RBP-8000, under current clinical development for cocaine overdose treatment is our previously designed T172R/G173Q mutant of bacterial cocaine esterase (CocE). The T172R/G173Q mutant is effective in hydrolyzing cocaine but inactive against benzoylecgonine (a major, biologically active metabolite of cocaine). Unlike cocaine itself, benzoylecgonine has an unusually stable zwitterion structure resistant to further hydrolysis in the body and environment. In fact, benzoylecgonine can last in the body for a very long time (a few days) and, thus, is responsible for the long-term toxicity of cocaine and a commonly used marker for drug addiction diagnosis in pre-employment drug tests. Because CocE and its mutants are all active against cocaine and inactive against benzoylecgonine, one might simply assume that other enzymes that are active against cocaine are also inactive against benzoylecgonine. Here, through combined computational modeling and experimental studies, we demonstrate for the first time that human butyrylcholinesterase (BChE) is actually active against benzoylecgonine, and that a rationally designed BChE mutant can not only more efficiently accelerate cocaine hydrolysis but also significantly hydrolyze benzoylecgonine in vitro and in vivo. This sets the stage for advanced studies to design more efficient mutant enzymes valuable for the development of an ideal cocaine overdose enzyme therapy and for benzoylecgonine detoxification in the environment.

  1. An analytical and experimental study of sound propagation and attenuation in variable-area ducts. [reducing aircraft engine noise

    Science.gov (United States)

    Nayfeh, A. H.; Kaiser, J. E.; Marshall, R. L.; Hurst, L. J.

    1978-01-01

    The performance of sound suppression techniques in ducts that produce refraction effects due to axial velocity gradients was evaluated. A computer code based on the method of multiple scales was used to calculate the influence of axial variations due to slow changes in the cross-sectional area as well as transverse gradients due to the wall boundary layers. An attempt was made to verify the analytical model through direct comparison of experimental and computational results and the analytical determination of the influence of axial gradients on optimum liner properties. However, the analytical studies were unable to examine the influence of non-parallel ducts on the optimum linear conditions. For liner properties not close to optimum, the analytical predictions and the experimental measurements were compared. The circumferential variations of pressure amplitudes and phases at several axial positions were examined in straight and variable-area ducts, hard-wall and lined sections with and without a mean flow. Reasonable agreement between the theoretical and experimental results was obtained.

  2. 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.

  3. BRG1 in the Nucleus Accumbens Regulates Cocaine-Seeking Behavior.

    Science.gov (United States)

    Wang, Zi-Jun; Martin, Jennifer A; Mueller, Lauren E; Caccamise, Aaron; Werner, Craig T; Neve, Rachael L; Gancarz, Amy M; Li, Jun-Xu; Dietz, David M

    2016-11-01

    Drug addiction is defined as a chronic disease characterized by compulsive drug seeking and episodes of relapse despite prolonged periods of drug abstinence. Neurobiological adaptations, including transcriptional and epigenetic alterations in the nucleus accumbens, are thought to contribute to this life-long disease state. We previously demonstrated that the transcription factor SMAD3 is increased after 7 days of withdrawal from cocaine self-administration. However, it is still unknown which additional factors participate in the process of chromatin remodeling and facilitate the binding of SMAD3 to promoter regions of target genes. Here, we examined the possible interaction of BRG1-also known as SMARCA4, an adenosine triphosphatase-containing chromatin remodeler-and SMAD3 in response to cocaine exposure. The expression of BRG1, as well as its binding to SMAD3 and target gene promoter regions, was evaluated in the nucleus accumbens and dorsal striatum of rats using western blotting, co-immunoprecipitation, and chromatin immunoprecipitation following abstinence from cocaine self-administration. Rats were assessed for cocaine-seeking behaviors after either intra-accumbal injections of the BRG1 inhibitor PFI3 or viral-mediated overexpression of BRG1. After withdrawal from cocaine self-administration, BRG1 expression and complex formation with SMAD3 are increased in the nucleus accumbens, resulting in increased binding of BRG1 to the promoter regions of Ctnnb1, Mef2d, and Dbn1. Intra-accumbal infusion of PFI3 attenuated, whereas viral overexpression of Brg1 enhanced, cocaine-reinstatement behavior. BRG1 is a key mediator of the SMAD3-dependent regulation of cellular and behavioral plasticity that mediates cocaine seeking after a period of withdrawal. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  4. Abstinence environment contributes to age differences in reinstatement of cocaine seeking between adolescent and adult male rats.

    Science.gov (United States)

    Li, Chen; Frantz, Kyle J

    2017-07-01

    Extinction responding and cue-induced reinstatement of cocaine seeking after 60-days of forced abstinence are attenuated in male rats that self-administered cocaine during adolescence, compared with adults. Given that environmental enrichment during abstinence decreases reinstatement among adults, a possible explanation for attenuated reinstatement among adolescents is that standard pair-housing in prior studies creates a more stimulating environment for younger rats. Therefore, we tested whether standard pair-housing is necessary for the attenuated reinstatement among adolescents by determining whether an impoverished environment during abstinence would increase reinstatement among adolescents, up to adult levels. Conversely, we also tested whether environmental enrichment could further decrease reinstatement among adolescents, and whether we could replicate effects of environmental enrichment to decrease reinstatement among adults down to adolescent levels (positive controls). Adolescent and adult male Wistar rats self-administered cocaine intravenously for 12days (fixed ratio 1; 0.36mg/kg per infusion; 2h sessions). Rats were then moved into enriched (grouped, large cages, novel toys), standard (pair-housed, shoebox cages), or impoverished (isolated, hanging cages) housing conditions. After 60days, extinction and cue-induced reinstatement of cocaine seeking were tested, followed by drug-primed reinstatement (0, 5, 10mg/kg cocaine, i.p.). Consistent with previous results, extinction and cue-induced reinstatement were attenuated in adolescent-onset groups compared with adults; this age difference also extended to drug-primed reinstatement. In support of the present hypothesis, an impoverished environment during abstinence increased reinstatement among adolescents to levels that were not different from adult standard-housing levels. These data suggest that abstinence environment influences the enduring effects of cocaine among adolescents as well as adults

  5. Variations in the stimulus salience of cocaine reward influences drug-associated contextual memory.

    Science.gov (United States)

    Liddie, Shervin; Itzhak, Yossef

    2016-03-01

    Drugs of abuse act as reinforcers because they influence learning and memory processes resulting in long-term memory of drug reward. We have previously shown that mice conditioned by fixed daily dose of cocaine (Fix-C) or daily escalating doses of cocaine (Esc-C) resulted in short- and long-term persistence of drug memory, respectively, suggesting different mechanisms in acquisition of cocaine memory. The present study was undertaken to investigate the differential contribution of N-methyl-D-aspartate receptor (NMDAR) subunits in the formation of Fix-C and Esc-C memory in C57BL/6J mice. Training by Esc-C resulted in marked elevation in hippocampal expression of Grin2b mRNA and NR2B protein levels compared with training by Fix-C. The NR2B-containing NMDAR antagonist ifenprodil had similar attenuating effects on acquisition and reconsolidation of Fix-C and Esc-C memory. However, the NMDAR antagonist MK-801 had differential effects: (1) higher doses of MK-801 were required for post-retrieval disruption of reconsolidation of Esc-C memory than Fix-C memory; and (2) pre-retrieval MK-801 inhibited extinction of Fix-C memory but it had no effect on Esc-C memory. In addition, blockade of NMDAR downstream signaling pathways also showed differential regulation of Fix-C and Esc-C memory. Inhibition of neuronal nitric oxide synthase attenuated acquisition and disrupted reconsolidation of Fix-C but not Esc-C memory. In contrast, the mitogen-activating extracellular kinase inhibitor SL327 attenuated reconsolidation of Esc-C but not Fix-C memory. These results suggest that NMDAR downstream signaling molecules associated with consolidation and reconsolidation of cocaine-associated memory may vary upon changes in the salience of cocaine reward during conditioning. © 2014 Society for the Study of Addiction.

  6. Regional influence of cocaine on evoked dopamine release in the nucleus accumbens core: A role for the caudal brainstem.

    Science.gov (United States)

    Gerth, Ashlynn I; Alhadeff, Amber L; Grill, Harvey J; Roitman, Mitchell F

    2017-01-15

    Cocaine increases dopamine concentration in the nucleus accumbens through competitive binding to the dopamine transporter (DAT). However, it also increases the frequency of dopamine release events, a finding that cannot be explained by action at the DAT alone. Rather, this effect may be mediated by cocaine-induced modulation of brain regions that project to dopamine neurons. To explore regional contributions of cocaine to dopamine signaling, we administered cocaine to the lateral or fourth ventricles and compared the effects on dopamine release in the nucleus accumbens evoked by electrical stimulation of the ventral tegmental area to that of systemically-delivered cocaine. Stimulation trains caused a sharp rise in dopamine followed by a slower return to baseline. The magnitude of dopamine release ([DA]max) as well as the latency to decay to fifty percent of the maximum (t(1/2); index of DAT activity) by each stimulation train were recorded. All routes of cocaine delivery caused an increase in [DA]max; only systemic cocaine caused an increase in t(1/2). Importantly, these data are the first to show that hindbrain (fourth ventricle)-delivered cocaine modulates phasic dopamine signaling. Fourth ventricular cocaine robustly increased cFos immunoreactivity in the nucleus of the solitary tract (NTS), suggesting a neural substrate for hindbrain cocaine-mediated effects on [DA]max. Together, the data demonstrate that cocaine-induced effects on phasic dopamine signaling are mediated via actions throughout the brain including the hindbrain. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  7. 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.

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

    Science.gov (United States)

    Zheng, Fang; Zhan, Chang-Guo

    2012-01-01

    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.

  9. Cocaine produces conditioned place aversion in mice with a cocaine insensitive dopamine transporter

    OpenAIRE

    O’Neill, Brian; Tilley, Michael R.; Gu, Howard H.

    2012-01-01

    Cocaine is an inhibitor of the dopamine, norepinephrine, and serotonin reuptake transporters. Because its administration would therefore elevate signaling of all these three neurotransmitters, many studies have been aimed at attributing individual effects of cocaine to specific transmitter systems. Using mice with a cocaine insensitive dopamine transporter (DAT-CI mice), we previously showed that cocaine-induced dopamine elevations were necessary for its rewarding and stimulating effects. In ...

  10. The dual orexin/hypocretin receptor antagonist, almorexant, in the ventral tegmental area attenuates ethanol self-administration.

    Directory of Open Access Journals (Sweden)

    Subhashini Srinivasan

    Full Text Available Recent studies have implicated the hypocretin/orexinergic system in reward-seeking behavior. Almorexant, a dual orexin/hypocretin R(1 and R(2 receptor antagonist, has proven effective in preclinical studies in promoting sleep in animal models and was in Phase III clinical trials for sleep disorders. The present study combines behavioral assays with in vitro biochemical and electrophysiological techniques to elucidate the role of almorexant in ethanol and sucrose intake. Using an operant self-administration paradigm, we demonstrate that systemic administration of almorexant decreased operant self-administration of both 20% ethanol and 5% sucrose. We further demonstrate that intra-ventral tegmental area (VTA infusions, but not intra-substantia nigra infusions, of almorexant reduced ethanol self-administration. Extracellular recordings performed in VTA neurons revealed that orexin-A increased firing and this enhancement of firing was blocked by almorexant. The results demonstrate that orexin/hypocretin receptors in distinct brain regions regulate ethanol and sucrose mediated behaviors.

  11. Modelling natural attenuation of heavy-metal groundwater contamination in the Selebi-Phikwe mining area, Botswana

    Science.gov (United States)

    Schwartz, M. O.; Kgomanyane, J.

    2008-04-01

    Seepage from a tailings dam is the major source of groundwater pollution in the Selebi-Phikwe area, where mining of sulphidic nickel-copper-cobalt ore started in 1973 and will continue until 2014. The seepage water has a pH in the range of 1.7-2.8 and is strongly enriched in SO4 2- (5,680 g/L) and heavy metals (6,230 μg/L Ni, 1,860 μg/L Cu and 410 μg/L Co). The fracture aquifer affected by pollution from the dam exhibits a remarkable capacity of heavy-metal sorption. Most of the Ni, Cu and Co is scavenged at less than 500 m distance downgradient from the polluting source, whereas SO4 2- is not immobilized significantly. The heavy-metal sorption process is assumed to be due to surface complexation, which is supported by a relatively high groundwater pH (in the range of 6.2-7.8 at >200 m distance from the tailings dam). The objective of this study is to demonstrate that the sorption process can be incorporated into a realistic three-dimensional reactive-transport groundwater model that is implicitly charge-balanced. The simulations are performed with the PHAST1.2 program, which is based on the HST3D flow and transport code and the hydrochemical PHREEQC2.12 code.

  12. Expiratory CT in cigarette smokers: correlation between areas of decreased lung attenuation, pulmonary function tests and smoking history

    Energy Technology Data Exchange (ETDEWEB)

    Verschakelen, J.A.; Scheinbaum, K.; Bogaert, J.; Baert, A.L. [Department of Radiology, University Hospitals, Leuven (Belgium); Demedts, M.; Lacquet, L.L. [Department of Pneumology, University Hospitals, Leuven (Belgium)

    1998-10-01

    The aim of this study was to determine the correlation between cigarette-smoke-related bronchial disease and air trapping as assessed by expiratory high-resolution CT (HRCT) scans. Thirty healthy subjects (11 non-smokers, 7 ex-smokers for > 2 years, 12 current smokers; age range 35-55 years) with a smoking history between 0 and 28.5 pack-years underwent pulmonary function tests (PFT) and HRCT in inspiration and expiration in supine and prone position. The extent of air trapping was scored in ventral and dorsal aspects of the upper, middle and lower lung portions. In 24 subjects (7 non-smokers, 7 ex-smokers, 10 current smokers) areas of focal air trapping were found, and were present significantly more often in dependent lung portions (p < 0.05) compared with non-dependent portions. No significant differences were found between apical and basal lung zones. Scores of focal air trapping were not significantly different between smokers and ex-smokers, but were significantly lower (p < 0.05) in non-smokers and showed a significant (p < 0.0005) correlation with pack-years. The degree of air trapping was also associated with several lung function tests, especially RV, DLCO, FRC, FEV1 and FEV1/VC. Air trapping is seen in smokers with normal PFT and correlates with the severity of the smoking history, independently of current smoking status. (orig.) (orig.) With 4 figs., 4 tabs., 59 refs.

  13. The impact of recent cocaine use on plasma levels of methadone and buprenorphine in patients with and without HIV-infection.

    Science.gov (United States)

    Tetrault, Jeanette M; McCance-Katz, Elinore F; Moody, David E; Fiellin, David A; Lruie, Bonnie S; DInh, An T; Fiellin, Lynn E

    2015-04-01

    Cocaine decreases methadone and buprenorphine plasma concentrations. HIV infection and/or antiretroviral medication use may impact these relationships. We sought to determine the association between recent cocaine use and methadone and buprenorphine concentrations in HIV-infected and uninfected subjects in clinical care. R- and S-methadone or buprenorphine and norbuprenorphine concentrations were assessed at 0.5, 1, 2, and 24 hours after dosing in subjects with confirmed cocaine use and abstinence. We compared methadone and buprenorphine concentrations for cocaine use vs. abstinence, by HIV status in 16 subjects receiving methadone (6 HIV-infected) and 17 receiving buprenorphine (8 HIV-infected). With recent cocaine use, peak R-methadone (244 vs. 297 ng/mL, p = 0.03) and peak S-methadone (285 vs. 339 ng/mL); p = 0.03 concentrations were lower in HIV-uninfected subjects only. Peak buprenorphine and norbuprenorphine concentrations were unchanged regardless of cocaine use or HIV status. Cocaine may decrease methadone concentrations in HIV-uninfected subjects. HIV infection or its treatment may attenuate cocaine's effect on methadone. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. 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.

  15. Hormones, Nicotine and Cocaine: Clinical Studies

    Science.gov (United States)

    Mello, Nancy K.

    2009-01-01

    Nicotine and cocaine each stimulate hypothalamic-pituitary-adrenal and -gonadal axis hormones, and there is increasing evidence that the hormonal milieu may modulate the abuse-related effects of these drugs. This review summarizes some clinical studies of the acute effects of cigarette smoking or IV cocaine on plasma drug and hormone levels, and subjective effects ratings. The temporal covariance between these dependent measures was assessed with a rapid (two min) sampling procedure in nicotine-dependent volunteers or current cocaine users. Cigarette smoking and IV cocaine each stimulated a rapid increase in LH and ACTH, followed by gradual increases in cortisol and DHEA. Positive subjective effects ratings increased immediately after initiation of cigarette smoking or IV cocaine administration. However, in contrast to cocaine’s sustained positive effects (hormones on nicotine dependence and cocaine abuse, and implications for treatment of these addictive disorders is discussed. PMID:19835877

  16. Cellular Immune Responses to Live Attenuated Japanese Encephalitis (JE Vaccine SA14-14-2 in Adults in a JE/Dengue Co-Endemic Area.

    Directory of Open Access Journals (Sweden)

    Lance Turtle

    2017-01-01

    Full Text Available Japanese encephalitis (JE virus (JEV causes severe epidemic encephalitis across Asia, for which the live attenuated vaccine SA14-14-2 is being used increasingly. JEV is a flavivirus, and is closely related to dengue virus (DENV, which is co-endemic in many parts of Asia, with clinically relevant interactions. There is no information on the human T cell response to SA14-14-2, or whether responses to SA14-14-2 cross-react with DENV. We used live attenuated JE vaccine SA14-14-2 as a model for studying T cell responses to JEV infection in adults, and to determine whether these T cell responses are cross-reactive with DENV, and other flaviviruses.We conducted a single arm, open label clinical trial (registration: clinicaltrials.gov NCT01656200 to study T cell responses to SA14-14-2 in adults in South India, an area endemic for JE and dengue.Ten out of 16 (62.5% participants seroconverted to JEV SA14-14-2, and geometric mean neutralising antibody (NAb titre was 18.5. Proliferation responses were commonly present before vaccination in the absence of NAb, indicating a likely high degree of previous flavivirus exposure. Thirteen of 15 (87% participants made T cell interferon-gamma (IFNγ responses against JEV proteins. In four subjects tested, at least some T cell epitopes mapped cross-reacted with DENV and other flaviviruses.JEV SA14-14-2 was more immunogenic for T cell IFNγ than for NAb in adults in this JE/DENV co-endemic area. The proliferation positive, NAb negative combination may represent a new marker of long term immunity/exposure to JE. T cell responses can cross-react between JE vaccine and DENV in a co-endemic area, illustrating a need for greater knowledge on such responses to inform the development of next-generation vaccines effective against both diseases.clinicaltrials.gov (NCT01656200.

  17. 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.

  18. Crack Cocaine Use in Adolescents: Clinical Characteristics and Predictors of Early Initiation.

    Science.gov (United States)

    Pianca, Thiago G; Rohde, Luis Augusto; Rosa, Ronaldo L; Begnis, Ana Paula A; Ferronatto, Pedro B; Jensen, Mariana C; Pechansky, Flavio; Ceresér, Keila Maria Mendes; Fairchild, Victoria P; Szobot, Claudia M

    2016-10-01

    To describe the clinical characteristics of adolescents with crack cocaine dependence and possible predictors of transition from drug experimentation to crack cocaine dependence. This cross-sectional study enrolled a consecutive sample of 90 adolescents admitted to a psychiatric inpatient unit in the city of Porto Alegre in southern Brazil for crack cocaine detoxification between May 2011 and November 2012. Comorbid psychological conditions were assessed using the Kiddie-SADS-Present and Lifetime Version, and severity of drug use was assessed using the Teen Addiction Severity Index (T-ASI). Comorbidities were compared with those in a community sample of non-drug using controls (n = 81). Patients' mean age was 15.6 years (85.6% boys, 14.4% girls). Seventy-nine (93.2%) met criteria for cocaine dependence (DSM-IV-TR), while 78 (91.8%) had symptoms consistent with cocaine abuse. All patients had experimented with at least 1 other addictive substance before crack cocaine: 61.4%, tobacco (mean age at first use = 11.61 years); 44.3%, alcohol (age at first use = 12.43 years); and 54.5%, cannabis (age at first use = 12.15 years). Patients had used crack cocaine 23.2 days in the last month, and the mean age at first use of crack cocaine was 13.38 years. The most common psychiatric comorbidity was conduct disorder (81.8%), followed by oppositional defiant disorder (52.3%) and attention-deficit/hyperactivity disorder (44.3%), all of which were more prevalent in the patient population than in controls (P < .001). The T-ASI questionnaire showed severe consequences of drug use in most areas of life assessed. The mean time between onset of drug experimentation and crack cocaine dependence was 2.53 (SD = 1.96) years. When Cox regression models were applied, we found that predictors of earlier progression to using crack cocaine were age at first use of any drug (hazard ratio [HR] = 0.79 [95% CI, 0.71-0.88]; P < .001) and age at admission (HR = 0.7 [95% CI, 0.57-0.87]; P = .001

  19. Dyadic social interaction as an alternative reward to cocaine

    Directory of Open Access Journals (Sweden)

    Gerald eZernig

    2013-09-01

    Full Text Available Individuals suffering from substance use disorders often show severely impaired social interaction, preferring drugs of abuse to the contact with others. Their impaired social interaction is doubly harmful for them as (1 therapy itself is based and dependent on social interaction and as (2 social interaction is not available to them as an "alternative", i.e., non-drug reward, decreasing their motivation to stop drug use. We therefore developed an animal experimental model to investigate the neurobiology of dyadic social interaction- vs cocaine reward. We took care to avoid (a engaging sexual attraction-related aspects of such a social interaction and (b hierarchical difference as confounding stimuli. The cocaine- or social interaction stimulus was offered - in a mutually exclusive setting - within the confines of a conditioned place preference (CPP apparatus. In our paradigm, only four 15-min episodes of social interaction proved sufficient to (i switch the rats' preference from cocaine-associated contextual stimuli to social interaction CPP and (ii inhibit the subsequent reacquisition/reexpression of cocaine CPP. The behavioral effect was paralleled by a reversal of brain activation (i.e., EGR1 expression in the nucleus accumbens, the central and basolateral amygdala, and the ventral tegmental area. Of relevance for the psychotherapy of addictive disorders, the most rewarding sensory component of the composite stimulus 'social interaction' was touch. To test our hypothesis that motivation is encoded in neuron ensembles dedicated to specific reward scenarios, we are currently (1 mapping the neural circuits involved in cocaine- vs social interaction reward and (2 adapting our paradigm for C57BL/6 mice to make use of the plethora of transgenic models available in this species.

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

    Science.gov (United States)

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

    2017-05-01

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

  1. Cocaine addicts prone to cocaine-induced psychosis have lower body mass index than cocaine addicts resistant to cocaine-induced psychosis--Implications for the cocaine model of psychosis proneness.

    Science.gov (United States)

    Rosse, Richard; Deutsch, Stephen; Chilton, Melissa

    2005-01-01

    The specific pathogenesis of increased vulnerability to cocaine-induced paranoia/psychosis is unknown. Weight loss has been long observed in patients abusing stimulants (including cocaine and the amphetamines). In the current study, we compared Body Mass Index (calculated as weight in kilograms divided by the square of height in meters) in Cocaine-Induced Psychosis cases, referred to as "Cocaine-Induced Psychosis-prone" (n=40) and non-Cocaine-Induced Psychosis cases, referred to as "Cocaine-Induced Psychosis-resistant" (n=29) consecutively admitted to a research substance abuse unit to determine whether Body Mass Index is associated with Cocaine-Induced Psychosis. Height and weight were measured and Body Mass Index calculated by a licensed nutritionist using a standardized protocol. Cocaine-induced psychosis and cocaine use patterns were assessed using the Cocaine Experience Questionnaire. Body Mass Index in the Cocaine-Induced Psychosis-prone patients was significantly lower than in the Cocaine-Induced Psychosis-resistant patients (i.e., 23.1 kg/m2 +/-2.5 vs. 25.4 kg/m2 +/-3.5 (P=.003), respectively). Percentage of Ideal Body Weight also differed significantly between the two groups. The data suggest that lower Body Mass Index may be associated with increasing proneness to developing psychotic symptoms in the context of crack cocaine use or that higher Body Mass Index might be associated with some protection against Cocaine-Induced Psychosis in the context of similar use patterns. In the Discussion the authors speculate as to why Cocaine-Induced Psychosis is more commonly observed in the patient population with lower Body Mass Index and lower percentage of Ideal Body Weight. They evoke possible involvement of cocaine's influence on the anorexigenic cytokine Tumor Necrosis Factor, Cocaine-and-Amphetamine-Regulated Transcript, or suppression of the appetite stimulating Neuropeptide Y, or cocaine-induced deficits in nicotinic cholinergic neural-transmission, all of

  2. 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...

  3. Cocaine: from addiction to functional imaging

    International Nuclear Information System (INIS)

    Tamgac, F.; Baillet, G.; Moretti, J.L.; Tikofski, R.

    1997-01-01

    Cocaine is wrongly held as a benign recreative drug whereas it is a highly addictive substance with possible dreadful cardiac a neurologic complications. Cocaine abuse results in patchy cerebral hypoperfusion and hypo-metabolism, clearly demonstrated by PET and SPECT imaging. Improvement after drug withdrawal is still unclear. Cocaine binds with a very high affinity to the dopamine reuptake transporter. Labelled cocaine congeners can be used to assess dopaminergic pathways, especially nigrostriatal neurons that play a key role in movement control. 123 I labelled beta-CIT can reproducibly be used to measure dopamine transporter density in the striatum, in one day. This approach seems very promising. (authors)

  4. Nonfatal pulmonary edema after "freebase" cocaine smoking.

    Science.gov (United States)

    Cucco, R A; Yoo, O H; Cregler, L; Chang, J C

    1987-07-01

    Pulmonary edema is known to develop in users of heroin and methadone. Its association with cocaine use is usually a postmortem finding. There has been only 1 report of pulmonary edema being diagnosed clinically after cocaine use. In that case the cocaine was used intravenously, and death occurred within 3 h after the onset of symptoms. Here we describe a patient who developed acute pulmonary edema after smoking "freebase" cocaine. The pulmonary edema resolved spontaneously within 72 h. The cause of the acute reversible pulmonary edema was probably related to both pressure- and permeability-related changes.

  5. ELEVATIONS OF FOSB IN THE NUCLEUS ACCUMBENS DURING FORCED COCAINE ABSTINENCE CORRELATE WITH DIVERGENT CHANGES IN REWARD FUNCTION

    Science.gov (United States)

    Harris, Glenda C.; Hummel, Michele; Wimmer, Mathieu; Mague, Stephen D.; Aston-Jones, Gary

    2007-01-01

    Dysregulation of hedonic processing, in which seeking of drug reward becomes more desirable than seeking natural rewards, like food, sex, and novelty, is a consequence of chronic drug exposure and potentially leads to escalating drug usage and addiction. Here, we investigated the effects of chronic cocaine treatment (10 days of escalating doses of cocaine, 10-30 mg/kg) and multiple forced abstinence periods (2, 3 or 5 weeks) on the acute rewarding properties of either cocaine (10 mg/kg) or novel-objects using the conditioned place preference procedure. Following all cocaine withdrawal periods, cocaine preference was significantly elevated while novel object preference was abolished compared to saline-treated rats. At the earliest withdrawal period, these behavioral changes were accompanied by elevations in FosB-like immunoreactive staining in the basolateral amygdala (BLA) and nucleus accumbens shell (NAc-Sh) and core (NAc-C). FosB staining in all three brain areas correlated positively with cocaine preference, but negatively with novelty preference. After 5 weeks of withdrawal, FosB staining was only elevated in the NAc-Sh and again correlated positively with elevated cocaine preference but negatively with decreased novelty preference. These data indicate that alterations in the expression of FosB-like transcription factors in the NAc can predict the dysregulation of hedonic processing that occurs during protracted withdrawal from cocaine. PMID:17560044

  6. Rat-strain dependent changes of dendritic and spine morphology in the hippocampus after cocaine self-administration.

    Science.gov (United States)

    Selvas, Abraham; Coria, Santiago M; Kastanauskaite, Asta; Fernaud-Espinosa, Isabel; DeFelipe, Javier; Ambrosio, Emilio; Miguéns, Miguel

    2017-01-01

    We previously showed that cocaine self-administration increases spine density in CA1 hippocampal neurons in Lewis (LEW) but not in Fischer 344 (F344) rats. Dendritic spine morphology is intimately related to its function. Thus, we conducted a 3D morphological analysis of CA1 dendrites and dendritic spines in these two strains of rats. Strain-specific differences were observed prior to cocaine self-administration: LEW rats had significantly larger dendritic diameters but lower spine density than the F344 strain. After cocaine self-administration, proximal dendritic volume, dendritic surface area and spine density were increased in LEW rats, where a higher percentage of larger spines were also observed. In addition, we found a strong positive correlation between dendritic volume and spine morphology, and a moderate correlation between dendritic volume and spine density in cocaine self-administered LEW rats, an effect that was not evident in any other condition. By contrast, after cocaine self-administration, F334 rats showed decreased spine head volumes. Our findings suggest that genetic differences could play a key role in the structural plasticity induced by cocaine in CA1 pyramidal neurons. These cocaine-induced alterations could be related to differences in the memory processing of drug reward cues that could potentially explain differential individual vulnerability to cocaine addiction. © 2015 Society for the Study of Addiction.

  7. Treatment of cocaine cardiovascular toxicity: a systematic review.

    Science.gov (United States)

    Richards, John R; Garber, Dariush; Laurin, Erik G; Albertson, Timothy E; Derlet, Robert W; Amsterdam, Ezra A; Olson, Kent R; Ramoska, Edward A; Lange, Richard A

    2016-06-01

    tachycardia. Alpha-adrenoceptor blocking drugs: There were two Level I studies and three case reports. Alpha-1 blockers may improve hypertension and vasospasm, but not tachycardia, although evidence is limited. Alpha-2-adrenoceptor agonists: There were two high-quality studies and one case report detailing the successful use of dexmedetomidine. Beta-blockers and β/α-blockers: There were nine Level I/II, seven Level III, and 34 Level IV/V studies of β-blockers, with 1744 subjects, seven adverse drug events, and three treatment failures. No adverse events were reported for use of combined β/α-blockers such as labetalol and carvedilol, which were effective in attenuating both hypertension and tachycardia. Antipsychotics: Seven Level I/II studies, three Level III studies, and seven Level IV/V case series and reports involving 168 subjects have been published. Antipsychotics may improve agitation and psychosis, but with inconsistent reduction in tachycardia and hypertension and risk of extrapyramidal adverse effects. Other agents: There was only one high level study of morphine, which reversed cocaine-induced coronary vasoconstriction but increased heart rate. Other agents reviewed included lidocaine, sodium bicarbonate, amiodarone, procainamide, propofol, intravenous lipid emulsion, propofol, and ketamine. High-quality evidence for pharmacological treatment of cocaine cardiovascular toxicity is limited but can guide acute management of associated tachycardia, dysrhythmia, hypertension, and coronary vasospasm. Future randomized prospective trials are needed to evaluate new agents and further define optimal treatment of cocaine-toxic patients.

  8. Cocaine in surface waters: a new evidence-based tool to monitor community drug abuse

    Science.gov (United States)

    Zuccato, Ettore; Chiabrando, Chiara; Castiglioni, Sara; Calamari, Davide; Bagnati, Renzo; Schiarea, Silvia; Fanelli, Roberto

    2005-01-01

    Background Cocaine use seems to be increasing in some urban areas worldwide, but it is not straightforward to determine the real extent of this phenomenon. Trends in drug abuse are currently estimated indirectly, mainly by large-scale social, medical, and crime statistics that may be biased or too generic. We thus tested a more direct approach based on 'field' evidence of cocaine use by the general population. Methods Cocaine and its main urinary metabolite (benzoylecgonine, BE) were measured by mass spectrometry in water samples collected from the River Po and urban waste water treatment plants of medium-size Italian cities. Drug concentration, water flow rate, and population at each site were used to estimate local cocaine consumption. Results We showed that cocaine and BE are present, and measurable, in surface waters of populated areas. The largest Italian river, the Po, with a five-million people catchment basin, steadily carried the equivalent of about 4 kg cocaine per day. This would imply an average daily use of at least 27 ± 5 doses (100 mg each) for every 1000 young adults, an estimate that greatly exceeds official national figures. Data from waste water treatment plants serving medium-size Italian cities were consistent with this figure. Conclusion This paper shows for the first time that an illicit drug, cocaine, is present in the aquatic environment, namely untreated urban waste water and a major river. We used environmental cocaine levels for estimating collective consumption of the drug, an approach with the unique potential ability to monitor local drug abuse trends in real time, while preserving the anonymity of individuals. The method tested here – in principle extendable to other drugs of abuse – might be further refined to become a standardized, objective tool for monitoring drug abuse. PMID:16083497

  9. Cocaine in surface waters: a new evidence-based tool to monitor community drug abuse

    Directory of Open Access Journals (Sweden)

    Bagnati Renzo

    2005-08-01

    Full Text Available Abstract Background Cocaine use seems to be increasing in some urban areas worldwide, but it is not straightforward to determine the real extent of this phenomenon. Trends in drug abuse are currently estimated indirectly, mainly by large-scale social, medical, and crime statistics that may be biased or too generic. We thus tested a more direct approach based on 'field' evidence of cocaine use by the general population. Methods Cocaine and its main urinary metabolite (benzoylecgonine, BE were measured by mass spectrometry in water samples collected from the River Po and urban waste water treatment plants of medium-size Italian cities. Drug concentration, water flow rate, and population at each site were used to estimate local cocaine consumption. Results We showed that cocaine and BE are present, and measurable, in surface waters of populated areas. The largest Italian river, the Po, with a five-million people catchment basin, steadily carried the equivalent of about 4 kg cocaine per day. This would imply an average daily use of at least 27 ± 5 doses (100 mg each for every 1000 young adults, an estimate that greatly exceeds official national figures. Data from waste water treatment plants serving medium-size Italian cities were consistent with this figure. Conclusion This paper shows for the first time that an illicit drug, cocaine, is present in the aquatic environment, namely untreated urban waste water and a major river. We used environmental cocaine levels for estimating collective consumption of the drug, an approach with the unique potential ability to monitor local drug abuse trends in real time, while preserving the anonymity of individuals. The method tested here – in principle extendable to other drugs of abuse – might be further refined to become a standardized, objective tool for monitoring drug abuse.

  10. 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

  11. Mazindol treatment for cocaine dependence.

    Science.gov (United States)

    Stine, S M; Krystal, J H; Kosten, T R; Charney, D S

    1995-10-01

    This double-blind placebo-controlled treatment study tested the efficacy of mazindol in currently cocaine-dependent out-patients. Forty-three patients were randomized to mazindol (2 mg QD) vs. placebo treatment for 6 weeks. All patients received weekly group counseling. Patients improved with respect to objective (urine toxicology) and subjective (self-report of times used, dollars spent, craving, etc.) measures. There was no response difference between patients treated with mazindol and those who received placebo.

  12. Sensitization to the psychosis-inducing effects of cocaine compared with measures of cocaine craving and cue reactivity.

    Science.gov (United States)

    Reid, Malcolm S; Ciplet, Debra; O'Leary, Siobhan; Branchey, Marc; Buydens-Branchey, Laure; Angrist, Burt

    2004-01-01

    A previous study has suggested that sensitization to the psychosis-inducing effects of cocaine may be a marker of vulnerability to relapse in cocaine addiction. In this report, cocaine-dependent subjects participating in a study on naturally occurring and cue-induced cocaine craving were interviewed about prior experience of cocaine-induced psychosis and the degree to which this effect had become more frequent or severe or had occurred at lower cumulative doses. Sensitization to cocaine-induced psychosis was negatively correlated with baseline measures of drug dependence severity and indices of cocaine craving over the preceding 24 hours but not with measures of cocaine cue reactivity.

  13. Role of TAAR1 within the Subregions of the Mesocorticolimbic Dopaminergic System in Cocaine-Seeking Behavior.

    Science.gov (United States)

    Liu, Jian-Feng; Siemian, Justin N; Seaman, Robert; Zhang, Yanan; Li, Jun-Xu

    2017-01-25

    A novel G-protein coupled receptor, trace amine-associated receptor 1 (TAAR1), has been shown to be a promising target to prevent stimulant relapse. Our recent studies showed that systemic administration of TAAR1 agonists decreased abuse-related behaviors of cocaine. However, the role of TAAR1 in specific subregions of the reward system in drug addiction is unknown. Here, using a local pharmacological activation method, we assessed the role of TAAR1 within the subregions of the mesocorticolimbic system: that is, the VTA, the prelimbic cortex (PrL), and infralimbic cortex of medial prefrontal cortex, the core and shell of NAc, BLA, and CeA, on cue- and drug-induced cocaine-seeking in the rat cocaine reinstatement model. We first showed that TAAR1 mRNA was expressed throughout these brain regions. Rats underwent cocaine self-administration, followed by extinction training. RO5166017 (1.5 or 5.0 μg/side) or vehicle was microinjected into each brain region immediately before cue- and drug-induced reinstatement of cocaine-seeking. The results showed that microinjection of RO5166017 into the VTA and PrL decreased both cue- and drug priming-induced cocaine-seeking. Microinjection of RO5166017 into the NAc core and shell inhibited cue- and drug-induced cocaine-seeking, respectively. Locomotor activity or food reinforced operant responding was unaffected by microinjection of RO5166017 into these brain regions. Cocaine-seeking behaviors were not affected by RO5166017 when microinjected into the substantia nigra, infralimbic cortex, BLA, and CeA. Together, these results indicate that TAAR1 in different subregions of the mesocorticolimbic system distinctly contributes to cue- and drug-induced reinstatement of cocaine-seeking behavior. TAAR1 has been indicated as a modulator of the dopaminergic system. Previous research showed that systemic administration of TAAR1 agonists could attenuate cocaine-related behaviors, suggesting that TAAR1 may be a promising drug target for the

  14. Effects of the combination of metyrapone and oxazepam on cocaine-induced increases in corticosterone in the medial prefrontal cortex and nucleus accumbens.

    Science.gov (United States)

    Keller, Courtney M; Breaux, Kelly N; Goeders, Nicholas E

    2017-03-01

    We have previously demonstrated that a combination of drugs (i.e., metyrapone and oxazepam) known to attenuate HPA-axis activity effectively decreases cocaine self-administration and cue reactivity in rats. However, we did not find changes in plasma corticosterone that matched the behavioral effects we observed, indicating that a different mechanism of action must be involved. Therefore, we hypothesized that the combination of metyrapone and oxazepam attenuates cocaine taking and seeking by decreasing cocaine-induced increases in corticosterone in the brain. Male rats were implanted with guide cannulae targeting the medial prefrontal cortex or nucleus accumbens. After the rats recovered from surgery, the microdialysis session was conducted. Rats were housed in the experimental chamber and the dialysis probes inserted into the guide cannulae the night before the session. The following day, dialysate samples were collected over a five-hour session. Baseline samples were collected for the first two hours, every 20min. Samples were then collected following administration of cocaine (15mg/kg, ip). Before injections of cocaine, rats were pretreated with either vehicle or the combination of metyrapone (50mg/kg, ip) and oxazepam (10mg/kg, ip). The administration of cocaine resulted in an increase in corticosterone in the medial prefrontal cortex following vehicle pretreatment, which was not observed in the nucleus accumbens. This cocaine-induced increase in corticosterone was attenuated by metyrapone/oxazepam. Reducing cocaine-induced increases in corticosterone in the medial prefrontal cortex might represent a novel mechanism through which the combination of metyrapone/oxazepam produces its behavioral effects. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Manipulating a "cocaine engram" in mice.

    Science.gov (United States)

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

    2014-10-15

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

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

    Science.gov (United States)

    Schindler, Charles W; Goldberg, Steven R

    2012-01-01

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

  17. Prenatal and acute cocaine exposure affects neural responses and habituation to visual stimuli.

    Science.gov (United States)

    Riley, Elizabeth; Kopotiyenko, Konstantin; Zhdanova, Irina

    2015-01-01

    Psychostimulants have many effects on visual function, from adverse following acute and prenatal exposure to therapeutic on attention deficit. To determine the impact of prenatal and acute cocaine exposure on visual processing, we studied neuronal responses to visual stimuli in two brain regions of a transgenic larval zebrafish expressing the calcium indicator GCaMP-HS. We found that both red light (LF) and dark (DF) flashes elicited similar responses in the optic tectum neuropil (TOn), while the dorsal telencephalon (dTe) responded only to LF. Acute cocaine (0.5 μM) reduced neuronal responses to LF in both brain regions but did not affect responses to DF. Repeated stimulus presentation (RSP) led to habituation of dTe neurons to LF. Acute cocaine prevented habituation. TOn habituated to DF, but not LF, and DF habituation was not modified by cocaine. Remarkably, prenatal cocaine exposure (PCE) prevented the effects of acute cocaine on LF response amplitude and habituation later in development in both brain regions, but did not affect DF responses. We discovered that, in spite of similar neural responses to LF and DF in the TO (superior colliculus in mammals), responses to LF are more complex, involving dTe (homologous to the cerebral cortex), and are more vulnerable to cocaine. Our results demonstrate that acute cocaine exposure affects visual processing differentially by brain region, and that PCE modifies zebrafish visual processing in multiple structures in a stimulus-dependent manner. These findings are in accordance with the major role that the optic tectum and cerebral cortex play in sustaining visual attention, and support the hypothesis that modification of these areas by PCE may be responsible for visual deficits noted in humans. This model offers new methodological approaches for studying the adverse and therapeutic effects of psychostimulants on attention, and for the development of new pharmacological interventions.

  18. Auranofin protects against cocaine-induced hepatic injury through induction of heme oxygenase-1.

    Science.gov (United States)

    Ashino, Takashi; Sugiuchi, Jinko; Uehara, Junna; Naito-Yamamoto, Yumiko; Kenmotsu, Sachiyo; Iwakura, Yoichiro; Shioda, Seiji; Numazawa, Satoshi; Yoshida, Takemi

    2011-10-01

    Auranofin, a disease-modifying gold compound, has been empirically applying to the management of rheumatoid arthritis. We investigated a protective effect of auranofin against hepatic injury induced by cocaine. Cocaine (75 mg/kg) markedly increased serum alanine amino transferase (ALT) (4,130 IU/l) and aspartate amino transferase (AST) (1,730 IU/l) activities at 16 hr after treatment, and induced hepatic necrosis surrounding central veins in mice. Concurrently, overexpression of heme oxygenase-1 (HO-1), a rate-limiting enzyme for heme degradation and an oxidative stress marker, was identified at the edges of cocaine-mediated necrotic area. Auranofin (10 mg/ml, i.p.) significantly induced hepatic HO-1 protein in mice from 12 hr after treatment. Interestingly, pretreatment with auranofin resulted in the prevention of the increase of serum ALT and AST activities in a dose-dependent manner. On the other hand, although cocaine increased tumor necrosis factor α (TNFα) gene expression in mouse livers, cocaine-induced liver injury was observed in TNFα deficient mice as well as wild-type mice. Auranofin-inducted HO-1 gene expression was observed in human primary hepatocytes as well as mouse primary hepatocytes. The present findings suggest that auranofin is effective in preventing cocaine-induced hepatic injury, and HO-1 may contribute to protect against chemically-induced cytotoxicity.

  19. Relapse to cocaine seeking in an invertebrate.

    Science.gov (United States)

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

    2017-06-01

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

  20. DARK Classics in Chemical Neuroscience: Cocaine.

    Science.gov (United States)

    Drake, Lindsey R; Scott, Peter J H

    2018-04-09

    In this review, we consider the story of cocaine from its humble origins in South America to its status as one of the most abused substances in 21st century society. The synthesis and biosynthesis of cocaine are discussed, as well as its pharmacokinetics, metabolism, pharmacology, and importance in modern neuroscience and molecular imaging.

  1. Manipulating a "cocaine engram" in mice

    NARCIS (Netherlands)

    Hisang, H.L.; Epp, J.R.; van den Oever, M.C.; Yan, C.; Rashid, J.; Insel, N.; Ye, L.; Niibori, Y.; Deisseroth, K.; Frankland, P.W.; Josselyn, S.A.

    2014-01-01

    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

  2. Is Cannabis a Stepping Stone for Cocaine?

    NARCIS (Netherlands)

    van Ours, J.C.

    2001-01-01

    This paper uses a unique dataset collected among inhabitants of Amsterdam, to study the dynamics in the consumption of cannabis and cocaine.If people start using these drugs they are most likely to do so at age 18-20 for cannabis and age 20-25 for cocaine.An analysis of the starting rates shows some

  3. 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.

  4. Fetal cocaine exposure: analysis of vernix caseosa.

    Science.gov (United States)

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

    1996-10-01

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

  5. Cocaine-induced psychosis and impulsivity in cocaine-dependent patients.

    Science.gov (United States)

    Roncero, Carlos; Daigre, Constanza; Grau-López, Lara; Rodríguez-Cintas, Laia; Barral, Carmen; Pérez-Pazos, Jesús; Gonzalvo, Begoña; Corominas, Margarita; Casas, Miguel

    2013-01-01

    Cocaine-dependent patients have high impulsiveness. Cocaine-induced psychosis is common among cocaine-dependent patients. Different risk factors associated with cocaine-induced psychosis have been reported. The aim of this study is to analyze the relationship between psychotic symptoms in cocaine-dependent patients and impulsivity and mental disorders characterized by impulsivity. This descriptive study included 287 outpatients with cocaine dependence according to the DSM-IV-TR criteria. The Structured Clinical Interview for DSM-IV Axis I and II, the Barratt Impulsiveness Scale, and a specific questionnaire on the presence of cocaine-induced psychosis were used to assess patients. Symptoms were observed in 59.9% of the study population. Total and cognitive impulsiveness scores obtained from the Barratt Impulsiveness Scale were significantly higher in patients with cocaine-induced psychosis. Individuals from this group reported more overdose incidents, initiated more treatments during their lifetime, and had a significantly greater prevalence of attention deficit hyperactivity disorder. Patients with cocaine-induced psychosis have a greater degree of impulsivity and a higher prevalence of attention deficit hyperactivity disorder. Thus, if these disorders are observed in cocaine-dependent participants, the presence of psychotic symptoms should be evaluated to prevent further occurrence and their consequences.

  6. Diagnosis and consequences of cocaine addiction.

    Science.gov (United States)

    Karila, L; Petit, A; Lowenstein, W; Reynaud, M

    2012-01-01

    Cocaine remains the second most commonly used and trafficked illicit drug in the world after cannabis. This psychostimulant drug has become an essential part of the world drug scene with a different use among countries. Prevalence of cocaine use (lifetime, last year, last month use) is particulary high among males aged between 15 and 34 years. Five per cent of cocaine users will develop a substance- dependence during the first year of use, and 20% of these will become long-term cocaine-dependent patients. The number of patients entering drug treatment for primary cocaine use has been increasing in Europe for several years. Cocaine addiction is a worldwide public health problem, which has somatic, psychological, psychiatric, socio-economic and judicial complications. This article aims to provide the clinician with a detailed description of the clinical aspects, the adverse effects and the complications of cocaine addiction. Literature searches were conducted for the period from January 1985 to February 2012 using PubMed, EMBASE, PsycInfo, and Google Scholar.

  7. Evaluation of cocaine-induced hepatotoxicity

    International Nuclear Information System (INIS)

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

    1991-01-01

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

  8. Fatal cocaine intoxication in a body packer

    Directory of Open Access Journals (Sweden)

    Brajković Gordana

    2016-01-01

    Full Text Available Introduction. ‘Body packer’ syndrome with severe intoxication or sudden death may happen in persons who smuggle drugs in their body cavities. In case of lethal outcome when carrying cocaine, it is important, but sometimes difficult to determine whether death was due to intoxication or due to other causes. Therefore, it is necessary not only to quantify cocaine and its metabolites in biological material, but also based on their distribution in body fluids and tissues to conclude whether it is acute intoxication. We described a well-documented case of fatal poisoning in a body packer and post mortem distribution of the drug in biological samples. Case report. A 26-year-old man was brought to hospital with no vital signs. Resuscitation measures started at once, but with no success. Autopsy revealed 66 packets of cocaine in his digestive tract, one of which was ruptured. Hyperemia of the most of all internal organs and pulmonary and brain edema were found. High concentrations of cocaine, its metabolites benzoylecgonine and ecgonine methyl ester, as well as cocaine adulteration levamisole were proven in the post mortem blood and tissues by liquid chromatography-mass spectrometry (LC-MC method with selective-ion monitoring. Conclusion. The ratio of cocaine and its metabolites concentrations in the brain and blood obtained by LC-MS method can be used for forensic confirmation of acute intoxication with cocaine.

  9. [11]Cocaine: PET studies of cocaine pharmacokinetics, dopamine transporter availability and dopamine transporter occupancy

    International Nuclear Information System (INIS)

    Fowler, Joanna S.; Volkow, Nora D.; Wang, Gene-Jack; Gatley, S. John; Logan, Jean

    2001-01-01

    Cocaine was initially labeled with carbon-11 in order to track the distribution and pharmacokinetics of this powerful stimulant and drug of abuse in the human brain and body. It was soon discovered that [ 11 C]cocaine was not only useful for measuring cocaine pharmacokinetics and its relationship to behavior but that it is also a sensitive radiotracer for dopamine transporter (DAT) availability. Measures of DAT availability were facilitated by the development of a graphical analysis method (Logan Plot) for reversible systems which streamlined kinetic analysis. This expanded the applications of [ 11 C]cocaine to studies of DAT availability in the human brain and allowed the first comparative measures of the degree of DAT occupancy by cocaine and another stimulant drug methylphenidate. This article will summarize preclinical and clinical research with [ 11 C]cocaine

  10. [{sup 11}]Cocaine: PET studies of cocaine pharmacokinetics, dopamine transporter availability and dopamine transporter occupancy

    Energy Technology Data Exchange (ETDEWEB)

    Fowler, Joanna S. E-mail: fowler@bnl.gov; Volkow, Nora D.; Wang, Gene-Jack; Gatley, S. John; Logan, Jean

    2001-07-01

    Cocaine was initially labeled with carbon-11 in order to track the distribution and pharmacokinetics of this powerful stimulant and drug of abuse in the human brain and body. It was soon discovered that [{sup 11}C]cocaine was not only useful for measuring cocaine pharmacokinetics and its relationship to behavior but that it is also a sensitive radiotracer for dopamine transporter (DAT) availability. Measures of DAT availability were facilitated by the development of a graphical analysis method (Logan Plot) for reversible systems which streamlined kinetic analysis. This expanded the applications of [{sup 11}C]cocaine to studies of DAT availability in the human brain and allowed the first comparative measures of the degree of DAT occupancy by cocaine and another stimulant drug methylphenidate. This article will summarize preclinical and clinical research with [{sup 11}C]cocaine.

  11. Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors

    Science.gov (United States)

    Papale, Alessandro; Morella, Ilaria Maria; Indrigo, Marzia Tina; Bernardi, Rick Eugene; Marrone, Livia; Marchisella, Francesca; Brancale, Andrea; Spanagel, Rainer; Brambilla, Riccardo; Fasano, Stefania

    2016-01-01

    Ras-ERK signalling in the brain plays a central role in drug addiction. However, to date, no clinically relevant inhibitor of this cascade has been tested in experimental models of addiction, a necessary step toward clinical trials. We designed two new cell-penetrating peptides - RB1 and RB3 - that penetrate the brain and, in the micromolar range, inhibit phosphorylation of ERK, histone H3 and S6 ribosomal protein in striatal slices. Furthermore, a screening of small therapeutics currently in clinical trials for cancer therapy revealed PD325901 as a brain-penetrating drug that blocks ERK signalling in the nanomolar range. All three compounds have an inhibitory effect on cocaine-induced ERK activation and reward in mice. In particular, PD325901 persistently blocks cocaine-induced place preference and accelerates extinction following cocaine self-administration. Thus, clinically relevant, systemically administered drugs that attenuate Ras-ERK signalling in the brain may be valuable tools for the treatment of cocaine addiction. DOI: http://dx.doi.org/10.7554/eLife.17111.001 PMID:27557444

  12. Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors.

    Science.gov (United States)

    Papale, Alessandro; Morella, Ilaria Maria; Indrigo, Marzia Tina; Bernardi, Rick Eugene; Marrone, Livia; Marchisella, Francesca; Brancale, Andrea; Spanagel, Rainer; Brambilla, Riccardo; Fasano, Stefania

    2016-08-24

    Ras-ERK signalling in the brain plays a central role in drug addiction. However, to date, no clinically relevant inhibitor of this cascade has been tested in experimental models of addiction, a necessary step toward clinical trials. We designed two new cell-penetrating peptides - RB1 and RB3 - that penetrate the brain and, in the micromolar range, inhibit phosphorylation of ERK, histone H3 and S6 ribosomal protein in striatal slices. Furthermore, a screening of small therapeutics currently in clinical trials for cancer therapy revealed PD325901 as a brain-penetrating drug that blocks ERK signalling in the nanomolar range. All three compounds have an inhibitory effect on cocaine-induced ERK activation and reward in mice. In particular, PD325901 persistently blocks cocaine-induced place preference and accelerates extinction following cocaine self-administration. Thus, clinically relevant, systemically administered drugs that attenuate Ras-ERK signalling in the brain may be valuable tools for the treatment of cocaine addiction.

  13. Neuropsychological effects associated with recreational cocaine use.

    Science.gov (United States)

    Soar, Kirstie; Mason, Colette; Potton, Anita; Dawkins, Lynne

    2012-08-01

    Recent evidence suggests that recreational cocaine use is on the increase, with the UK reporting one of the highest levels of use in the EU (EMCDDA 2010). Nevertheless, very few studies have addressed the neuropsychological effects associated with non-dependent recreational cocaine use. The current study aimed to assess whether recreational cocaine users show neuropsychological deficits on a battery of tests, previously shown to be sensitive to cocaine-dependent and psychosis-prone individuals. Schizotypal traits were also measured. Recreational cocaine users (n = 17) were compared with controls (n = 24) on drug use patterns, the General Health Questionnaire, the Brief Schizotypal Personality Questionnaire (SPQ-B) and four neuropsychological tasks: spatial working memory, intra/extra-dimensional set shifting, the Stocking of Cambridge and the rapid visual processing. Relative to controls, recreational cocaine users produced significantly more errors on the intra/extra-dimensional set shift task and completed fewer stages, made significantly more six box stage errors on the spatial working memory task, and made significantly more errors and fewer hits, with overall poorer detection rates on the rapid visual processing task. Recreational cocaine users reported significantly higher scores on the cognitive perceptual and disorganised thinking SPQ-B subscales and total SPQ-B scores compared to controls. Recreational cocaine users displayed impairments on tasks tapping sustained attention, attentional shifting and spatial memory and reported higher schizotypal trait expression. These findings are consistent with the emerging literature suggesting subtle cognitive deficits, putatively reflecting underlying dopaminergic dysfunction, in non-dependent, recreational cocaine users.

  14. Pathological gambling among cocaine-dependent outpatients.

    Science.gov (United States)

    Hall, G W; Carriero, N J; Takushi, R Y; Montoya, I D; Preston, K L; Gorelick, D A

    2000-07-01

    The authors investigated the occurrence of pathological gambling among cocaine-dependent outpatients, its influence on short-term outcome of treatment, and comparative characteristics of patients with and without pathological gambling. The subjects were 313 cocaine-dependent (200 also opiate-dependent) outpatients in clinical trials of medication for cocaine dependence. Pathological gambling (DSM-III-R criteria) was assessed with the Diagnostic Interview Schedule, and sociodemographic and socioeconomic characteristics were determined with the Addiction Severity Index. Outcome was defined as time in treatment (proportion of maximum scheduled time) and proportion of cocaine-positive urine samples during treatment. Pathological gambling had a lifetime occurrence rate of 8.0% and a current (past month) occurrence of 3.8%. Onset preceded the onset of cocaine dependence in 72.0% of the patients (and preceded onset of opiate dependence in 44.4%). Patients with pathological gambling (lifetime or current) did not differ significantly from other patients in length of treatment or proportion of cocaine-positive urine samples. Those with lifetime pathological gambling were significantly more likely to have tobacco dependence (84.0% versus 61.1%) and antisocial personality disorder (56.0% versus 19.8%), to be unemployed (84.0% versus 49.3%), to have recently engaged in illegal activity for profit (64.0% versus 38.5%), and to have been incarcerated (62.5% versus 33.9%). Pathological gambling is substantially more prevalent among cocaine-dependent outpatients than in the general population. Patients with pathological gambling differ from other cocaine-dependent outpatients in some sociodemographic characteristics but not in short-term outcome of treatment for cocaine dependence.

  15. Risk factors for cocaine-induced psychosis in cocaine-dependent patients

    OpenAIRE

    Roncero, C.; Daigre, C.; Gonzalvo, B.; Valero, S.; Castells, X.; Grau-López, L.; Eiroá Orosa, Francisco José; Casas, Miquel

    2013-01-01

    Cocaine consumption can induce transient psychotic symptoms, expressed as paranoia or hallucinations. Cocaine induced psychosis (CIP) is common but not developed in all cases. This is the first European study on the relationship between CIP, consumption pattern variables and personality disorders. We evaluated 173 cocaine-dependent patients over 18 years; mostly males, whose average age was 33.6 years (SD=7.8). Patients attending an outpatient addictions department were enrolled in the study ...

  16. Cocaine-associated lower limb ischemia.

    LENUS (Irish Health Repository)

    Collins, Chris G

    2011-07-25

    Cocaine-associated thrombosis has been reported in the literature with reports of vascular injuries to cardiac, pulmonary, intestinal, placental, and musculoskeletal vessels; however, injury of the pedal vessels is rare. We report on a 31-year-old man who presented 2 months following a cocaine binge with limb-threatening ischemia without an otherwise identifiable embolic source. Angiography confirmed extensive occlusive disease of the tibioperoneal vessels. The patient improved following therapy with heparin and a prostacyclin analogue. Cocaine-induced thrombosis should be considered in patients presenting with acute arterial insufficiency in the lower limb without any other identifiable cause.

  17. Synthesis of deuterium labelled cocaine and pseudococaine

    International Nuclear Information System (INIS)

    Casale, J.F.; Raney, H.T.; Cooper, D.A.

    1991-01-01

    Cocaine and pseudococaine were mass-labelled with deuterium at various positions on the tropane ring. The synthetic procedures followed were adaptations of those previously published for the unlabelled compounds. The isotopic purity was greater than 95% for 2-[ 2 H]-, 4,4-[ 2 H2]-, and 1,5,6,6,7,7-[ 2 H6]-cocaine and 3-[ 2 H]-, 4,4-[ 2 H2]-, and 1,5,6,6,7,7-[ 2 H6]-pseudococaine, while that of 3-[ 2 H]-cocaine exceeded 90%. (author)

  18. Cocaine abuse: dermatologic manifestations and therapeutic approaches.

    Science.gov (United States)

    Brewer, Jerry D; Meves, Alexander; Bostwick, J Michael; Hamacher, Kirsten Lyn; Pittelkow, Mark R

    2008-09-01

    Cocaine affects the cutaneous system and other organ systems. Cocaine use is associated with vasculitides, infectious complications, and numerous dermatologic conditions. It has been associated with formication (ie, tactile hallucinations of insects crawling underneath the skin), which leads to delusions of parasitosis and other psychosis-related dermatologic disorders. When a patient presents to a dermatology clinic with chronic skin lesions, a vague medical history, negative findings from previous evaluations, labile affect, and delusional behavior, drug screening should be performed to identify possible cocaine use.

  19. Cocaine abuse and delusions of parasitosis.

    Science.gov (United States)

    Elpern, D J

    1988-10-01

    We report two persons in their thirties with the shared delusion of parasitosis. Both abused cocaine, and both recovered from their delusions after a period of abstinence. Although the literature does not stress that a specific cause is usually found for delusions of parasitosis, this may be changing for persons in groups among whom cocaine and possibly other illicit drug use is common. It is a service to these desperate patients to establish their confidence and then discretely ask about the use of illegal drugs, especially cocaine.

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

    Science.gov (United States)

    Banks, Matthew L; Negus, S Stevens

    2017-04-01

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

  1. Lack of cocaine self-administration in mice expressing a cocaine-insensitive dopamine transporter.

    Science.gov (United States)

    Thomsen, Morgane; Han, Dawn D; Gu, Howard H; Caine, S Barak

    2009-10-01

    Cocaine addiction is a worldwide public health problem for which there are no established treatments. The dopamine transporter (DAT) is suspected as the primary target mediating cocaine's abuse-related effects based on numerous pharmacological studies. However, in a previous study, DAT knockout mice were reported to self-administer cocaine, generating much debate regarding the importance of the DAT in cocaine's abuse-related effects. Here, we show that mice expressing a "knockin" of a cocaine-insensitive but functional DAT did not self-administer cocaine intravenously despite normal food-maintained responding and normal intravenous self-administration of amphetamine and a direct dopamine agonist. Our results have three implications. First, they imply a crucial role for high-affinity DAT binding of cocaine in mediating its reinforcing effects, reconciling mouse genetic engineering approaches with data from classic pharmacological studies. Second, they demonstrate the usefulness of knockin strategies that modify specific amino acid sequences within a protein. Third, they show that it is possible to alter the DAT protein sequence in such a way as to selectively target its interaction with cocaine, while sparing other behaviors dependent on DAT function. Thus, molecular engineering technology could advance the development of highly specialized compounds such as a dopamine-sparing "cocaine antagonist."

  2. Neonatal body proportionality and body composition after in utero exposure to cocaine and marijuana.

    Science.gov (United States)

    Frank, D A; Bauchner, H; Parker, S; Huber, A M; Kyei-Aboagye, K; Cabral, H; Zuckerman, B

    1990-10-01

    The relationship of maternal use of marijuana and cocaine during pregnancy to measures of neonatal body proportionality and body composition was assessed in a multiethnic sample of 1082 newborn infants. Maternal use of marijuana and cocaine during pregnancy was ascertained by self-report and by an enzyme-multiplied immunoassay technique for screening of urine samples obtained prenatally and again post partum. After each substance was analytically controlled for use of the other and for other potentially confounding variables, detection of marijuana metabolites in maternal urine was associated (p less than 0.05) with depressed mean arm muscle circumference and nonfat area of the arm but not with any measure of neonatal fatness. In contrast, detection of cocaine in maternal urine was associated (p less than 0.05) with decrements of subscapular fat folds and of the fat and nonfat areas of the arm. Although both substances were associated with depressed birth weight, there was no decrement of neonatal ponderal index or of the arm circumference/head circumference ratio in association with exposure to either substance. We conclude that both marijuana exposure and cocaine exposure during pregnancy are associated with symmetric intrauterine growth retardation, but that deficits are in differing compartments of intrauterine growth. These findings suggest that marijuana may retard fetal growth through maternal-fetal hypoxia, whereas cocaine may alter nutrient transfer to the fetus and fetal metabolism.

  3. Interfacial area measurement in two-phase bubbly flows - 3. Part - comparison between the light attenuation technique and a local method

    International Nuclear Information System (INIS)

    Veteau, Jean-Michel; Charlot, Roland.

    1981-09-01

    Initially designed for rectangular test sections the light attenuation technique is reconsidered for an application in circular tubes. Principles of a two-head local probe method are discussed, including the problems related to the measurement of interface velocities. The two techniques are compared experimentally and results lead to the conclusion that, in view of its global nature, the light attenuation method is more suitable for homogeneous two-phase flows. A new experimental set up is proposed to overcome this limitation in order to obtain local values as in the probe technique [fr

  4. Guanfacine enhances inhibitory control and attentional shifting in early abstinent cocaine-dependent individuals.

    Science.gov (United States)

    Fox, Helen; Sofuoglu, Mehmet; Sinha, Rajita

    2015-03-01

    Attenuation of adrenergic drive and cognitive enhancement, via stimulation of alpha2 pre- and post-synaptic receptors, may selectively enhance executive performance in early abstinent cocaine-dependent individuals. As these cognitive processes underpin important treatment-related behaviors, the alpha2 agonist, guanfacine HCl, may represent an effective pharmaco-therapeutic intervention. Twenty-five early abstinent cocaine-dependent individuals were administered a battery of neurocognitive tasks on entry into treatment (baseline) and again following 3 weeks of either placebo or guanfacine treatment (up to 3 mg). Tasks included: Stop Signal, Stroop, 3-Dimentional Intra-dimensional/Extra-dimensional (IDED) task, Spatial Working Memory (SWM), Paired Associates Learning (PAL), Verbal Fluency and the Rey Auditory Verbal Learning Test (RAVLT). Compared with placebo, the guanfacine group demonstrated attenuated anxiety and negative affect as well as improved performance on selective executive tests. This included fewer directional errors on the stop signal task, fewer errors on the extra-dimensional shift component of the IDED task and better attentional switching during verbal fluency. Guanfacine did not improve strategic working memory or peripheral memory. Guanfacine improves selective cognitive processes which may underlie salient treatment-related regulatory behaviors. Alpha2 agonists may therefore represent important agents for cocaine dependence. © The Author(s) 2015.

  5. Cocaine activates Homer1 immediate early gene transcription in the mesocorticolimbic circuit: differential regulation by dopamine and glutamate signaling.

    Science.gov (United States)

    Ghasemzadeh, M Behnam; Windham, Lindsay K; Lake, Russell W; Acker, Christopher J; Kalivas, Peter W

    2009-01-01

    Homer proteins are intracellular scaffolding proteins that, among glutamate receptors, selectively bind to group1 metabotropic glutamate receptors and regulate their trafficking and intracellular signaling. Homer proteins have been implicated in synaptic and behavioral plasticity, including drug-seeking behavior after cocaine treatment. Homer1 gene activation leads to transcription of a variant mRNA (Homer1a), which functions as an immediate early gene. Homer1a competes with the constitutive Homer proteins (Homer1b/c/d, Homer2a/b, Homer3) for binding to group1 metabotropic glutamate and IP3 receptors. Binding of Homer1a to these proteins disrupts their association with the intracellular signaling scaffold and modulates receptor function. In this study, using RT-PCR, activation of Homer1a mRNA transcription in response to acute and repeated administration of cocaine was characterized in prefrontal cortex, nucleus accumbens, and ventral tegmental area, three mesocorticolimbic nuclei of the rat brain. Moreover, the dopaminergic and glutamatergic regulation of Homer1 gene activation by cocaine was investigated. Acute cocaine rapidly and transiently activated transcription of Homer1a mRNA in all three nuclei. However, repeated administration of cocaine was not effective in inducing the Homer1a mRNA transcription after various withdrawal times ranging from 2 h to 3 weeks. The acute cocaine-mediated activation of Homer1 gene was regulated by D1 but not D2 dopamine receptors. The blockade of AMPA or NMDA glutamate receptors did not prevent cocaine-mediated activation of Homer1 gene in the three mesocorticolimbic nuclei. These data indicate that acute administration of cocaine transiently activates Homer1 gene producing the immediate early gene Homer1a mRNA in the three mesocorticolimbic nuclei of the rat brain. Activation of Homer1 gene may contribute to the cocaine-mediated synaptic and behavioral plasticity.

  6. Synergism between a serotonin 5-HT2A receptor (5-HT2AR) antagonist and 5-HT2CR agonist suggests new pharmacotherapeutics for cocaine addiction.

    Science.gov (United States)

    Cunningham, Kathryn A; Anastasio, Noelle C; Fox, Robert G; Stutz, Sonja J; Bubar, Marcy J; Swinford, Sarah E; Watson, Cheryl S; Gilbertson, Scott R; Rice, Kenner C; Rosenzweig-Lipson, Sharon; Moeller, F Gerard

    2013-01-16

    Relapse to cocaine dependence, even after extended abstinence, involves a number of liability factors including impulsivity (predisposition toward rapid, unplanned reactions to stimuli without regard to negative consequences) and cue reactivity (sensitivity to cues associated with cocaine-taking which can promote cocaine-seeking). These factors have been mechanistically linked to serotonin (5-hydroxytryptamine, 5-HT) signaling through the 5-HT(2A) receptor (5-HT(2A)R) and 5-HT(2C)R; either a selective 5-HT(2A)R antagonist or a 5-HT(2C)R agonist suppresses impulsivity and cocaine-seeking in preclinical models. We conducted proof-of-concept analyses to evaluate whether a combination of 5-HT(2A)R antagonist plus 5-HT(2C)R agonist would have synergistic effects over these liability factors for relapse as measured in a 1-choice serial reaction time task and cocaine self-administration/reinstatement assay. Combined administration of a dose of the selective 5-HT(2A)R antagonist M100907 plus the 5-HT(2C)R agonist WAY163909, each ineffective alone, synergistically suppressed cocaine-induced hyperactivity, inherent and cocaine-evoked impulsive action, as well as cue- and cocaine-primed reinstatement of cocaine-seeking behavior. The identification of synergism between a 5-HT(2A)R antagonist plus a 5-HT(2C)R agonist to attenuate these factors important in relapse indicates the promise of a bifunctional ligand as an anti-addiction pharmacotherapeutic, setting the stage to develop new ligands with improved efficacy, potency, selectivity, and in vivo profiles over the individual molecules.

  7. A new exposure model to evaluate smoked illicit drugs in rodents: A study of crack cocaine.

    Science.gov (United States)

    Hueza, Isis M; Ponce, Fernando; Garcia, Raphael C T; Marcourakis, Tânia; Yonamine, Maurício; Mantovani, Cínthia de C; Kirsten, Thiago B

    2016-01-01

    The use of smoked illicit drugs has spread dramatically, but few studies use proper devices to expose animals to inhalational abused drugs despite the availability of numerous smoking devices that mimic tobacco exposure in rodents. Therefore, the present study developed an inexpensive device to easily expose laboratory animals to smoked drugs. We used crack cocaine as the drug of abuse, and the cocaine plasma levels and the behaviors of animals intoxicated with the crack cocaine were evaluated to prove inhaled drug absorption and systemic activity. We developed an acrylic device with two chambers that were interconnected and separated by a hatch. Three doses of crack (100, 250, or 500 mg), which contained 63.7% cocaine, were burned in a pipe, and the rats were exposed to the smoke for 5 or 10 min (n=5/amount/period). Exposure to the 250-mg dose for 10 min achieved cocaine plasma levels that were similar to those of users (170 ng/mL). Behavioral evaluations were also performed to validate the methodology. Rats (n=10/group) for these evaluations were exposed to 250 mg of crack cocaine or air for 10 min, twice daily, for 28 consecutive days. Open-field evaluations were performed at three different periods throughout the experimental design. Exposed animals exhibited transient anorexia, increased motor activity, and shorter stays in central areas of the open field, which suggests reduced anxiety. Therefore, the developed model effectively exposed animals to crack cocaine, and this model may be useful for the investigation of other inhalational abused drugs. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Regulation of nucleus accumbens transcript levels in mice by early-life social stress and cocaine.

    Science.gov (United States)

    Lo Iacono, Luisa; Valzania, Alessandro; Visco-Comandini, Federica; Viscomi, Maria Teresa; Felsani, Armando; Puglisi-Allegra, Stefano; Carola, Valeria

    2016-04-01

    Much interest has been piqued regarding the quality of one's environment at early ages in modulating the susceptibility to drug addiction in adulthood. However, the molecular mechanisms that are engaged during early trauma and mediate the risk for drug addiction are poorly understood. In rodents, exposure to early-life stress alters the rewarding effects of cocaine, amphetamine, and morphine in adulthood. Recently, we demonstrated that the exposure of juvenile mice to social threat (Social Stress, S-S) promoted cocaine-seeking behavior and relapse of cocaine-seeking after periods of withdrawal, compared with unhandled controls (UN) and with juvenile mice that experienced only daily isolation in a novel environment (no social stress, NS-S). Interestingly, while the exposure to NS-S slightly increased cocaine-seeking behavior compared with UN, the same was not sufficient to promote cocaine reinstatement. In this study, we examined the long-term transcriptional changes that are induced by S-S compared to NS-S and linked the increased susceptibility of S-S mice to cocaine reinstatement. To this end, we performed genome-wide RNA sequencing analysis in the nucleus accumbens (NAC), which revealed that 89 transcripts were differentially expressed between S-S and NS-S mice. By Gene Ontology classification, these hits were enriched in genes that mediate cell proliferation, neuronal differentiation, and neuron/forebrain development. Eleven of these genes have been reported to be involved in substance use disorders, and the remaining genes are novel candidates in this area. We characterized 4 candidates with regard to their significant neurobiological relevance (ZIC1, ZIC2, FABP7, and PRDM12) and measured their expression in the NAC by immunohistochemistry. These findings provide insights into novel molecular mechanisms in NAC that might be associated with the risk of relapse in cocaine-dependent individuals. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. 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.

  10. Recurrent encephalic hemorrhage associated with cocaine abuse

    International Nuclear Information System (INIS)

    Pumar, J.; Otero, E.; Castineira, A.; Arrojo, L.; Linares, M.; Castineira, J.A.; Vidal, J.

    1994-01-01

    We report a case of recurrent intracerebral hemorrhage secondary to cocaine abuse in a patient with no other predisposing factors. The hemorrhages were located both supra- and infratentorially. (orig.)

  11. Decrease of GSK3β phosphorylation in the rat nucleus accumbens core enhances cocaine-induced hyper-locomotor activity.

    Science.gov (United States)

    Kim, Wha Y; Jang, Ju K; Lee, Jung W; Jang, Hyunduk; Kim, Jeong-Hoon

    2013-06-01

    Glycogen synthase kinase 3β (GSK3β), which is abundantly present in the brain, is known to contribute to psychomotor stimulant-induced locomotor behaviors. However, most studies have been focused in showing that GSK3β is able to attenuate psychomotor stimulants-induced hyperactivity by increasing its phosphorylation levels in the nucleus accumbens (NAcc). So, here we examined in the opposite direction about the effects of decreased phosphorylation of GSK3β in the NAcc core on both basal and cocaine-induced locomotor activity by a bilateral microinjection into this site of an artificially synthesized peptide, S9 (0.5 or 5.0 μg/μL), which contains sequences around N-terminal serine 9 residue of GSK3β. We found that decreased levels of GSK3β phosphorylation in the NAcc core enhance cocaine-induced hyper-locomotor activity, while leaving basal locomotor activity unchanged. This is the first demonstration, to our knowledge, that the selective decrease of GSK3β phosphorylation levels in the NAcc core may contribute positively to cocaine-induced locomotor activity, while this is not sufficient for the generation of locomotor behavior by itself without cocaine. Taken together, these findings importantly suggest that GSK3β may need other molecular targets which are co-activated (or deactivated) by psychomotor stimulants like cocaine to contribute to generation of locomotor behaviors. © 2013 International Society for Neurochemistry.

  12. Bidirectional effects of inhibiting or activating NMDA receptors on extinction after cocaine self-administration in rats

    Science.gov (United States)

    Hafenbreidel, Madalyn; Todd, Carolynn Rafa; Twining, Robert C.; Tuscher, Jennifer J.; Mueller, Devin

    2014-01-01

    Rationale Extinction of drug seeking is facilitated by NMDA receptor (NMDAr) agonists, but it remains unclear whether extinction is dependent on NMDAr activity. Objectives We investigated the necessity of NMDArs for extinction of cocaine seeking, and whether extinction altered NMDAr expression within extinction-related neuroanatomical loci. Methods Rats were trained to lever press for i.v. infusions of cocaine or sucrose reinforcement prior to extinction training or withdrawal. Results Administration of the NMDAr competitive antagonist CPP prior to four brief extinction sessions impaired subsequent extinction retention. In contrast, post-extinction administration of the NMDAr coagonist D-serine attenuated lever pressing across days as compared to saline administration, indicative of facilitated consolidation of extinction. Furthermore, expression of the NMDAr subunits, GluN2A and GluN2B, was not altered in the ventromedial prefrontal cortex. However, both GluN2A and GluN2B subunit expression in the nucleus accumbens was increased following cocaine self-administration, and this increased expression was relatively resistant to modulation by extinction. Conclusions Our findings demonstrate that extinction of cocaine seeking is bidirectionally mediated by NMDArs and suggest that selective modulation of NMDAr activity could facilitate extinction-based therapies for treatment of cocaine abuse. PMID:24847958

  13. Heterotypic Dengue Infection with Live Attenuated Monotypic Dengue Virus Vaccines: Implications for Vaccination of Populations in Areas Where Dengue Is Endemic

    OpenAIRE

    Durbin, Anna P.; Schmidt, Alexander; Elwood, Dan; Wanionek, Kimberli A.; Lovchik, Janece; Thumar, Bhavin; Murphy, Brian R.; Whitehead, Stephen S.

    2011-01-01

    Background. Because infection with any of the 4 Dengue virus serotypes may elicit both protective neutralizing antibodies and nonneutralizing antibodies capable of enhancing subsequent heterotypic Dengue virus infections, the greatest risk for severe dengue occurs during a second, heterotypic Dengue virus infection. It remains unclear whether the replication of live attenuated vaccine viruses will be similarly enhanced when administered to Dengue-immune individuals.

  14. Main mental disorders in crack-cocaine users treated at Psychosocial Care Centers for Alcohol and Drugs in the city of Recife, Brazil

    Directory of Open Access Journals (Sweden)

    Antonio Gomes de Castro Neto

    Full Text Available Abstract Introduction: Brazil's Northeast region has the highest crack-cocaine consumption in the country. Crack-cocaine has more intense effects than cocaine powder and can cause greater chemical dependence. Psychosocial Care Centers for Alcohol and Drugs (CAPSad are public health services that provide treatment for drug dependence. It is common for drug users, and particularly crack-cocaine users, to develop mental disorders. Objective: To evaluate the most common mental disorders in crack-cocaine dependents in treatment at CAPSad in the city of Recife, Brazil. Methods: The research database "Between rocks and shots: user profiles, consumption strategies, and social impact of crack cocaine" (CEP/CCS/UFPE no. 206/11 was consulted to establish the areas of crack cocaine consumption in the city of Recife. Results: There were 885 patients in treatment for crack-cocaine use, with a mean age of 29.8±9.4 years. The mean duration of drug use was 6.1±4.6 years. Most of the patients were males (80.3%, had left school at some point between the 1st and 9th grades (45.6%, were unemployed and/or seeking employment (52% and used drugs daily (56.4%. Cocaine chemical dependence was more significant when correlated with use of crack-cocaine and other drugs such as medications and hallucinogens (p = 0.01. Conclusions: Data from this study showed strong associations between crack-cocaine uses and development of mental disorders, particularly when abuse of multiple substances occurs. Based on these data, there is a clear need for coordination of related public policies for support and social reintegration to provide these people with comprehensive care.

  15. Cocaine smuggling in the gastrointestinal tract resulting in mechanical pylorostenosis.

    Science.gov (United States)

    Sein Anand, Jacek; Chodorowski, Zygmunt; Masal, Andrzej; Nowak-Banasik, Livia

    2005-01-01

    A 45-year-old male, body packer, who confessed to have swallowed 44 packages of cocaine in a total dose of approx. 360 g, was admitted to hospital because of clinical signs of acute intoxication with cocaine followed by ileus. The emergency surgical gastrotomy was initiated, and the conglomerate of Scotch tape and packages with cocaine were removed. Small rupture of one package of cocaine in a body packer stomach caused acute poisoning with cocaine, confirmed additionally by the presence of its metabolites in the urine. Mechanical pylorostenosis provoked by cocaine packages required emergency surgical operation.

  16. Positron emitting tracers for studies of cocaine

    International Nuclear Information System (INIS)

    Fowler, J.S.; Gatley, S.J.; MacGregor, R.R.; Wolf, A.P.; Yu, D.W.; Dewey, S.L.; Schlyer, D.J.; Volkow, N.D.; Bendriem, B.; Logan, J.

    1990-01-01

    The use of PET to study the behavior and mechanism of action of therapeutic drugs and substances of abuse can be approached from a number of perspectives. The most common approach is to measure the effect of a drug on some aspect of metabolism and requires well characterized radiotracers whose behavior in vivo can be related to a discrete biochemical transformation. A second approach is to study the labeled drug itself. This provides information on the drug's regional distribution and kinetics as well as its pharmacological profile and metabolism. Cocaine has been labeled in different positions with carbon-11 and with fluorine-18 and the stereoisomers of cocaine have also been labeled to characterize its binding and metabolism in human and baboon brain. Regional cocaine binding as measured by PET is consistent with reversible binding to striatal dopamine reuptake sites and its time course parallels the behavioral activation of cocaine. The behaviorally inactive enantiomer (+)-cocaine is rapidly metabolized in serum preventing its entry into the brain. These PET tracers are useful in understanding the neurochemical basis of cocaine's action

  17. Financing Cocaine Use in a Homeless Population

    Directory of Open Access Journals (Sweden)

    Carol S. North

    2017-10-01

    Full Text Available Background: Cocaine use is highly prevalent among homeless populations, yet little is known about how it is financed. This study examined associations of income sources with cocaine use and financing of drugs in a longitudinal evaluation of a homeless sample. Methods: A homeless sample was recruited systematically in St. Louis in 1999–2001 and longitudinally assessed annually over two years using the Diagnostic Interview Schedule and the Homeless Supplement, with urine drug testing. Results: More than half (55% of participants with complete follow-up data (N = 255/400 had current year cocaine use. Current users spent nearly $400 (half their income in the last month on drugs at baseline. Benefits, welfare, and disability were negatively associated and employment and income from family/friends, panhandling, and other illegal activities were positively associated with cocaine use and monetary expenditures for cocaine. Conclusions: Findings suggest that illegal and informal income-generating activities are primary sources for immediate gratification with cocaine use and public entitlements do not appear to be primary funding sources used by homeless populations. Policy linking drug testing to benefits is likely to have little utility, and public expenditures on measures to unlink drug use and income might be more effectively used to fund employment and treatment programs.

  18. Cocaine-Induced Behavioral Sensitization Is Associated With Changes in the Expression of Endocannabinoid and Glutamatergic Signaling Systems in the Mouse Prefrontal Cortex

    Science.gov (United States)

    Blanco, Eduardo; Pavón, Francisco J.; Palomino, Ana; Luque-Rojas, María Jesús; Serrano, Antonia; Rivera, Patricia; Bilbao, Ainhoa; Alen, Francisco; Vida, Margarita; Suárez, Juan

    2015-01-01

    transmission-related genes. An overall decrease was observed in the mRNA expression of the glutamate-synthesizing gene kidney-type glutaminase (KGA), the metabotropic glutamate receptors (mGluR3 and GluR), and subunits of NMDA ionotropic receptors (NR1, NR2A, NR2B and NR2C) after acute cocaine administration, while mice repeatedly exposed to cocaine only displayed an increase in NR2C. However, in cocaine-sensitized mice primed with cocaine, this inhibition was reversed and a strong increase was detected in the mGluR5, NR2 subunits, and both GluR1 and GluR3. Conclusions: These findings indicate that cocaine sensitization is associated with an endocannabinoid downregulation and a hyperglutamatergic state in the PFC that, overall, contribute to an enhanced glutamatergic input into PFC-projecting areas. PMID:25539508

  19. Cocaine-induced behavioral sensitization is associated with changes in the expression of endocannabinoid and glutamatergic signaling systems in the mouse prefrontal cortex.

    Science.gov (United States)

    Blanco, Eduardo; Pavón, Francisco J; Palomino, Ana; Luque-Rojas, María Jesús; Serrano, Antonia; Rivera, Patricia; Bilbao, Ainhoa; Alen, Francisco; Vida, Margarita; Suárez, Juan; Rodríguez de Fonseca, Fernando

    2014-10-31

    overall decrease was observed in the mRNA expression of the glutamate-synthesizing gene kidney-type glutaminase (KGA), the metabotropic glutamate receptors (mGluR3 and GluR), and subunits of NMDA ionotropic receptors (NR1, NR2A, NR2B and NR2C) after acute cocaine administration, while mice repeatedly exposed to cocaine only displayed an increase in NR2C. However, in cocaine-sensitized mice primed with cocaine, this inhibition was reversed and a strong increase was detected in the mGluR5, NR2 subunits, and both GluR1 and GluR3. These findings indicate that cocaine sensitization is associated with an endocannabinoid downregulation and a hyperglutamatergic state in the PFC that, overall, contribute to an enhanced glutamatergic input into PFC-projecting areas. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  20. Changes in gene expression and sensitivity of cocaine reward produced by a continuous fat diet.

    Science.gov (United States)

    Blanco-Gandía, M Carmen; Aracil-Fernández, Auxiliadora; Montagud-Romero, Sandra; Aguilar, Maria A; Manzanares, Jorge; Miñarro, José; Rodríguez-Arias, Marta

    2017-08-01

    Preclinical studies report that free access to a high-fat diet (HFD) alters the response to psychostimulants. The aim of the present study was to examine how HFD exposure during adolescence modifies cocaine effects. Gene expression of CB1 and mu-opioid receptors (MOr) in the nucleus accumbens (N Acc) and prefrontal cortex (PFC) and ghrelin receptor (GHSR) in the ventral tegmental area (VTA) were assessed. Mice were allowed continuous access to fat from PND 29, and the locomotor (10 mg/kg) and reinforcing effects of cocaine (1 and 6 mg/kg) on conditioned place preference (CPP) were evaluated on PND 69. Another group of mice was exposed to a standard diet until the day of post-conditioning, on which free access to the HFD began. HFD induced an increase of MOr gene expression in the N Acc, but decreased CB1 receptor in the N Acc and PFC. After fat withdrawal, the reduction of CB1 receptor in the N Acc was maintained. Gene expression of GHSR in the VTA decreased during the HFD and increased after withdrawal. Following fat discontinuation, mice exhibited increased anxiety, augmented locomotor response to cocaine, and developed CPP for 1 mg/kg cocaine. HFD reduced the number of sessions required to extinguish the preference and decreased sensitivity to drug priming-induced reinstatement. Our results suggest that consumption of a HFD during adolescence induces neurobiochemical changes that increased sensitivity to cocaine when fat is withdrawn, acting as an alternative reward.

  1. Cocaine abstinence following chronic treatment alters cerebral metabolism in dopaminergic reward regions. Bromocriptine enhances recovery

    International Nuclear Information System (INIS)

    Clow, D.W.; Hammer, R.P. Jr.

    1991-01-01

    2-[14C]deoxyglucose autoradiography was used to determine local cerebral glucose utilization (lCGU) in rats following chronic cocaine treatment and subsequent abstinence. lCGU was examined in 43 discrete brain regions in animals which had received daily injections of cocaine for 14 days (10 mg/kg) followed by 3 days of saline or bromocriptine (10 mg/kg) treatment. Cocaine abstinence following chronic treatment significantly reduced lCGU in several regions including mesocorticolimbic structures such as ventral tegmental area, medial prefrontal cortex, and nucleus accumbens (NAc). Within the NAc, however, only the rostral pole showed significant reduction. In contrast, when bromocriptine treatment accompanied abstinence, lCGU was no longer reduced in mesocorticolimbic and most other regions, implying that metabolic recovery was enhanced by bromocriptine treatment during early abstinence following chronic cocaine treatment. These data suggest that cerebral metabolism is decreased during cocaine abstinence following chronic treatment in critical brain regions, and that this alteration can be prevented by treatment with direct-acting dopamine agonists such as bromocriptine

  2. Psychological stress, cocaine and natural reward each induce endoplasmic reticulum stress genes in rat brain.

    Science.gov (United States)

    Pavlovsky, A A; Boehning, D; Li, D; Zhang, Y; Fan, X; Green, T A

    2013-08-29

    Our prior research has shown that the transcription of endoplasmic reticulum (ER) stress transcription factors activating transcription factor 3 (ATF3) and ATF4 are induced by amphetamine and restraint stress in rat striatum. However, presently the full extent of ER stress responses to psychological stress or cocaine, and which of the three ER stress pathways is activated is unknown. The current study examines transcriptional responses of key ER stress target genes subsequent to psychological stress or cocaine. Rats were subjected to acute or repeated restraint stress or cocaine treatment and mRNA was isolated from dorsal striatum, medial prefrontal cortex and nucleus accumbens brain tissue. ER stress gene mRNA expression was measured using quantitative polymerase chain reaction (PCR) and RNA sequencing. Restraint stress and cocaine-induced transcription of the classic ER stress-induced genes (BIP, CHOP, ATF3 and GADD34) and of two other ER stress components x-box binding protein 1 (XBP1) and ATF6. In addition, rats living in an enriched environment (large group cage with novel toys changed daily) exhibited rapid induction of GADD34 and ATF3 after 30 min of exploring novel toys, suggesting these genes are also involved in normal non-pathological signaling. However, environmental enrichment, a paradigm that produces protective addiction and depression phenotypes in rats, attenuated the rapid induction of ATF3 and GADD34 after restraint stress. These experiments provide a sensitive measure of ER stress and, more importantly, these results offer good evidence of the activation of ER stress mechanisms from psychological stress, cocaine and natural reward. Thus, ER stress genes may be targets for novel therapeutic targets for depression and addiction. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  3. Risk factors for cocaine-induced psychosis in cocaine-dependent patients.

    Science.gov (United States)

    Roncero, C; Daigre, C; Gonzalvo, B; Valero, S; Castells, X; Grau-López, L; Eiroa-Orosa, F J; Casas, M

    2013-03-01

    Cocaine consumption can induce transient psychotic symptoms, expressed as paranoia or hallucinations. Cocaine induced psychosis (CIP) is common but not developed in all cases. This is the first European study on the relationship between CIP, consumption pattern variables and personality disorders. We evaluated 173 cocaine-dependent patients over 18 years; mostly males, whose average age was 33.6 years (SD=7.8). Patients attending an outpatient addictions department were enrolled in the study and subsequently systematically evaluated using SCID I and SCID II interviews for comorbid disorders, a clinical interview for psychotic symptoms and EuropASI for severity of addiction. A high proportion of cocaine dependent patients reported psychotic symptoms under the influence of cocaine (53.8%), the most frequently reported being paranoid beliefs and suspiciousness (43.9%). A logistic regression analysis was performed, finding that a model consisting of amount of cocaine consumption, presence of an antisocial personality disorder and cannabis dependence history had 66.2% sensitivity 75.8% specificity predicting the presence of CIP. In our conclusions, we discuss the relevance of evaluating CIP in all cocaine dependent-patients, and particularly in those fulfilling the clinical profile derived from our results. These findings could be useful for a clinical approach to the risks of psychotic states in cocaine-dependent patients. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  4. Comorbid psychiatric diagnoses and their association with cocaine-induced psychosis in cocaine-dependent subjects.

    Science.gov (United States)

    Tang, Yi-Lang; Kranzler, Henry R; Gelernter, Joel; Farrer, Lindsay A; Cubells, Joseph F

    2007-01-01

    Comorbidity between drug abuse and mental illness is very common, but the association of such comorbidity with specific responses to drugs of abuse remains obscure. The current study examined the relationship between the presence of non-psychotic Axis I psychiatric diagnoses and the frequency and severity of cocaine-induced psychosis. We interviewed 243 unrelated cocaine-dependent adults [37% European American (EA), 52.3% African American (AA); 58.8% male] using the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) to establish DSM-IV diagnoses, and two instruments for the identification of cocaine-induced paranoia, the Cocaine Experience Questionnaire (CEQ) and the Scale for Assessment of Positive Symptoms for Cocaine-Induced Psychosis (SAPS-CIP). Comorbid substance use and psychiatric disorders were common in this cocaine-dependent sample. Ninety percent of subjects met criteria for substance use disorders other than cocaine dependence; common non-substance-use disorders included antisocial personality disorder (ASPD), adult ASPD, major depression, and attention deficit-hyperactivity disorder (ADHD). Comorbid opioid dependence was more common in EA subjects than in AA participants. After correction for multiple comparisons, a lifetime diagnosis of ADHD was associated with the categorical presence of CIP (p = 0.007), as well as significantly more severe CIP symptoms. Comorbid substance use and psychiatric disorders are very common among individuals with cocaine dependence. Comorbid ADHD increases the odds of an individual endorsing CIP, suggesting some common basis for these phenomena.

  5. The protective effects of free wheel-running against cocaine psychomotor sensitization persist after exercise cessation in C57BL/6J mice.

    Science.gov (United States)

    Lespine, L-F; Tirelli, E

    2015-12-03

    Previous literature suggests that free access to a running wheel can attenuate the behavioral responsiveness to addictive drugs in rodents. In a few studies, wheel-running cessation accentuated drug responsiveness. Here, we tested whether free wheel-running cessation is followed by (1) an accentuation or (2) an attenuation of cocaine psychomotor sensitization, knowing that no cessation of (continuous) wheel-running is associated with an attenuation of cocaine responsiveness. Male C57BL/6J mice, aged 35 days, were housed singly either with (exercising mice) or without (non-exercising mice) a running wheel. At the end of a period of 36 days, half of the exercising mice were deprived of their wheel whereas the other half of exercising mice kept their wheel until the end of experimentation (which lasted 85 days). The non-exercising mice were housed without wheel throughout experimentation. Testing took place 3 days after exercise cessation. After 2 once-daily drug-free test sessions, mice were tested for initiation of psychomotor sensitization over 13 once-daily injections of 8 mg/kg cocaine. Post-sensitization conditioned activation (saline challenge) and long-term expression of sensitization were assessed 2 or 30 days after the last sensitizing injection (same treatments as for initiation of sensitization), respectively. Exercising mice and mice undergoing wheel-running cessation exhibited comparable degrees of attenuation of all cocaine effects in comparison with the continuously non-exercising mice, which showed the greatest effects. Thus, the efficaciousness of wheel-running at attenuating cocaine sensitization not only resisted to exercise cessation but was also unambiguously persistent (an important effect rarely reported in previous literature). Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

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

    2017-10-25

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

  7. Modafinil decreases cocaine choice in human cocaine smokers only when the response requirement and the alternative reinforcer magnitude are large.

    Science.gov (United States)

    Foltin, Richard W; Haney, Margaret; Bedi, Gillinder; Evans, Suzette M

    This study examined how response effort (pressing a keyboard button) for cocaine and the value of an alternative reinforcer (opportunity to play a game of chance for money) combined with 'free' cocaine (with no response effort) affected cocaine choice when participants were maintained on modafinil or placebo. Nontreatment-seeking current cocaine smokers were enrolled in a placebo-controlled, double-blind, within-subject study comprising both inpatient and outpatient phases. Participants were maintained on placebo capsules (0mg/day) during one inpatient phase and modafinil (300mg/day) capsules during another inpatient phase in counter-balanced order. A minimum of 8 medication-free days separated the two 15-day inpatient phases to allow for medication clearance. Under each medication condition participants had the opportunity to self-administer smoked cocaine (25mg) when the response effort for cocaine was low (500responses/dose) and had a low value alternative (2 game plays for money) or when the response effort for cocaine was large (2500responses/dose) and had a more valuable alternative (4 game plays for money). Under both conditions, participants received one free dose of cocaine (0, 12, 25 or 50mg) prior to making their first choice of the session. Fifteen individuals began the study and 7 completed it. Participants chose fewer cocaine doses when the response effort for cocaine and the alternative value was high (4.4±0.19) compared to when the response effort for cocaine and the alternative value was low (5.3±0.14). Providing individuals a free "priming" dose of cocaine prior to making their cocaine choice did not alter cocaine taking. Modafinil decreased cocaine choice only when the response effort for cocaine and the alternative value was high. These results suggest that modafinil may be most effective when combined with therapy emphasizing the large personal costs of using cocaine. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Early cannabis use is associated with severity of Cocaine-Induced Psychosis among cocaine smokers in Martinique, French West Indies.

    Science.gov (United States)

    Trape, Sandrine; Charles-Nicolas, Aimé; Jehel, Louis; Lacoste, Jérôme

    2014-01-01

    Cocaine intoxication can induce transient psychotic symptoms. The principal aim of this study was to determine sociodemographic and clinical characteristics associated with cocaine-induced psychosis (CIP) and to identify clinical factors predicting CIP in crack cocaine smokers in Martinique. The second aim was to identify clinical factors associated with severity of CIP, assessed with the Scale for Assessment of Positive Symptoms for Cocaine-Induced Psychosis (SAPS-CIP). Fifty-three cocaine-dependent smokers (45 men and 8 women) seeking treatment for cocaine dependence were included. Patients were assessed using the Cocaine Experience Questionnaire (CEQ), an instrument for the identification of cocaine-induced paranoia, and a French version of the SAPS-CIP, for the severity of CIP. Thirty-five (66%) patients reported cocaine-induced paranoia on the CEQ (CIP(+) patients). The mean SAPS-CIP total score was 6.1 ± 3.7, with a significant difference between CIP(+) and CIP(-) patients (P crack cocaine smokers in Martinique, and early cannabis use is associated with the occurrence and the severity of psychotic symptoms during cocaine intoxication in this population. Patients developing psychotic symptoms during cocaine use began smoking cannabis earlier during adolescence than patients without CIP. These results confirm those of previous studies, highlighting the need to better assess early cannabis use in cocaine users, because early cannabis use is associated with severity of CIP.

  9. The use of brain imaging to elucidate neural circuit changes in cocaine addiction

    Directory of Open Access Journals (Sweden)

    Hanlon CA

    2012-09-01

    Full Text Available Colleen A Hanlon,1,2 Melanie Canterberry11Department of Psychiatry and Behavioral Sciences, 2Department of Neurosciences Medical University of South Carolina, Charleston, SC, USAAbstract: Within substance abuse, neuroimaging has experienced tremendous growth as both a research method and a clinical tool in the last decade. The application of functional imaging methods to cocaine dependent patients and individuals in treatment programs, has revealed that the effects of cocaine are not limited to dopamine-rich subcortical structures, but that the cortical projection areas are also disrupted in cocaine dependent patients. In this review, we will first describe several of the imaging methods that are actively being used to address functional and structural abnormalities in addiction. This will be followed by an overview of the cortical and subcortical brain regions that are most often cited as dysfunctional in cocaine users. We will also introduce functional connectivity analyses currently being used to investigate interactions between these cortical and subcortical areas in cocaine users and abstainers. Finally, this review will address recent research which demonstrates that alterations in the functional connectivity in cocaine users may be associated with structural pathology in these circuits, as demonstrated through diffusion tensor imaging. Through the use of these tools in both a basic science setting and as applied to treatment seeking individuals, we now have a greater understanding of the complex cortical and subcortical networks which contribute to the stages of initial craving, dependence, abstinence, and relapse. Although the ability to use neuroimaging to predict treatment response or identify vulnerable populations is still in its infancy, the next decade holds tremendous promise for using neuroimaging to tailor either behavioral or pharmacologic treatment interventions to the individual.Keywords: addiction, neural circuit, functional

  10. The fast and furious : Cocaine, amphetamines and harm reduction

    NARCIS (Netherlands)

    J-P.C. Grund (Jean-Paul); P. Coffin (Philip); M. Jauffret-Roustide (Marie); M. Dijkstra (Minke); D. de Bruin (Dick); P. Blanken (Peter)

    2010-01-01

    textabstractCocaine and amphetamines (‘stimulants’) are distinct central nervous system stimulants with similar effects (Pleuvry, 2009; Holman, 1994). Cocaine is a crystalline tropane alkaloid extracted from coca leaves. Amphetamines are a subclass of phenylethylamines with primarily stimulant

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

    Science.gov (United States)

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

    2012-05-01

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

  12. Butyrylcholinesterase Genetic Variants: Association with Cocaine Dependence and Related Phenotypes

    OpenAIRE

    Negr?o, Andr? Brooking; Pereira, Alexandre Costa; Guindalini, Camila; Santos, Hadassa Campos; Messas, Guilherme Peres; Laranjeira, Ronaldo; Vallada, Homero

    2013-01-01

    OBJECTIVE: The search for genetic vulnerability factors in cocaine dependence has focused on the role that neuroplasticity plays in addiction. However, like many other drugs, the ability of an individual to metabolize cocaine can also influence susceptibility to dependence. Butyrylcholinesterase (BChE) metabolizes cocaine, and genetic variants of the BChE gene (BCHE) alter its catalytic activity. Therefore, we hypothesize that cocaine users with polymorphisms in BCHE can show diverse addictiv...

  13. Mice lacking neuropeptide Y show increased sensitivity to cocaine

    DEFF Research Database (Denmark)

    Sørensen, Gunnar; Woldbye, David Paul Drucker

    2012-01-01

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

  14. Individual differences in cocaine addiction: maladaptive behavioural traits

    NARCIS (Netherlands)

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

    2014-01-01

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

  15. Cocaine-Induced Reinstatement of a Conditioned Place Preference in Developing Rats: Involvement of the D2 Receptor

    Directory of Open Access Journals (Sweden)

    Kimberly A. Badanich

    2012-10-01

    Full Text Available Reinstatement of conditioned place preferences have been used to investigate physiological mechanisms mediating drug-seeking behavior in adolescent and adult rodents; however, it is still unclear how psychostimulant exposure during adolescence affects neuron communication and whether these changes would elicit enhanced drug-seeking behavior later in adulthood. The present study determined whether the effects of intra-ventral tegmental area (VTA or intra-nucleus accumbens septi (NAcc dopamine (DA D2 receptor antagonist infusions would block (or potentiate cocaine-induced reinstatement of conditioned place preferences. Adolescent rats (postnatal day (PND 28–39 were trained to express a cocaine place preference. The involvement of D2 receptors on cocaine-induced reinstatement was determined by intra-VTA or intra-NAcc infusion of the DA D2 receptor antagonist sulpiride (100 μM during a cocaine-primed reinstatement test (10 mg/kg cocaine, i.p.. Infusion of sulpiride into the VTA but not the NAcc blocked reinstatement of conditioned place preference. These data suggest intrinsic compensatory mechanisms in the mesolimbic DA pathway mediate responsivity to cocaine-induced reinstatement of a conditioned place preference during development.

  16. Neuroticism Associated with Cocaine-Induced Psychosis in Cocaine-Dependent Patients: A Cross-Sectional Observational Study

    OpenAIRE

    Roncero, Carlos; Daigre, Constanza; Barral, Carmen; Ros-Cucurull, Elena; Grau-López, Lara; Rodríguez-Cintas, Laia; Tarifa, Nuria; Casas, Miguel; Valero, Sergi

    2014-01-01

    BACKGROUND: Cocaine consumption can induce transient psychotic symptoms, which has been correlated with more severe addiction and aggressive behavior. However, little is known about the nature of the relationship between personality traits and psychotic symptoms in cocaine-dependent patients. This study examined the relationship between neuroticism and cocaine-induced psychosis. METHODS: A total of 231 cocaine-dependent patients seeking treatment were recruited to the study. Personality was e...

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

    OpenAIRE

    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.; Crystal, Ronald G.

    2012-01-01

    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...

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

    International Nuclear Information System (INIS)

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

    2011-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Nora D Volkow

    2011-02-01

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

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

    Directory of Open Access Journals (Sweden)

    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.

  1. Low and High Locomotor Responsiveness to Cocaine Predicts Intravenous Cocaine Conditioned Place Preference in Male Sprague-Dawley Rats

    Science.gov (United States)

    Allen, Richard M.; Everett, Carson V.; Nelson, Anna M.; Gulley, Joshua M.; Zahniser, Nancy R.

    2009-01-01

    Outbred, male Sprague-Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on cocaine-induced locomotor activity in an open-field arena. This difference reflects cocaine’s ability to inhibit the striatal dopamine transporter and predicts development of sensitization. To investigate the relationship between initial cocaine locomotor responsiveness and cocaine reward, here we first classified rats as either LCRs or HCRs in a conditioned place preference (CPP) apparatus. Subsequently, we conducted cocaine conditioning trials, twice daily over four days with vehicle and cocaine (10 mg/kg, i.p. or 1 mg/kg, i.v.). When cocaine was administered by the i.p. route, similar to previous findings in the open-field, LCRs and HCRs were readily classified and locomotor sensitization developed in LCRs, but not HCRs. However, cocaine CPP was not observed. In contrast, when cocaine was administered by the i.v. route, the LCR/HCR classification not only predicted sensitization, but also CPP, with only LCR rats exhibiting sensitization and cocaine conditioning. Our findings show that the initial locomotor response to cocaine can predict CPP in male Sprague-Dawley rats under conditions when place conditioning develops, and that LCRs may be more prone to develop conditioning in the context of cocaine reward. PMID:17250883

  2. Post-training cocaine administration facilitates habit learning and requires the infralimbic cortex and dorsolateral striatum.

    Science.gov (United States)

    Schmitzer-Torbert, Neil; Apostolidis, Steven; Amoa, Romeo; O'Rear, Connor; Kaster, Michael; Stowers, Josh; Ritz, Robert

    2015-02-01

    Human drug addiction is a complex disorder, in which exogenous substances are able to recruit and maintain behaviors involved in drug taking. Many drugs that are addictive in humans are able to act on natural brain systems for learning and memory, and while many memory systems may be affected by addictive drugs, work with operant tasks has shown that addictive drugs (e.g. cocaine and alcohol) are particularly effective in recruiting habit learning systems, compared to natural rewards. It is currently unknown if the ability of addictive drugs to facilitate habit learning depends on a direct action on habit learning systems in the brain, versus the rewarding properties of drug administration. To differentiate between these options, rats were trained to perform two actions (lever pressing), each of which was rewarded with a different natural reward. After acquiring the behavior, rats received three training sessions which were followed by post-training injections of saline or cocaine (5 or 10mg/kg, i.p.). Using sensory-specific satiety, extinction tests revealed that lever pressing for actions which were paired with saline were sensitive to devaluation (typical of goal-directed behaviors) while actions which were paired with cocaine were not sensitive to devaluation (typical of habitual behaviors). Lesions of the infralimbic or dorsolateral striatum were able to block the action of post-training cocaine injections. These data indicate that, within individual rats, cocaine injections facilitate the transition of behavior to habitual control for actions that have been recently performed, without a general facilitation of habit learning, and that this action of cocaine requires brain areas that are critical for learning natural habits. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Heterotypic dengue infection with live attenuated monotypic dengue virus vaccines: implications for vaccination of populations in areas where dengue is endemic.

    Science.gov (United States)

    Durbin, Anna P; Schmidt, Alexander; Elwood, Dan; Wanionek, Kimberli A; Lovchik, Janece; Thumar, Bhavin; Murphy, Brian R; Whitehead, Stephen S

    2011-02-01

    Because infection with any of the 4 Dengue virus serotypes may elicit both protective neutralizing antibodies and nonneutralizing antibodies capable of enhancing subsequent heterotypic Dengue virus infections, the greatest risk for severe dengue occurs during a second, heterotypic Dengue virus infection. It remains unclear whether the replication of live attenuated vaccine viruses will be similarly enhanced when administered to Dengue-immune individuals. We recruited 36 healthy adults who had previously received a monovalent live Dengue virus vaccine 0.6-7.4 years earlier. Participants were assigned to 1 of 4 cohorts and were randomly chosen to receive placebo or a heterotypic vaccine. The level of replication, safety, and immunogenicity of the heterotypic vaccine virus was compared with that of Dengue virus immunologically naive vaccinees. Vaccine virus replication and reactogenicity after monovalent Dengue virus vaccination in naive and heterotypically immune vaccinees was similar. In contrast to naive vaccinees, the antibody response in heterotypically immune vaccinees was broadly neutralizing and mimicked the response observed by natural secondary Dengue virus infection. Enhanced replication of these live attenuated Dengue virus vaccines was minimal in heterotypically immune vaccinees and suggests that the further evaluation of these candidate vaccines in populations with preexisting DENV immunity can proceed safely.

  4. Butyrylcholinesterase genetic variants: association with cocaine dependence and related phenotypes.

    Directory of Open Access Journals (Sweden)

    André Brooking Negrão

    Full Text Available OBJECTIVE: The search for genetic vulnerability factors in cocaine dependence has focused on the role that neuroplasticity plays in addiction. However, like many other drugs, the ability of an individual to metabolize cocaine can also influence susceptibility to dependence. Butyrylcholinesterase (BChE metabolizes cocaine, and genetic variants of the BChE gene (BCHE alter its catalytic activity. Therefore, we hypothesize that cocaine users with polymorphisms in BCHE can show diverse addictive behaviors due to differences in effective plasma concentrations of cocaine. Those polymorphisms might also influence users to prefer one of the two main preparations (crack or powder cocaine, despite having equal access to both. The present work investigates polymorphisms in BCHE and if those genetic variants constitute risk factors for cocaine dependence and for crack cocaine use. METHODS: A total of 1,436 individuals (698 cocaine-dependent patients and 738 controls were genotyped for three single nucleotide polymorphisms (SNPs in BCHE: rs1803274, rs4263329, and rs4680662. RESULTS: For rs4263329, a nominal difference was found between cases and controls. For rs1803274 (the functional SNP, a statistically significant difference was found between patients who used crack cocaine exclusively and those who used only powder cocaine (P = 0.027; OR = 4.36; 95% CI = 1.18-16.04. Allele frequencies and genotypes related to other markers did not differ between cases and controls or between the two cocaine subgroups. CONCLUSIONS: Our findings suggest that the AA genotype of rs1803274 is a risk factor for crack cocaine use, which is more addictive than powder cocaine use. Further studies are needed in order to confirm this preliminary result and clarify the role of BCHE and its variants in cocaine dependence.

  5. Pulmonary complications of crack cocaine use: high-resolution computed tomography of the chest

    International Nuclear Information System (INIS)

    Mancano, Alexandre

    2008-01-01

    Here, we report high-resolution computed tomography (HRCT) findings in a patient who developed sudden hemoptysis, dyspnea and chest pain after smoking crack cocaine. Chest X-rays showed consolidations, primarily in the upper lobes, and HRCT scans showed ground glass attenuation opacities, consolidations and air-space nodules. A follow-up CT, after drug use discontinuation and administration of corticosteroids, showed partial resolution of pulmonary lesions and the appearance of cavitations. Clinical, imaging and laboratory findings led to a diagnosis of 'crack lung'. (author)

  6. Pulmonary complications of crack cocaine use: high-resolution computed tomography of the chest

    Energy Technology Data Exchange (ETDEWEB)

    Mancano, Alexandre [Taguatinga Regional Hospital, Taguatinga, DF (Brazil). Medical Residency in Radiology and Diagnostic Imaging; Marchiori, Edson [Universidade Federal Fluminense (UFF), Niteroi, RJ (Brazil). Dept. of Radiology]. E-mail: edmarchiori@bol.com.br; Zanetti, Glaucia [Faculdade de Medicina de Petropolis (FMP), RJ (Brazil). School of Medicine; Escuissato, Dante Luiz [Universidade Federal do Parana (UFPR), Curitiba, PR (Brazil). Radiology; Duarte, Beatriz Cunha; Apolinario, Lourenco de Araujo [Radiologia Anchieta, Taguatinga, DF (Brazil)

    2008-05-15

    Here, we report high-resolution computed tomography (HRCT) findings in a patient who developed sudden hemoptysis, dyspnea and chest pain after smoking crack cocaine. Chest X-rays showed consolidations, primarily in the upper lobes, and HRCT scans showed ground glass attenuation opacities, consolidations and air-space nodules. A follow-up CT, after drug use discontinuation and administration of corticosteroids, showed partial resolution of pulmonary lesions and the appearance of cavitations. Clinical, imaging and laboratory findings led to a diagnosis of 'crack lung'. (author)

  7. The cutting of cocaine and heroin: A critical review.

    Science.gov (United States)

    Broséus, Julian; Gentile, Natacha; Esseiva, Pierre

    2016-05-01

    The illicit drug cutting represents a complex problem that requires the sharing of knowledge from addiction studies, toxicology, criminology and criminalistics. Therefore, cutting is not well known by the forensic community. Thus, this review aims at deciphering the different aspects of cutting, by gathering information mainly from criminology and criminalistics. It tackles essentially specificities of cocaine and heroin cutting. The article presents the detected cutting agents (adulterants and diluents), their evolution in time and space and the analytical methodology implemented by forensic laboratories. Furthermore, it discusses when, in the history of the illicit drug, cutting may take place. Moreover, researches studying how much cutting occurs in the country of destination are analysed. Lastly, the reasons for cutting are addressed. According to the literature, adulterants are added during production of the illicit drug or at a relatively high level of its distribution chain (e.g. before the product arrives in the country of destination or just after its importation in the latter). Their addition seems hardly justified by the only desire to increase profits or to harm consumers' health. Instead, adulteration would be performed to enhance or to mimic the illicit drug effects or to facilitate administration of the drug. Nowadays, caffeine, diltiazem, hydroxyzine, levamisole, lidocaïne and phenacetin are frequently detected in cocaine specimens, while paracetamol and caffeine are almost exclusively identified in heroin specimens. This may reveal differences in the respective structures of production and/or distribution of cocaine and heroin. As the relevant information about cutting is spread across different scientific fields, a close collaboration should be set up to collect essential and unified data to improve knowledge and provide information for monitoring, control and harm reduction purposes. More research, on several areas of investigation, should be

  8. Mucocutaneous manifestations of cocaine abuse: a review.

    Science.gov (United States)

    Moreno-Artero, Ester; Querol-Cisneros, Elena; Rodríguez-Garijo, Nuria; Tomás-Velázquez, Alejandra; Antoñanzas, Javier; Fernández, Secundino; Gil-Sánchez, María Pilar; España, Agustín

    2018-03-06

    Cocaine is an alkaloid extracted from the leaves of the Erythroxylum coca plant that emerged in the 1970s as a fashionable drug among members of certain social backgrounds. Cocaine abuse is a problem of current interest, which is mostly hidden and under-diagnosed, but dramatically widespread among all socioeconomic strata, and with an incidence which is increasing at an alarming rate. There are 1.5 million cocaine consumers in the USA. In Spain, the prevalence of consumption among the population between 15 and 65 years-old is higher, reaching 3.1%. Because of this, it seems important to understand and recognize all the mucocutaneous manifestations of cocaine abuse which have been reported in the literature in order to clarify and help dermatologists in their daily practice. In this article, we describe the principal mucocutaneous manifestations of cocaine abuse and we review isolated case reports which have been published in the literature. Because the dermatologist may deal with an unknown problem as well as with an already well-known history of cocaine abuse, it seems logical to separate the mucocutaneous manifestations into those which are frequent and highly suggestive, such as those caused by vascular injury, damage to mucosal membranes, infectious diseases or neutrophilic dermatosis, especially when suffered by young people and in consonance with other systemic manifestations and, those which have been reported in the literature as isolated case reports. We also summarize the main aspects of its pathogeny, principal pharmacodynamic and pharmacokinetic characteristics, and diagnostic tools. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  9. Cocaine use in nightlife in Slovenia and Italy

    OpenAIRE

    Sande, Matej; Purkart, Barbara

    2011-01-01

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

  10. Effects of chronic cocaine abuse on postsynaptic dopamine receptors

    International Nuclear Information System (INIS)

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

    1990-01-01

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

  11. Polysomnographic Sleep Dysregulation in Cocaine Dependence

    Directory of Open Access Journals (Sweden)

    Edwin M. Valladares

    2007-01-01

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

  12. Novel Cocaine Vaccine Linked to a Disrupted Adenovirus Gene Transfer Vector Blocks Cocaine Psychostimulant and Reinforcing Effects

    Science.gov (United States)

    Wee, Sunmee; Hicks, Martin J; De, Bishnu P; Rosenberg, Jonathan B; Moreno, Amira Y; Kaminsky, Stephen M; Janda, Kim D; Crystal, Ronald G; Koob, George F

    2012-01-01

    Immunotherapy is a promising treatment for drug addiction. However, insufficient immune responses to vaccines in most subjects pose a challenge. In this study, we tested the efficacy of a new cocaine vaccine (dAd5GNE) in antagonizing cocaine addiction-related behaviors in rats. This vaccine used a disrupted serotype 5 adenovirus (Ad) gene transfer vector coupled to a third-generation cocaine hapten, termed GNE (6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2.1] octane-2-carboxamido-hexanoic acid). Three groups of rats were immunized with dAd5GNE. One group was injected with 3H-cocaine, and radioactivity in the blood and brain was determined. A second group was tested for cocaine-induced locomotor sensitization. A third group was examined for cocaine self-administration, extinction, and reinstatement of responding for cocaine. Antibody titers were determined at various time-points. In each experiment, we added a control group that was immunized with dAd5 without a hapten. The vaccination with dAd5GNE produced long-lasting high titers (>105) of anti-cocaine antibodies in all of the rats. The vaccination inhibited cocaine-induced hyperlocomotor activity and sensitization. Vaccinated rats acquired cocaine self-administration, but they showed less motivation to self-administer cocaine under a progressive-ratio schedule than control rats. When cocaine was not available in a session, control rats exhibited ‘extinction burst' responding, whereas vaccinated rats did not. Moreover, when primed with cocaine, vaccinated rats did not reinstate responding, suggesting a blockade of cocaine-seeking behavior. These data strongly suggest that our dAd5GNE vector-based vaccine may be effective in treating cocaine abuse and addiction. PMID:21918504

  13. Causal pathways between impulsiveness, cocaine use consequences, and depression.

    Science.gov (United States)

    Lister, Jamey J; Ledgerwood, David M; Lundahl, Leslie H; Greenwald, Mark K

    2015-02-01

    The present study examined whether lifetime cocaine use consequences mediate the relationship between trait impulsiveness and current depression symptoms among regular cocaine users. Regular cocaine users (N=108) were assessed using: Barratt Impulsiveness Scale subscales (non-planning, attentional, motor sub-scales) to measure trait impulsiveness; a standardized Drug History and Use Questionnaire to measure cocaine use and related consequences; and Beck Depression Inventory to measure current depression symptoms. All impulsiveness subscales were positively associated with an earlier age of first cocaine use, a higher degree of current depression symptoms and a greater number of lifetime cocaine use consequences. In three separate simple mediation tests, lifetime cocaine use consequences partially mediated the relationship between each of the impulsiveness subscales (non-planning: R(2)=.42; attentional: R(2)=.40; motor: R(2)=.24) and current depression symptoms. Separate moderated mediation analyses failed to demonstrate an interaction between lifetime cocaine use and cocaine-related consequences predicting depression symptoms for the mediation models. Cocaine-related consequences function in a more nuanced manner than just an outcome of impulsiveness or cocaine use, but as a pathway between trait impulsiveness and current depression symptoms. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

    DEFF Research Database (Denmark)

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

    2010-01-01

    -trimester pregnant nonhuman primates, cocaine at doses typically used by drug abusers significantly increased brain glucose metabolism to the same extent in the mother as in the fetus (approximately 100%). Inasmuch as brain glucose metabolism is a sensitive marker of brain function, the current findings provide...... evidence that cocaine use by a pregnant mother will also affect the function of the fetal brain. We are also unique in showing that cocaine's effects in brain glucose metabolism differed in pregnant (increased) and nonpregnant (decreased) animals, which suggests that the psychoactive effects of cocaine...... are influenced by the state of pregnancy. Our findings have clinical implications because they imply that the adverse effects of prenatal cocaine exposure to the newborn child include not only cocaine's deleterious effects to the placental circulation, but also cocaine's direct pharmacological effect...

  15. Cocaine and other illicit drugs in airborne particulates in urban environments: A reflection of social conduct and population size

    International Nuclear Information System (INIS)

    Viana, M.; Postigo, C.; Querol, X.; Alastuey, A.; Lopez de Alda, M.J.; Barcelo, D.; Artinano, B.; Lopez-Mahia, P.; Garcia Gacio, D.; Cots, N.

    2011-01-01

    Levels of cocaine and other psychoactive substances in atmospheric particulate matter (PM) were determined in urban environments representing distinct social behaviours with regard to drug abuse: night-life, university and residential areas. Three cities (with population >1 million and 3 for cocaine, 23-34 pg/m 3 for cannabinoids, and 5-90 pg/m 3 for heroin. The highest levels were recorded on weekends, with factors with respect to weekdays of 1-3 for cocaine, 1-2 for cannabinoids and 1.1-1.7 for heroin. Higher levels were detected in the night-life areas, pointing towards consumption and trafficking as major emission sources, and possibly ruling out drug manufacture. The similarities in temporal trends at all sites suggested a city-scale transport of psychoactive substances. Correlations were detected between cocaine and amphetamine consumption (r 2 = 0.98), and between heroin and cannabinoids (r 2 >0.82). - Highlights: → Cocaine, heroin, cannabis and related illicit drugs are found in detectable amounts in urban air. → Illicit drug consumption and small-scale trafficking are the major emission sources. → Illicit drugs remain in atmospheric particles and are transported across cities during at least 5 days. → Levels of illicit drugs increase from residential to night-life areas, and maximise on weekends. → Correlations between illicit drugs were detected, suggesting differences in consumer groups. - The presence of illicit drugs in atmospheric particles can be used to track illicit drug abuse.

  16. Detection and Characterization of Cocaine and Related Tropane Alkaloids in Coca Leaf, Cocaine, and Biological Specimens.

    Science.gov (United States)

    Moore, J M; Moore, J F; Fodor, G; Jones, A B

    1995-12-01

    Cocaine, atropine and scopolamine are the three most important alkaloids in the tropane group. The detection of these alkaloids and their metabolites, at trace levels in biological matrices, is reviewed. These matrices include human and rat physiological fluids such as blood, urine, and saliva as well as human body tissue and hair. The detection, isolation, and determination of cocaine and related tropane alkaloids in cocaine-bearing leaf of South American and greenhouse-cultivated coca is discussed. The relationship between tropane alkaloids in coca leaf and their presence in illicit refined cocaine is addressed. A survey of modern methods for the detection of tropane alkaloids, including mass spectrometry, ultraviolet, infrared and Raman spectroscopy, gas and high-performance liquid chromatography and immunoassay techniques, is presented. Copyright © 1995 Central Police University.

  17. Repeated electroconvulsive seizure treatment in rats reduces inducibility of early growth response genes and hyperactivity in response to cocaine administration.

    Science.gov (United States)

    Park, Hong Geun; Kim, Se Hyun; Kim, Han Soo; Ahn, Yong Min; Kang, Ung Gu; Kim, Yong Sik

    2011-06-01

    Regulated expression of immediate early genes (IEGs) in the brain reflects neuronal activity in response to various stimuli and recruits specific gene programs involved in long-term neuronal modification and behavioral alterations. Repeated electroconvulsive seizure (ECS) treatment reduces the expression level of several IEGs, such as c-fos, which play important roles in psychostimulant-induced behavioral changes. In this study, we investigated the effects of repeated ECS treatment on the basal expression level of IEGs and its effects on cocaine-induced activation of IEGs and locomotor activity in rats. Repeated ECS treatment for 10days (E10×) reduced Egr1, Egr2, Egr3, and c-fos mRNA and protein levels in the rat frontal cortex at 24h after the last ECS treatment, and these changes were evident in the neuronal cells of the prefrontal cortex. In particular, downregulation of Egr1 and c-fos was evident until 5days after the last ECS treatment. Moreover, E10× pretreatment attenuated the cocaine-induced increase in Egr1, Egr2, and c-fos expression in the rat frontal cortex, whereas phosphorylation of ERK1/2, one of the representative upstream activators of these genes, increased significantly following cocaine treatment. Additionally, E10× pretreatment attenuated the increase in locomotor activity in response to a cocaine injection. In conclusion, repeated ECS treatment reduced the expression and inducibility of Egrs and c-fos, which could attenuate the response of the brain to psychostimulants. Copyright © 2011 Elsevier Inc. All rights reserved.

  18. Nonuniform alteration of dendritic development in the cerebral cortex following prenatal cocaine exposure.

    Science.gov (United States)

    Jones, L; Fischer, I; Levitt, P

    1996-01-01

    Prenatal exposure to cocaine has the potential to modify normal brain development and result in behavioral dysfunction. We used a new animal model in which cocaine was administered intravenously during prenatal development in pregnant rabbits twice daily at low dosages. Analysis of brain development focused on two areas of the cerebral cortex, anterior cingulate and primary visual, in which dopamine afferents, a target of cocaine, are differentially distributed. All postnatal rabbits exposed to cocaine prenatally exhibited normal features of cortical organization, including thickness, lamination patterns, and cytoarchitectonic differentiation. General axonal and astroglial organization, assessed by neurofilament-H and glial fibrillary acidic protein immunostaining, also was unchanged in the cocaine-exposed animals. Analysis of dendritic organization was done using antibodies against microtubule-associated protein 2 (MAP2), which reveals mostly the larger apical shafts of cortical pyramidal cells. In the anterior cingulate cortex of adolescent rabbits exposed to cocaine in utero, there is a marked decrease in both dendritic bundling and typical long, straight MAP2-stained profiles. In normal animals, the long, bundled dendrites area readily traced in a single focal plane from layer III or V pyramidal cell somata to the pial surface in saline-treated animals. Instead, the drug-exposed animals contained many more short segments of MAP2-stained dendrites that could be viewed coursing in and out of the plane of focus in the sections. Apical dendrites in mature visual cortex appeared normal in the cocaine-exposed rabbits. Examination of MAP2 staining at various postnatal ages revealed that the dendritic changes expressed in the adolescent anterior cingulate cortex appeared less robust, but still evident at birth. By P10-14, dendritic modifications were similar to the adult. Counts of the number of MAP2-positive dendritic profiles crossing the layer II-III interface

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

    Science.gov (United States)

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

    2017-10-01

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

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

    Science.gov (United States)

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

    2016-11-25

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

  1. The skinny on cocaine: insights into eating behavior and body weight in cocaine-dependent men.

    Science.gov (United States)

    Ersche, Karen D; Stochl, Jan; Woodward, Jeremy M; Fletcher, Paul C

    2013-12-01

    There is a general assumption that weight loss associated with cocaine use reflects its appetite suppressing properties. We sought to determine whether this was justified by characterizing, in detail, alterations in dietary food intake and body composition in actively using cocaine-dependent individuals. We conducted a cross-sectional case-control comparison of 65 male volunteers from the local community, half of whom satisfied the DSM-IV-TR criteria for cocaine dependence (n=35) while the other half had no personal or family history of a psychiatric disorder, including substance abuse (n=30). Assessments were made of eating behavior and dietary food intake, estimation of body composition, and measurement of plasma leptin. Although cocaine users reported significantly higher levels of dietary fat and carbohydrates as well as patterns of uncontrolled eating, their fat mass was significantly reduced compared with their non-drug using peers. Levels of leptin were associated with fat mass, and with the duration of stimulant use. Tobacco smoking status or concomitant use of medication did not affect the significance of the results. Weight changes in cocaine users reflect fundamental perturbations in fat regulation. These are likely to be overlooked in clinical practice but may produce significant health problems when cocaine use is discontinued during recovery. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

  2. Cocaine profiling: Implementation of a predictive model by ATR-FTIR coupled with chemometrics in forensic chemistry.

    Science.gov (United States)

    Materazzi, Stefano; Gregori, Adolfo; Ripani, Luigi; Apriceno, Azzurra; Risoluti, Roberta

    2017-05-01

    In this study, a strategy based on Infrared Spectroscopy with Fourier Transformed and Attenuated Total Reflectance associated with chemometrics (ATR-FTIR) is proposed to identify the chemical "fingerprint" of cocaine samples. To this end, standard mixtures of cocaine and cuttings at differents ratio were investigated in order to develop a multivariate classification model to simultaneously predict the composition of the samples and to obtain a profile of adulteration of cocaine seizures. In addition, the application of a Partial Least Squares (PLS) and Principal Component Regression (PCR) calibration approaches were found to be a useful tool to predict the content of cocaine, caffeine, procaine, lidocaine and phenacetin in drug seizures. The achieved results on real confiscated samples, in cooperation with the Italian Scientific Investigation Department (Carabinieri-RIS) of Rome, allow to consider ATR-FTIR followed to chemometrics as a promising forensic tool in such situations involving profile comparisons and supporting forensic investigations. Copyright © 2017 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

    Anker, Justin J; Carroll, Marilyn E

    2010-11-01

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

  4. Cocaine-associated retiform purpura: a C5b-9-mediated microangiopathy syndrome associated with enhanced apoptosis and high levels of intercellular adhesion molecule-1 expression.

    Science.gov (United States)

    Magro, Cynthia M; Wang, Xuan

    2013-10-01

    Cocaine-associated retiform purpura is a recently described entity characterized by striking hemorrhagic necrosis involving areas of skin associated with administration of cocaine. Levamisole, an adulterant in cocaine, has been suggested as the main culprit pathogenetically. Four cases of cocaine-associated retiform purpura were encountered in the dermatopathology practice of C. M. Magro. The light microscopic findings were correlated with immunohistochemical and immunofluorescence studies. All 4 cases showed a very striking thrombotic diathesis associated with intravascular macrophage accumulation. Necrotizing vasculitis was noted in 1 case. Striking intercellular adhesion molecule-1 (ICAM-1)/CD54 expression in vessel wall along with endothelial expression of caspase 3 and extensive vascular C5b-9 deposition was observed in all biopsies examined. Cocaine-induced retiform purpura is a C5b-9-mediated microvascular injury associated with enhanced apoptosis and prominent vascular expression of ICAM-1, all of which have been shown in prior in vitro and in vivo murine models to be a direct effect of cocaine metabolic products. Antineutrophilic cytoplasmic antibody and antiphospholipid antibodies are likely the direct sequelae of the proapoptotic microenvironment. The inflammatory vasculitic lesion could reflect the downstream end point reflective of enhanced ICAM-1 expression and the development of antineutrophilic cytoplasmic antibody. Levamisole likely works synergistically with cocaine in the propagation of this syndromic complex.

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

    Science.gov (United States)

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

    2013-12-17

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

  6. Cocaine-induced pulmonary changes: HRCT findings

    International Nuclear Information System (INIS)

    Almeida, Renata Rocha de; Zanetti, Glaucia; Marchiori, Edson; Souza, Luciana Soares de; Silva, Jorge Luiz Pereira e; Mancano, Alexandre Dias; Nobre, Luiz Felipe; Hochhegger, Bruno; Marchiori, Edson

    2015-01-01

    Objective: To evaluate HRCT scans of the chest in 22 patients with cocaine-induced pulmonary disease. Methods: We included patients between 19 and 52 years of age. The HRCT scans were evaluated by two radiologists independently, discordant results being resolved by consensus. The inclusion criterion was an HRCT scan showing abnormalities that were temporally related to cocaine use, with no other apparent causal factors. Results: In 8 patients (36.4%), the clinical and tomographic findings were consistent with 'crack lung', those cases being studied separately. The major HRCT findings in that subgroup of patients included ground-glass opacities, in 100% of the cases; consolidations, in 50%; and the halo sign, in 25%. In 12.5% of the cases, smooth septal thickening, paraseptal emphysema, centrilobular nodules, and the tree-in-bud pattern were identified. Among the remaining 14 patients (63.6%), barotrauma was identified in 3 cases, presenting as pneumomediastinum, pneumothorax, and hemopneumothorax, respectively. Talcosis, characterized as perihilar conglomerate masses, architectural distortion, and emphysema, was diagnosed in 3 patients. Other patterns were found less frequently: organizing pneumonia and bullous emphysema, in 2 patients each; and pulmonary infarction, septic embolism, eosinophilic pneumonia, and cardiogenic pulmonary edema, in 1 patient each. Conclusions: Pulmonary changes induced by cocaine use are varied and nonspecific. The diagnostic suspicion of cocaine-induced pulmonary disease depends, in most of the cases, on a careful drawing of correlations between clinical and radiological findings. (author)

  7. Case Study: The Chemistry of Cocaine

    Science.gov (United States)

    Dewprashad, Brahmadeo

    2011-01-01

    This column provides original articles on innovations in case study teaching, assessment of the method, as well as case studies with teaching notes. This month's case study focuses on the chemistry of cocaine to teach a number of core concepts in organic chemistry. It also requires that students read and analyze an original research paper on…

  8. Cocaine-induced pulmonary changes: HRCT findings

    Directory of Open Access Journals (Sweden)

    Renata Rocha de Almeida

    2015-08-01

    Full Text Available AbstractObjective: To evaluate HRCT scans of the chest in 22 patients with cocaine-induced pulmonary disease.Methods: We included patients between 19 and 52 years of age. The HRCT scans were evaluated by two radiologists independently, discordant results being resolved by consensus. The inclusion criterion was an HRCT scan showing abnormalities that were temporally related to cocaine use, with no other apparent causal factors.Results:In 8 patients (36.4%, the clinical and tomographic findings were consistent with "crack lung", those cases being studied separately. The major HRCT findings in that subgroup of patients included ground-glass opacities, in 100% of the cases; consolidations, in 50%; and the halo sign, in 25%. In 12.5% of the cases, smooth septal thickening, paraseptal emphysema, centrilobular nodules, and the tree-in-bud pattern were identified. Among the remaining 14 patients (63.6%, barotrauma was identified in 3 cases, presenting as pneumomediastinum, pneumothorax, and hemopneumothorax, respectively. Talcosis, characterized as perihilar conglomerate masses, architectural distortion, and emphysema, was diagnosed in 3 patients. Other patterns were found less frequently: organizing pneumonia and bullous emphysema, in 2 patients each; and pulmonary infarction, septic embolism, eosinophilic pneumonia, and cardiogenic pulmonary edema, in 1 patient each.Conclusions: Pulmonary changes induced by cocaine use are varied and nonspecific. The diagnostic suspicion of cocaine-induced pulmonary disease depends, in most of the cases, on a careful drawing of correlations between clinical and radiological findings.

  9. The effects of cocaine on HIV transcription.

    Science.gov (United States)

    Tyagi, Mudit; Weber, Jaime; Bukrinsky, Michael; Simon, Gary L

    2016-06-01

    Illicit drug users are a high-risk population for infection with the human immunodeficiency virus (HIV). A strong correlation exists between prohibited drug use and an increased rate of HIV transmission. Cocaine stands out as one of the most frequently abused illicit drugs, and its use is correlated with HIV infection and disease progression. The central nervous system (CNS) is a common target for both drugs of abuse and HIV, and cocaine intake further accelerates neuronal injury in HIV patients. Although the high incidence of HIV infection in illicit drug abusers is primarily due to high-risk activities such as needle sharing and unprotected sex, several studies have demonstrated that cocaine enhances the rate of HIV gene expression and replication by activating various signal transduction pathways and downstream transcription factors. In order to generate mature HIV genomic transcript, HIV gene expression has to pass through both the initiation and elongation phases of transcription, which requires discrete transcription factors. In this review, we will provide a detailed analysis of the molecular mechanisms that regulate HIV transcription and discuss how cocaine modulates those mechanisms to upregulate HIV transcription and eventually HIV replication.

  10. Vulnerability to cocaine : role of stress hormones

    NARCIS (Netherlands)

    Jong, Inge Elisabeth Maria de

    2007-01-01

    Not everyone who experiments with cocaine acquires compulsive drug use. The mechanism underlying this individual difference in susceptibility to addiction is poorly understood. Recent studies have identified genes and adverse life events (stress) as risk factors. The objective of this thesis is to

  11. Cocaine-induced pulmonary changes: HRCT findings

    Energy Technology Data Exchange (ETDEWEB)

    Almeida, Renata Rocha de; Zanetti, Glaucia; Marchiori, Edson, E-mail: edmarchiori@gmail.com [Universidade Federal do Rio de Janeiro (UFRJ), RJ (Brazil). Programa de Pos-Graduacao em Radiologia; Souza Junior, Arthur Soares [Faculdade de Medicina de Petropolis, Petropolis, RJ (Brazil); Souza, Luciana Soares de [Ultra-X, Sao Jose do Rio Preto, SP (Brazil); Silva, Jorge Luiz Pereira e [Universidade Federal da Bahia (UFBA), Salvador (Brazil). Dep. de Medicina e Apoio Diagnostico; Escuissato, Dante Luiz [Universidade Federal do Parana (UFPR), Curitiba (Brazil). Dept. de Clinica Medica; Irion, Klaus Loureiro [Liverpool Heart and Chest Hospital NHS Foundation Trust, Liverpool (United Kingdom); Mancano, Alexandre Dias [Hospital Anchieta, Taguatinga, DF (Brazil); Nobre, Luiz Felipe [Universidade Federal de Santa Catarina (UFSC), Florianopolis, SC (Brazil); Hochhegger, Bruno [Universidade Federal de Ciencias da Saude de Porto Alegre, Porto Alegre, RS (Brazil); Marchiori, Edson [Universidade Federal Fluminense (UFF), Niteroi, RJ (Brazil)

    2015-07-15

    Objective: To evaluate HRCT scans of the chest in 22 patients with cocaine-induced pulmonary disease. Methods: We included patients between 19 and 52 years of age. The HRCT scans were evaluated by two radiologists independently, discordant results being resolved by consensus. The inclusion criterion was an HRCT scan showing abnormalities that were temporally related to cocaine use, with no other apparent causal factors. Results: In 8 patients (36.4%), the clinical and tomographic findings were consistent with 'crack lung', those cases being studied separately. The major HRCT findings in that subgroup of patients included ground-glass opacities, in 100% of the cases; consolidations, in 50%; and the halo sign, in 25%. In 12.5% of the cases, smooth septal thickening, paraseptal emphysema, centrilobular nodules, and the tree-in-bud pattern were identified. Among the remaining 14 patients (63.6%), barotrauma was identified in 3 cases, presenting as pneumomediastinum, pneumothorax, and hemopneumothorax, respectively. Talcosis, characterized as perihilar conglomerate masses, architectural distortion, and emphysema, was diagnosed in 3 patients. Other patterns were found less frequently: organizing pneumonia and bullous emphysema, in 2 patients each; and pulmonary infarction, septic embolism, eosinophilic pneumonia, and cardiogenic pulmonary edema, in 1 patient each. Conclusions: Pulmonary changes induced by cocaine use are varied and nonspecific. The diagnostic suspicion of cocaine-induced pulmonary disease depends, in most of the cases, on a careful drawing of correlations between clinical and radiological findings. (author)

  12. Protecting against cocaine, heroin, and sarin gas.

    Science.gov (United States)

    McRee, Duncan

    2003-04-01

    The first X-ray structure of human carboxylesterase 1 (hCE1) and the structures of hCE1 with drug analogs bound reveal important molecular details of how the drugs cocaine, heroin, and tacrine are metabolized and cleared.

  13. Persistent increase in hypothalamic arginine vasopressin gene expression during protracted withdrawal from chronic escalating-dose cocaine in rodents.

    Science.gov (United States)

    Zhou, Yan; Litvin, Yoav; Piras, Anna Paola; Pfaff, Donald W; Kreek, Mary Jeanne

    2011-09-01

    Arginine vasopressin (AVP) from the paraventricular nucleus (PVN) of hypothalamus has important roles in regulation of the hypothalamic-pituitary-adrenal (HPA) axis and stress-related behaviors during chronic stress. It is unknown, however, whether AVP in the PVN is involved in the modulation of HPA activity after chronic cocaine exposure. Here, we examined the gene expression alterations of AVP in the hypothalamus, and V1b receptor and pro-opiomelanocortin (POMC) in the anterior pituitary, as well as HPA hormonal changes, in Fischer rats after chronic cocaine and withdrawal, using two different chronic (14-day) 'binge' pattern administration regimens: steady-dose cocaine (SDC, 45 mg/kg/day) and escalating-dose cocaine (EDC, 45 up to 90 mg/kg/day). There was a significant (7-fold) plasma adrenocorticotropic hormone (ACTH) elevation after chronic EDC (but not SDC), coupled with increased V1b and POMC mRNA levels in the anterior pituitary. From acute (1-day) to protracted (14-day) withdrawal from chronic EDC (but not from SDC), we found persistent elevations of both plasma ACTH and corticosterone levels and AVP mRNA levels in the PVN. Selective V1b antagonist SSR149415 (5 mg/kg) attenuated acute withdrawal-induced HPA activation after EDC. To study potential roles of endogenous opioids in modulating the AVP gene, we administered naloxone (1 mg/kg); we found that opioid receptor antagonism increased AVP mRNA levels in cocaine-naive rats, but not in cocaine-withdrawn rats, suggesting less tonic opioid inhibition of PVN AVP neurons after chronic EDC. To assess the effects of cocaine withdrawal on sub-populations of PVN AVP neurons, we utilized AVP-enhanced green fluorescent protein (EGFP) promoter transgenic mice and found that acute withdrawal following chronic EDC increased the number of AVP-EGFP neurons in the parvocellular PVN (pPVN). These results suggest that during protracted withdrawal, enhanced pPVN AVP gene expression is associated with persistent elevations

  14. Natural attenuation and environmental quality of the mining rivers at the Carboniferous Area of El Bierzo (Leon); Atenuacion natural y calidad ambiental de los rios mineros de la Cuenca Carbonifera del Bierzo (Leon)

    Energy Technology Data Exchange (ETDEWEB)

    Rodriguez Gomez, V.; Vadillo Fernandez, L.; Lacal Guzman, M.; Alberruche del Campo, E.; Herrero Barrero, T.; Losa Roman, A. de la

    2010-07-01

    The study tackles the environmental impact on aquatic ecosystems caused by coal mining activity in the Carboniferous Area of El Bierzo. This survey is based on the methodology of the USGS (Geological Survey of the United States of America) Assessment of Metal Bioavailability in a Watershed Affected by Abandoned Mine Lands. The application of this methodology to the mining area of El Bierzo, with a declining coal mining that entails the closure of many underground mines and the dismantling of the coal washing plants, has allowed to assess, in time and distance to contamination sources, the impact, environmental quality, and the attenuation and natural recovery processes of the aquatic ecosystems, once the mines are closed. (Author) 31 refs.

  15. Clinical value of periventricular low-intensity areas detected by fluid attenuated inversion recovery (FLAIR). Relationships between perinatal vital parameter and neonatal MRI

    Energy Technology Data Exchange (ETDEWEB)

    Kadowaki, Sachiko; Iwata, Osuke; Tamura, Masanori [Nagano Children' s Hospital, Toyoshina (Japan)] (and others)

    2002-01-01

    A follow-up study was performed to assess the correlation among the incidence of periventricular low intensities (PVLI) on MRI (magnetic resonance imaging) FLAIR (fluid attenuated inversion recovery) imaging, clinical evidence of perinatal insults that may cause white matter damage, and the outcome of the infants. We evaluated periventricular white matter lesions of 329 neonates whose MRI were obtained before two months corrected age. The detective rate of periventricular abnormalities on FLAIR imaging was significantly higher than that of T1-T2 weighted imaging. The most typical lesion detected on FLAIR imaging was periventricular low intensities (PVLI), frequently observed in the neonates with a history of preterm labour, very low birth weight, birth asphyxia and severe respiratory failure. Although we could not characterize the risk factors of PVLI, the incidence of PVLI had a strong correlation with the scores of motor and developmental tests at 12 and 36-months corrected age. In conclusion, FLAIR imaging, detecting the border zone damage of white matter, would be a strong tool to pick out neonates at high risk of neurological disturbances from those without clinical evidence of neurological insults in the neonatal period. (author)

  16. Availability of N-Methyl-d-Aspartate Receptor Coagonists Affects Cocaine-Induced Conditioned Place Preference and Locomotor Sensitization: Implications for Comorbid Schizophrenia and Substance Abuse.

    Science.gov (United States)

    Puhl, Matthew D; Berg, Alexandra R; Bechtholt, Anita J; Coyle, Joseph T

    2015-06-01

    Schizophrenia is associated with high prevalence of substance abuse. Recent research suggests that dysregulation of N-methyl-d-aspartate receptor (NMDAR) function may play a role in the pathophysiology of both schizophrenia and drug addiction, and thus, may account for this high comorbidity. Our laboratory has developed two transgenic mouse lines that exhibit contrasting NMDAR activity based on the availability of the glycine modulatory site (GMS) agonists d-serine and glycine. Glycine transporter 1 knockdowns (GlyT1(+/-)) exhibit NMDAR hyperfunction, whereas serine racemase knockouts (SR(-/-)) exhibit NMDAR hypofunction. We characterized the behavior of these lines in a cocaine-induced (20 mg/kg) conditioned place preference (CPP) and locomotor sensitization paradigm. Compared with wild-type mice, GlyT1(+/-) mice displayed hastened extinction of CPP and robust cocaine-induced reinstatement. SR(-/-) mice appeared to immediately "forget" the learned preference, because they did not exhibit cocaine-induced reinstatement and also displayed attenuated locomotor sensitization. Treatment of GlyT1(+/-) mice with gavestinel (10 mg/kg on day 1; 5 mg/kg on days 2-17), a GMS antagonist, attenuated cocaine-induced CPP and caused them to immediately "forget" the learned preference. Treatment of SR(-/-) mice with d-serine (300 mg/kg on day 1; 150 mg/kg on days 2-17) to normalize brain levels caused them to avoid the cocaine-paired side of the chamber during extinction. These results highlight NMDAR dysfunction as a possible neural mechanism underlying comorbid schizophrenia and substance abuse. Also, these findings suggest drugs that directly or indirectly activate the NMDAR GMS could be an effective treatment of cocaine abuse. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  17. Public crack cocaine smoking and willingness to use a supervised inhalation facility: implications for street disorder

    Directory of Open Access Journals (Sweden)

    Qi Jiezhi

    2011-02-01

    Full Text Available Abstract Background The health risks of crack cocaine smoking in public settings have not been well described. We sought to identify factors associated with public crack smoking, and assess the potential for a supervised inhalation facility to reduce engagement in this behavior, in a setting planning to evaluate a medically supervised crack cocaine smoking facility. Methods Data for this study were derived from a Canadian prospective cohort of injection drug users. Using multivariate logistic regression we identified factors associated with smoking crack cocaine in public areas. Among public crack smokers we then identified factors associated with willingness to use a supervised inhalation facility. Results Among our sample of 623 people who reported crack smoking, 61% reported recently using in public locations. In multivariate analysis, factors independently associated with public crack smoking included: daily crack cocaine smoking; daily heroin injection; having encounters with police; and engaging in drug dealing. In sub analysis, 71% of public crack smokers reported willingness to use a supervised inhalation facility. Factors independently associated with willingness include: female gender, engaging in risky pipe sharing; and having encounters with police. Conclusion We found a high prevalence of public crack smoking locally, and this behavior was independently associated with encounters with police. However, a majority of public crack smokers reported being willing to use a supervised inhalation facility, and individuals who had recent encounters with police were more likely to report willingness. These findings suggest that supervised inhalation facilities offer potential to reduce street-disorder and reduce encounters with police.

  18. Cocaine-Associated Seizures and Incidence of Status Epilepticus

    Directory of Open Access Journals (Sweden)

    Majlesi, Nima DO

    2010-05-01

    Full Text Available Objectives: Acute complications from cocaine abuse are commonly treated in the emergency department (ED; one of the most consequential is status epilepticus. The incidence of this complication is not clearly defined in the prior literature on cocaine-associated sequelae. We evaluated the incidence of status epilepticus in patients with seizures secondary to suspected cocaine use.Methods: We performed a retrospective multi-center study of patients with seizures resulting from cocaine use. We identified study subjects at 15 hospitals by record review and conducted a computer-assisted records search to identify patients with seizures for each institution over a four-year period. We selected subjects from this group on the basis of cocaine use and determined the occurrence of status epilepticus among them. Data were collected on each subject using a standardized data collection form.Results: We evaluated 43 patients in the ED for cocaine-associated seizures. Their age range was 17 to 54, with a mean age was 31 years; 53% were male. Of 43 patients, 42 experienced a single tonic-clonic seizure and one developed status epilepticus. All patients had either a history of cocaine use or positive urine drug screen for cocaine.Conclusion: Despite reported cases of status epilepticus with cocaine-induced seizures, the incidence of this complication was unclear based on prior literature. This study shows that most cocaine-associated seizures are self-limited. [West J Emerg Med. 2010; 11(2:157-160.

  19. ABSORPTION, SCATTERING, ATTENUATION COEFFICIENTS and Other Data From TOGA Area - Pacific (30 N to 30 S) from 19920101 to 19931221 (NODC Accession 9600080)

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Satellite Sea Surface Temperature and other data in this accession was collected from NOAA AVHRR satellite in TOGA Area - Pacific (30 N to 30 S) as part of...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1992-12-31

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1992-01-01

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

  2. Sex differences in cocaine conditioned place preference in C57BL/6J mice

    OpenAIRE

    Hilderbrand, Elisa R.; Lasek, Amy W.

    2014-01-01

    Men and women respond differently to the subjective effects of cocaine and cocaine-associated cues, which has implications for the development and maintenance of cocaine addiction. Preclinical studies performed in rats, modeling various aspects of cocaine addiction, have largely validated these results, indicating that female rats may be more sensitive to the rewarding properties of cocaine. The molecular mechanisms leading to sex differences in cocaine reward have largely not been determined...

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

    DEFF Research Database (Denmark)

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

    2010-01-01

    Cocaine use during pregnancy is deleterious to the newborn child, in part via its disruption of placental blood flow. However, the extent to which cocaine can affect the function of the fetal primate brain is still an unresolved question. Here we used PET and MRI and show that in third......-trimester pregnant nonhuman primates, cocaine at doses typically used by drug abusers significantly increased brain glucose metabolism to the same extent in the mother as in the fetus (approximately 100%). Inasmuch as brain glucose metabolism is a sensitive marker of brain function, the current findings provide...... evidence that cocaine use by a pregnant mother will also affect the function of the fetal brain. We are also unique in showing that cocaine's effects in brain glucose metabolism differed in pregnant (increased) and nonpregnant (decreased) animals, which suggests that the psychoactive effects of cocaine...

  4. Dancing on coke: smuggling cocaine dispersed in polyvinyl alcohol.

    Science.gov (United States)

    van Nuijs, Alexander L N; Maudens, Kristof E; Lambert, Willy E; Van Calenbergh, Serge; Risseeuw, Martijn D P; Van hee, Paul; Covaci, Adrian; Neels, Hugo

    2012-01-01

    Recent trends suggest that cocaine smugglers have become more and more inventive to avoid seizures of large amounts of cocaine transported between countries. We report a case of a mail parcel containing a dance pad which was seized at the Customs Department of Brussels Airport, Belgium. After investigation, the inside of the dance pad was found to contain a thick polymer, which tested positive for cocaine. Analysis was performed using a routine colorimetric swipe test, gas chromatography coupled with mass spectrometry and nuclear magnetic resonance spectroscopy. The polymer was identified as polyvinyl alcohol (PVA) and contained 18% cocaine, corresponding to a street value of € 20,000. Laboratory experiments showed that cocaine could be easily extracted from the PVA matrix. This case report reveals a new smuggling technique for the transportation of large amounts of cocaine from one country to another. © 2011 American Academy of Forensic Sciences.

  5. The Religious and Spiritual Dimensions of Cutting Down and Stopping Cocaine Use: A Qualitative Exploration Among African Americans in the South

    Science.gov (United States)

    Cheney, Ann M.; Curran, Geoffrey M.; Booth, Brenda M.; Sullivan, Steve; Stewart, Katharine; Borders, Tyrone F.

    2014-01-01

    This study qualitatively examines the religious and spiritual dimensions of cutting down and stopping cocaine use among African Americans in rural and urban areas of Arkansas. The analyses compare and contrast the narrative data of 28 current cocaine users living in communities where the Black church plays a fundamental role in the social and cultural lives of many African Americans, highlighting the ways that participants used religious symbols, idiomatic expression, and Biblical scriptures to interpret and make sense of their substance-use experiences. Participants drew on diverse religious and spiritual beliefs and practices, including participation in organized religion, reliance on a personal relationship with God, and God’s will to cut down and stop cocaine use. Our findings suggest that culturally sensitive interventions addressing the influence of religion and spirituality in substance use are needed to reduce cocaine use and promote recovery in this at-risk, minority population. PMID:25364038

  6. 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.

  7. Effects of cocaine on honey bee dance behaviour

    OpenAIRE

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

    2008-01-01

    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 perfo...

  8. Translational control by eIF2α phosphorylation regulates vulnerability to the synaptic and behavioral effects of cocaine

    Science.gov (United States)

    Huang, Wei; Placzek, Andon N; Viana Di Prisco, Gonzalo; Khatiwada, Sanjeev; Sidrauski, Carmela; Krnjević, Krešimir; Walter, Peter; Dani, John A; Costa-Mattioli, Mauro

    2016-01-01

    Adolescents are especially prone to drug addiction, but the underlying biological basis of their increased vulnerability remains unknown. We reveal that translational control by phosphorylation of the translation initiation factor eIF2α (p-eIF2α) accounts for adolescent hypersensitivity to cocaine. In adolescent (but not adult) mice, a low dose of cocaine reduced p-eIF2α in the ventral tegmental area (VTA), potentiated synaptic inputs to VTA dopaminergic neurons, and induced drug-reinforced behavior. Like adolescents, adult mice with reduced p-eIF2α-mediated translational control were more susceptible to cocaine-induced synaptic potentiation and behavior. Conversely, like adults, adolescent mice with increased p-eIF2α became more resistant to cocaine's effects. Accordingly, metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD)—whose disruption is postulated to increase vulnerability to drug addiction—was impaired in both adolescent mice and adult mice with reduced p-eIF2α mediated translation. Thus, during addiction, cocaine hijacks translational control by p-eIF2α, initiating synaptic potentiation and addiction-related behaviors. These insights may hold promise for new treatments for addiction. DOI: http://dx.doi.org/10.7554/eLife.12052.001 PMID:26928234

  9. Translational control by eIF2α phosphorylation regulates vulnerability to the synaptic and behavioral effects of cocaine.

    Science.gov (United States)

    Huang, Wei; Placzek, Andon N; Viana Di Prisco, Gonzalo; Khatiwada, Sanjeev; Sidrauski, Carmela; Krnjević, Krešimir; Walter, Peter; Dani, John A; Costa-Mattioli, Mauro

    2016-03-01

    Adolescents are especially prone to drug addiction, but the underlying biological basis of their increased vulnerability remains unknown. We reveal that translational control by phosphorylation of the translation initiation factor eIF2α (p-eIF2α) accounts for adolescent hypersensitivity to cocaine. In adolescent (but not adult) mice, a low dose of cocaine reduced p-eIF2α in the ventral tegmental area (VTA), potentiated synaptic inputs to VTA dopaminergic neurons, and induced drug-reinforced behavior. Like adolescents, adult mice with reduced p-eIF2α-mediated translational control were more susceptible to cocaine-induced synaptic potentiation and behavior. Conversely, like adults, adolescent mice with increased p-eIF2α became more resistant to cocaine's effects. Accordingly, metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD)-whose disruption is postulated to increase vulnerability to drug addiction-was impaired in both adolescent mice and adult mice with reduced p-eIF2α mediated translation. Thus, during addiction, cocaine hijacks translational control by p-eIF2α, initiating synaptic potentiation and addiction-related behaviors. These insights may hold promise for new treatments for addiction.

  10. Novel sample preparation methods and field testing procedures used to determine the chemical basis of cocaine detection by canines

    Science.gov (United States)

    Furton, Kenneth G.; Hsu, Ya-Li; Luo, Tien-Ying; Alvarez, Nayiby; Lagos, Pedro

    1997-02-01

    The use of canines to signal money associated with drug trafficking is a major point of contention among dog handlers, forensic scientists, and the legal community particularly in light of recent reports that a significant amount of money in circulation is contaminated with detectable amounts of cocaine. The questions raised include: What exactly are the dogs alerting to? How selective are the dogs? How sensitive are the dogs? How reliable are the dogs? Tests with various volatile cocaine by-products confirm that the dominant chemical in cocaine odor is methyl benzoate. Field tests on fifteen different drug detector dogs with varying breeds, ages and training regimes show a consistent threshold level of 1 (mu) g of methyl benzoate spiked along with cocaine on U.S. currency required to initiate an alert. The majority of the canines did not alert to pharmaceutical grade cocaine even at levels as high as 1 g. Methyl benzoate is shown to evaporate rapidly from individual bills and is a function of the available surface area for wrapped currency. The canines tested were remarkably selective and reliable even under varying test conditions and using different delivery devices.

  11. Cocaine Hydrolase Gene Transfer Demonstrates Cardiac Safety and Efficacy against Cocaine-Induced QT Prolongation in Mice.

    Science.gov (United States)

    Murthy, Vishakantha; Reyes, Santiago; Geng, Liyi; Gao, Yang; Brimijoin, Stephen

    2016-03-01

    Cocaine addiction is associated with devastating medical consequences, including cardiotoxicity and risk-conferring prolongation of the QT interval. Viral gene transfer of cocaine hydrolase engineered from butyrylcholinesterase offers therapeutic promise for treatment-seeking drug users. Although previous preclinical studies have demonstrated benefits of this strategy without signs of toxicity, the specific cardiac safety and efficacy of engineered butyrylcholinesterase viral delivery remains unknown. Here, telemetric recording of electrocardiograms from awake, unrestrained mice receiving a course of moderately large cocaine doses (30 mg/kg, twice daily for 3 weeks) revealed protection against a 2-fold prolongation of the QT interval conferred by pretreatment with cocaine hydrolase vector. By itself, this prophylactic treatment did not affect QT interval duration or cardiac structure, demonstrating that viral delivery of cocaine hydrolase has no intrinsic cardiac toxicity and, on the contrary, actively protects against cocaine-induced QT prolongation. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

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

    DEFF Research Database (Denmark)

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

    2010-01-01

    -trimester pregnant nonhuman primates, cocaine at doses typically used by drug abusers significantly increased brain glucose metabolism to the same extent in the mother as in the fetus (approximately 100%). Inasmuch as brain glucose metabolism is a sensitive marker of brain function, the current findings provide...... evidence that cocaine use by a pregnant mother will also affect the function of the fetal brain. We are also unique in showing that cocaine's effects in brain glucose metabolism differed in pregnant (increased) and nonpregnant (decreased) animals, which suggests that the psychoactive effects of cocaine...

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

    Science.gov (United States)

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

    2017-08-30

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

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

    Science.gov (United States)

    Vilela, Luciano Rezende; Gomides, Lindisley Ferreira; David, Bruna Araújo; Antunes, Maísa Mota; Diniz, Ariane Barros; Moreira, Fabrício de Araújo; Menezes, Gustavo Batista

    2015-01-01

    Cocaine is a commonly abused illicit drug that causes significant morbidity and mortality. The most severe and common complications are seizures, ischemic strokes, myocardial infarction, and acute liver injury. Here, we demonstrated that acute cocaine intoxication promoted seizure along with acute liver damage in mice, with intense inflammatory infiltrate. Considering the protective role of the endocannabinoid system against cell toxicity, we hypothesized that treatment with an anandamide hydrolysis inhibitor, URB597, or with a phytocannabinoid, cannabidiol (CBD), protects against cocaine toxicity. URB597 (1.0 mg/kg) abolished cocaine-induced seizure, yet it did not protect against acute liver injury. Using confocal liver intravital microscopy, we observed that CBD (30 mg/kg) reduced acute liver inflammation and damage induced by cocaine and prevented associated seizure. Additionally, we showed that previous liver damage induced by another hepatotoxic drug (acetaminophen) increased seizure and lethality induced by cocaine intoxication, linking hepatotoxicity to seizure dynamics. These findings suggest that activation of cannabinoid system may have protective actions on both liver and brain induced by cocaine, minimizing inflammatory injury promoted by cocaine, supporting its further clinical application in the treatment of cocaine abuse. PMID:25999668

  15. Disrupted social development enhances the motivation for cocaine in rats.

    Science.gov (United States)

    Baarendse, Petra J J; Limpens, Jules H W; Vanderschuren, Louk J M J

    2014-04-01

    Early social experiences are of major importance for behavioural development. In particular, social play behaviour during post-weaning development is thought to facilitate the attainment of social, emotional and cognitive capacities. Conversely, social insults during development can cause long-lasting behavioural impairments and increase the vulnerability for psychiatric disorders, such as drug addiction. The aim of this study was to investigate whether a lack of social experiences during the juvenile and early adolescent stage, when social play behaviour is highly abundant, alters cocaine self-administration in rats. Rats were socially isolated from postnatal days 21 to 42 followed by re-socialization until adulthood. Cocaine self-administration was then assessed under a fixed ratio and progressive ratio schedule of reinforcement. Next, cue, cocaine and stress-induced reinstatement of cocaine seeking was determined following extinction of self-administration. Early social isolation resulted in an enhanced acquisition of self-administration of a low dose (0.083 mg/infusion) of cocaine, but the sensitivity to cocaine reinforcement, assessed using a dose-response analysis, was not altered in isolated rats. Moreover, isolated rats displayed an increased motivation for cocaine under a progressive ratio schedule of reinforcement. Extinction and reinstatement of cocaine seeking was not affected by early social isolation. Early social isolation causes a long-lasting increase in the motivation to self-administer cocaine. Thus, aberrations in post-weaning social development, such as the absence of social play, enhance the vulnerability for drug addiction later in life.

  16. Location-specific immunodetection of cocaine on banknotes.

    Science.gov (United States)

    van der Heide, Susan; Cunningham, Andrew; Hardwick, Sheila; Russell, David A

    2016-10-17

    A novel in-gel bioanalytical immunodetection method has been developed to determine both the presence and the location of cocaine on the surface of banknotes. The cocaine was 'fixed' to the surface of the banknote via a coating of a polyacrylamide gel matrix. Immunostaining of the immobilised cocaine on the banknote surface was performed using an anti-cocaine primary antibody, either pre-labelled with horse radish peroxidase (HRP) or in conjunction with a HRP-labelled secondary antibody. Visualisation of the location of the cocaine was achieved through chemiluminescence imaging of the banknote following application of a chemiluminescent substrate. The novel method was applied to the detection of cocaine on partial and whole banknote samples obtained from general circulation. Newly minted banknotes, with or without spiked cocaine, were used as positive and negative controls, respectively. The results obtained, for the first time, demonstrate the successful location-specific immunostaining of cocaine on banknotes. A preliminary analysis of six UK banknotes, obtained from general circulation, suggests that cocaine can be present at variable locations across the whole of the banknote.

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

    Directory of Open Access Journals (Sweden)

    Luciano Rezende Vilela

    2015-01-01

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

  18. Pressure surge attenuator

    Science.gov (United States)

    Christie, Alan M.; Snyder, Kurt I.

    1985-01-01

    A pressure surge attenuation system for pipes having a fluted region opposite crushable metal foam. As adapted for nuclear reactor vessels and heads, crushable metal foam is disposed to attenuate pressure surges.

  19. 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).

  20. Cocaine-induced Psychosis and Brain-derived Neurothrophic Factor in Patients with Cocaine Dependence: Report of Two Cases

    OpenAIRE

    Roncero, Carlos; Palma-?lvarez, Raul Felipe; Ros-Cucurull, Elena; Barral, Carmen; Gonzalvo, Bego?a; Corominas-Roso, Margarida; Casas, Miguel; Grau-L?pez, Lara

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) is linked to numerous brain functions. In addition, BDNF alterations contribute to neurological, mental, and addictive disorders. Cocaine dependence has received much attention recently due to its prevalence and psychological effects. Symptoms of psychosis are one of the most serious adverse events precipitated by cocaine use. It is particularly important to identify patients at risk of developing cocaine-induced psychosis (CIP). We described two cases...

  1. Role of environmental factors in cocaine addiction.

    Science.gov (United States)

    Badiani, Aldo; Spagnolo, Primavera A

    2013-01-01

    Decades of experimentation with a variety of pharmacological treatments have identified some effective therapies for heroin addiction but not for cocaine addiction. This may be due, at least in part, to our incomplete understanding of the factors involved in the differential vulnerability to these addictions, which are often considered mere variations of the same disorder. Indeed, the preference for one drug or another has been variously attributed to factors such as drug availability or price, to the addict's lifestyle, or even to chance. Yet, there is evidence of substance-specific influences on drug taking. Data from twin registries, for example, suggest that a sizeable portion of the variability in the susceptibility to drug abuse is due to environmental factors that are unique to opiates or to psychostimulants. Very little is known about the nature of these environmental influences. We report here original data, based on retrospective reports in human addicts, indicating that the setting of drug taking exerts a differential influence on heroin versus cocaine use. We also review additional clinical and pre-clinical data pointing to fundamental differences in the way in which the environment interacts with cocaine relative to heroin and other addictive drugs. These findings - as well as other evidence, including the lack of pharmacological treatments effective for both cocaine and heroin addiction - support the notion that much is to be gained by taking into account the substance-specific aspects of drug addiction. At a therapeutic level, for example, it appears reasonable to propose that cognitive-behavioral approaches should be tailored in a substance-specific manner in order to allow the addict to anticipate, and cope with, the risks associated to the various environmental settings of drug use.

  2. Clinical differences between cocaine-induced psychotic disorder and psychotic symptoms in cocaine-dependent patients.

    Science.gov (United States)

    Roncero, Carlos; Comín, Marina; Daigre, Constanza; Grau-López, Lara; Martínez-Luna, Nieves; Eiroa-Orosa, Francisco José; Barral, Carmen; Torrens, Marta; Casas, Miguel

    2014-05-30

    The aim of this study is to compare the clinical characteristics of three groups of patients in treatment for cocaine dependence: patients without any psychotic symptoms (NS), patients with transient psychotic symptoms (PS) and patients with cocaine-induced psychotic disorder (CIPD). An observational and retrospective study of 150 cocaine-dependent patients undergoing treatment in the Drug Unit of the Psychiatry Department of University Hospital Vall d׳Hebron in Barcelona (Spain) using these three groups, NS, PS and CIPD, was performed. All patients were evaluated with the PRISM interview. ANOVA, χ2 tests and multivariate multinomial regression analysis were used to perform statistical analyses. Seven patients with a primary psychotic disorder were discharged. Forty-six patients (32.1%) did not report any psychotic symptoms. Ninety-seven patients (67.9%) presented with a history of any cocaine-induced psychotic symptom and were considered as the cocaine-induced psychotic (CIP) group. Among them, 39 (27.3%) were included in the PS group and 58 (40.6%) were included in the CIPD group. A history of imprisonment was found significantly more frequently in the PS group than in the NS group. The distribution of age at onset of dependence, lifetime cannabis abuse or dependence and imprisonment were significantly different between the NS and CIPD groups. We conclude that in cocaine-dependent patients, clinicians should be advised about the risk of development of psychotic symptoms. The presence of some psychotic symptoms could increase the potential risks of disturbing behaviours. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  3. 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

  4. Long-acting cocaine hydrolase for addiction therapy.

    Science.gov (United States)

    Chen, Xiabin; Xue, Liu; Hou, Shurong; Jin, Zhenyu; Zhang, Ting; Zheng, Fang; Zhan, Chang-Guo

    2016-01-12

    Cocaine abuse is a world-wide public health and social problem without a US Food and Drug Administration-approved medication. An ideal anticocaine medication would accelerate cocaine metabolism, producing biologically inactive metabolites by administration of an efficient cocaine-specific exogenous enzyme. Our recent studies have led to the discovery of the desirable, highly efficient cocaine hydrolases (CocHs) that can efficiently detoxify and inactivate cocaine without affecting normal functions of the CNS. Preclinical and clinical data have demonstrated that these CocHs are safe for use in humans and are effective for accelerating cocaine metabolism. However, the actual therapeutic use of a CocH in cocaine addiction treatment is limited by its short biological half-life (e.g., 8 h or shorter in rats). Here we demonstrate a novel CocH form, a catalytic antibody analog, which is a fragment crystallizable (Fc)-fused CocH dimer (CocH-Fc) constructed by using CocH to replace the Fab region of human IgG1. The CocH-Fc not only has a high catalytic efficiency against cocaine but also, like an antibody, has a considerably longer biological half-life (e.g., ∼107 h in rats). A single dose of CocH-Fc was able to accelerate cocaine metabolism in rats even after 20 d and thus block cocaine-induced hyperactivity and toxicity for a long period. Given the general observation that the biological half-life of a protein drug is significantly longer in humans than in rodents, the CocH-Fc reported in this study could allow dosing once every 2-4 wk, or longer, for treatment of cocaine addiction in humans.

  5. Association of elevated ambient temperature with death from cocaine overdose.

    Science.gov (United States)

    Auger, Nathalie; Bilodeau-Bertrand, Marianne; Labesse, Maud Emmanuelle; Kosatsky, Tom

    2017-09-01

    Ecologic data suggest that elevated outdoor temperature is correlated with mortality rates from cocaine overdose. Using non-aggregated death records, we studied the association of hot temperatures with risk of death from cocaine overdose. We carried out a case-crossover study of all deaths from cocaine or other drug overdose between the months of May and September, from 2000 through 2013 in Quebec, Canada. We used conditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between maximum outdoor temperature and death from cocaine or other drug overdose. The main outcome measure was death from cocaine overdose as a function of maximum temperature the day of death and the days immediately preceding death. There were 316 deaths from cocaine overdose and 446 from other drug overdoses during the study. Elevated temperature the preceding week was associated with the likelihood of death from cocaine but not other drug overdose. Compared with 20°C, a maximum weekly temperature of 30°C was associated with an OR of 2.07 for death from cocaine overdose (95% CI 1.15-3.73), but an OR of 1.03 for other drug overdoses (95% CI 0.60-1.75). Associations for cocaine overdose were present with maximum daily temperature the day of and each of the three days preceding death. Elevated ambient temperature is associated with the risk of death from cocaine overdose. Public health practitioners and drug users should be aware of the added risk of mortality when cocaine is used during hot days. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Maturation of coordinated IEG expression by cocaine during adolescence

    Science.gov (United States)

    Caster, Joseph M.; Kuhn, Cynthia M.

    2009-01-01

    Adolescence may be critical period for drug addiction. Young adolescent male rats have greater locomotor responses than adults after acute low dose cocaine administration. Further, repeated cocaine administration produces as much or more conditioned place preference but reduced locomotor sensitization in adolescents compared to adults. Acute activation of neurons by cocaine induces long-term changes in behavior by activating transcriptional complexes. The purpose of the present study was to correlate cocaine-induced locomotor activity with neuronal activation in subregions of the striatum and cortex by acute cocaine in young adolescent (post natal (PN) 28) and adult (PN 65) male rats by measuring the induction of the plasticity-associated immediate early genes (IEGs) c-fos and zif268 using in situ hybridization. Animals were treated with saline, low (10 mg/kg), or high (40 mg/kg) dose cocaine in locomotor activity chambers and killed 30 min later. Low dose cocaine induced more locomotor activity and striatal c-fos expression in adolescents than adults whereas high dose cocaine induced more locomotor activity, striatal c-fos, and striatal zif268 expression in adults. Locomotor activity correlated with the expression of both genes in adults but correlated with striatal c-fos only in adolescents. Finally, there was a significant correlation between the expression of c-fos and zif268 in the adult striatum but not in adolescents. Our results suggest that the coordinated expression of transcription factors by cocaine continues to develop during adolescence. The immature regulation of transcription factors by cocaine could explain why adolescents show unique sensitivity to specific long-term behavioral alterations following cocaine treatment. PMID:19245875

  7. Hypocretin/orexin deficiency decreases cocaine abuse liability.

    Science.gov (United States)

    Steiner, Nadia; Rossetti, Clara; Sakurai, Takeshi; Yanagisawa, Masashi; de Lecea, Luis; Magistretti, Pierre J; Halfon, Olivier; Boutrel, Benjamin

    2018-02-15

    Compelling evidence indicates that hypocretin/orexin signaling regulates arousal, stress and reward-seeking behaviors. However, most studies on drug reward-related processes have so far described the effects of pharmacological blockers disrupting hypocretin/orexin transmission. We report here an extensive study on cocaine-related behaviors in hypocretin/orexin-deficient mice (KO) and their heterozygous (HET) and wildtype (WT) littermates. We evaluated behavioral sensitization following repeated administrations and preference for an environment repeatedly paired with cocaine injections (15 mg/kg). Mice were also trained to self-administer cocaine (0.5-1.5 mg/kg/infusion). Our observations show that whereas all mice exhibited quite similar responses to acute administration of cocaine, only Hcrt KO mice exhibited reduced cocaine-seeking behaviors following a period of abstinence or extinction, and reduced cocaine incubation craving. Further, if the present findings confirm that Hcrt deficient mice may display a hypoactive phenotype, possibly linked to a reduced alertness concomitant to a decreased exploration of their environment, hypocretin/orexin defiency did not cause any attentional deficit. We thus report that innate disruption of hypocretin/orexin signaling moderately alters cocaine reward but significantly reduces long-term affective dependence that may explain the lack of relapse for cocaine seeking seen in Hcrt KO mice. Overall, with blunted cocaine intake at the highest concentration and reduced responsiveness to cocaine cues after prolonged abstinence, our findings suggest that hypocretin deficient mice may display signs of resilience to cocaine addiction. Copyright © 2018. Published by Elsevier Ltd.

  8. Cocaine Allergy in Drug-Dependent Patients and Allergic People.

    Science.gov (United States)

    Armentia, Alicia; Martín-Armentia, Blanca; Martín-Armentia, Sara; Ruiz-Muñoz, Pedro; Quesada, Jorge Martínez; Postigo, Idoia; Conde, Rosa; González-Sagrado, Manuel; Pineda, Fernando; Castillo, Miriam; Palacios, Ricardo; Tejedor, Jesús

    Adverse reactions to local anesthetics (LAs), especially esters, are not uncommon, but true allergy is rarely diagnosed. To our knowledge, currently there is no reliable method of determining IgE-mediated hypersensitivity to LAs and cocaine. To assess the clinical value of allergy tests (prick, IgE, challenges, and arrays) in people suffering hypersensitivity reactions (asthma and anaphylaxis) during local anesthesia with cocaine derivatives and drug abusers with allergic symptoms after cocaine inhalation. We selected cocaine-dependent patients and allergic patients who suffered severe reactions during local anesthesia from a database of 23,873 patients. The diagnostic yield (sensitivity, specificity, and predictive value) of allergy tests using cocaine and coca leaf extracts in determining cocaine allergy was assessed, taking a positive challenge as the criterion standard. After prick tests, specific IgE, and challenge with cocaine extract, 41 of 211 patients (19.4%) were diagnosed as sensitized to cocaine. Prick tests and IgE to coca leaves (coca tea) had a good sensitivity (95.1% and 92.7%, respectively) and specificity (92.3 and 98.8%, respectively) for the diagnosis of cocaine allergy and LA-derived allergy. Cocaine may be an important allergen. Drug abusers and patients sensitized to local anesthesia and tobacco are at risk. Both prick tests and specific IgE against coca leaf extract detected sensitization to cocaine. The highest levels were related to severe clinical profiles. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  9. Reduction of Cocaine-Induced Locomotor Effects by Enriched Environment Is Associated with Cell-Specific Accumulation of ΔFosB in Striatal and Cortical Subregions.

    Science.gov (United States)

    Lafragette, Audrey; Bardo, Michael T; Lardeux, Virginie; Solinas, Marcello; Thiriet, Nathalie

    2017-03-01

    Early exposure to enriched environments has been shown to decrease the locomotor effects induced by repeated injections of cocaine and modify basal and cocaine-induced total protein levels of the transcription factor ΔFosB in the whole striatum of mice. In this study, we aimed at characterizing whether the profile of ΔFosB accumulation induced by enriched environments and cocaine would be similar or different in terms of brain areas and cell type. We used mice expressing the eGFP protein in D1 receptor positive (D1R(+)) neurons to determine whether Δ FosB induced by enriched environment or cocaine injections (5×15 mg/kg) would occur in selective subpopulations of neurons in several subregions of the striatum and prefrontal cortex. We found that: (1) exposure to enriched environment reduces cocaine-induced locomotor activation, confirming our previous findings; (2) exposure to enriched environment by itself increases the accumulation of Δ FosB mostly in D1R(-) cells in the shell part of the nucleus accumbens and dorsal striatum, whereas in the nucleus accumbens core, Δ FosB accumulates in both D1R(+) and D1R(-) neurons; (3) in standard environment mice, cocaine induces accumulation of Δ FosB selectively in D1R(+) cells in the nucleus accumbens, dorsal striatum, and infralimbic cortex; and (4) the effects of enriched environments and cocaine on accumulation of Δ FosB were reciprocally blocked by their combination. Altogether, these results suggest that the enriched environment-induced reduction in behavioral effects of cocaine might result from 2 distinct effects on ΔFosB in striatal medium-sized spiny neurons belonging to the direct and indirect pathways. © The Author 2016. Published by Oxford University Press on behalf of CINP.

  10. Evidence on unusual way of cocaine smuggling: cocaine-polymethyl methacrylate (PMMA) solid solution--study of clandestine laboratory samples.

    Science.gov (United States)

    Gostic, T; Klemenc, S

    2007-07-04

    An abandoned clandestine laboratory was seized in Slovenia. All confiscated exhibits were analysed in a forensic laboratory, where the following analytical methods were applied: capillary gas chromatography coupled with mass spectrometry (GC-MS) combined also by solid-phase micro extraction (SPME) and pyrolysis (Py) technique, Fourier transform infrared spectrometry (FTIR) and scanning electron microscopy with energy dispersive X-ray detector (SEM-EDX). The most interesting analytical findings can be summarised as follows: at the crime scene some plastic pieces, which contained cocaine dissolved (as solid solution) in polymethyl methacrylate-plexiglass (PMMA), were found. The highest cocaine concentration measured in the plastic sample was about 15% by weight. Two larger lumps of material (12 and 3 kg) were composed mainly of PMMA and CaCO3 and contained only 0.4 and 0.5% of cocaine, respectively. As for the low cocaine concentration, we assume that those two lumps of material represent discarded waste product--residue after the isolation of cocaine from plastic. Higher quantities of pure solvents (41 l) and solvent mixtures (87 l) were seized. We identified three types of pure solvents (acetone, gasoline and benzine) and two different types of solvent mixtures (benzine/acetone and gasoline/acetone). The total seized volume (87 l) of solvent mixtures holds approximately 395 g of solid residue formed mainly of PMMA and cocaine. Obviously solvent mixtures were used for isolation of cocaine from the plastic. Small quantities of relatively pure cocaine base were identified on different objects. There were two cotton sheets, most probably used for filtration. One sheet had traces of cocaine base (76% purity) on the surface, while cocaine in hydrochloride form (96%) was identified on the other sheet. GC-MS analyses of micro traces isolated from analytical balances showed the presence of cocaine and some common adulterants: phenacetine, lidocaine and procaine. A cocaine

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

    Science.gov (United States)

    Caffrey, Martha K; Febo, Marcelo

    2014-01-01

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

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

    Science.gov (United States)

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

    2017-09-01

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

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

    Directory of Open Access Journals (Sweden)

    MARIA ePEDRAZ

    2015-02-01

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

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

    Science.gov (United States)

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

    2015-08-01

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

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

    Science.gov (United States)

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

    2017-12-06

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

  16. The Multi-Scale Mass Transfer Processes Controlling Natural Attenuation and Engineered Remediation: An IFC Focused on Hanford’s 300 Area Uranium Plume Quality Assurance Project Plan

    Energy Technology Data Exchange (ETDEWEB)

    Fix, N. J.

    2008-01-31

    The purpose of the project is to conduct research at an Integrated Field-Scale Research Challenge Site in the Hanford Site 300 Area, CERCLA OU 300-FF-5 (Figure 1), to investigate multi-scale mass transfer processes associated with a subsurface uranium plume impacting both the vadose zone and groundwater. The project will investigate a series of science questions posed for research related to the effect of spatial heterogeneities, the importance of scale, coupled interactions between biogeochemical, hydrologic, and mass transfer processes, and measurements/approaches needed to characterize a mass-transfer dominated system. The research will be conducted by evaluating three (3) different hypotheses focused on multi-scale mass transfer processes in the vadose zone and groundwater, their influence on field-scale U(VI) biogeochemistry and transport, and their implications to natural systems and remediation. The project also includes goals to 1) provide relevant materials and field experimental opportunities for other ERSD researchers and 2) generate a lasting, accessible, and high-quality field experimental database that can be used by the scientific community for testing and validation of new conceptual and numerical models of subsurface reactive transport.

  17. Adolescent cocaine exposure simplifies orbitofrontal cortical dendritic arbors

    Directory of Open Access Journals (Sweden)

    Lauren M DePoy

    2014-10-01

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

  18. CRF1 receptor-deficiency increases cocaine reward.

    Science.gov (United States)

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

    2017-05-01

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

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

    African Journals Online (AJOL)

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

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

    LENUS (Irish Health Repository)

    Bernad, M

    1990-12-01

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

  1. Cocaine Inhibition of Nicotinic Acetylcholine ReceptorsInfluences Dopamine Release

    Directory of Open Access Journals (Sweden)

    Alexandra eAcevedo-Rodriguez

    2014-09-01

    Full Text Available Nicotinic acetylcholine receptors (nAChRs potently regulate dopamine (DA release in the striatum and alter cocaine’s ability to reinforce behaviors. Since cocaine is a weak nAChR inhibitor, we hypothesized that cocaine may alter DA release by inhibiting the nAChRs in DA terminals in the striatum and thus contribute to cocaine's reinforcing properties primarily associated with the inhibition of DA transporters. We found that biologically relevant concentrations of cocaine can mildly inhibit nAChR-mediated currents in midbrain DA neurons and consequently alter DA release in the dorsal and ventral striatum. At very high concentrations, cocaine also inhibits voltage-gated Na channels in DA neurons. Furthermore, our results show that partial inhibition of nAChRs by cocaine reduces evoked DA release. This diminution of DA release via nAChR inhibition more strongly influences release evoked at low or tonic stimulation frequencies than at higher (phasic stimulation frequencies, particularly in the dorsolateral striatum. This cocaine-induced shift favoring phasic DA release may contribute to the enhanced saliency and motivational value of cocaine-associated memories and behaviors.

  2. Canine olfactory sensitivity to cocaine hydrochloride and methyl benzoate

    Science.gov (United States)

    Waggoner, L. Paul; Johnston, James M.; Williams, Marc; Jackson, Jan; Jones, Meredith H.; Boussom, Teresa; Petrousky, James A.

    1997-02-01

    Methyl benzoate is a consistent product of cocaine hydrochloride exposed to humid air. The detection responses of dogs trained to detect illicit cocaine hydrochloride may be controlled by vapor from cocaine, methyl benzoate, or other constituents of illicit cocaine. The present study addressed the following questions: 1) How capable are dogs of detecting methyl benzoate compared to cocaine hydrochloride, 2) When dogs are trained to detect methyl benzoate, do they respond to cocaine hydrochloride as being the same or different from methyl benzoate. These questions were investigated using random source dogs trained and tested under laboratory conditions. Odor stimuli were generated and delivered by a vapor generation systems, the outputs from which were characterized by thermal desorption GC/MS. ONe group of dogs was trained to discriminate pharmaceutical grade and illicit cocaine hydrochloride from clean air and tested using a two lever procedure to determine their sensitivity to these substances. A second group of dogs was trained to discriminate between methyl benzoate and clean air and tested for their sensitivity to the substance. The dogs in this second group were then tested using a three lever procedure to determine their sensitivity to these substances. A second group of dogs was trained to discriminate between methyl benzoate and clean air and tested for their sensitivity to the substance. The dogs in this second group were then tested using a three lever procedure to determine whether they responded to cocaine hydrochloride as the same or different from methyl benzoate.

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

    Science.gov (United States)

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

    2017-05-01

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

  4. Multi-Scale Mass Transfer Processes Controlling Natural Attenuation and Engineered Remediation: An IFRC Focused on Hanford's 300 Area Uranium Plume

    International Nuclear Information System (INIS)

    Zachara, John M.; Bjornstad, Bruce N.; Christensen, John N.; Conrad, Mark E.; Fredrickson, Jim K.; Freshley, Mark D.; Haggerty, Roy; Hammon, Glenn; Kent, Douglas B.; Konopka, Allan; Lichtner, Peter C.; Liu, Chongxuan; McKinley, James P.; Murray, Christopher J.; Rockhold, Mark L.; Rubin, Yoram; Vermeul, Vincent R.; Versteeg, Roelof J.; Ward, Anderson L.; Zheng, Chunmiao

    2010-01-01

    The Integrated Field-Scale Subsurface Research Challenge (IFRC) at the Hanford Site 300 Area uranium (U) plume addresses multi-scale mass transfer processes in a complex hydrogeologic setting where groundwater and riverwater interact. A series of forefront science questions on mass transfer are posed for research which relate to the effect of spatial heterogeneities; the importance of scale; coupled interactions between biogeochemical, hydrologic, and mass transfer processes; and measurements and approaches needed to characterize and model a mass-transfer dominated system. The project was initiated in February 2007, with CY 2007 and CY 2008 progress summarized in preceding reports. The site has 35 instrumented wells, and an extensive monitoring system. It includes a deep borehole for microbiologic and biogeochemical research that sampled the entire thickness of the unconfined 300 A aquifer. Significant, impactful progress has been made in CY 2009 with completion of extensive laboratory measurements on field sediments, field hydrologic and geophysical characterization, four field experiments, and modeling. The laboratory characterization results are being subjected to geostatistical analyses to develop spatial heterogeneity models of U concentration and chemical, physical, and hydrologic properties needed for reactive transport modeling. The field experiments focused on: (1) physical characterization of the groundwater flow field during a period of stable hydrologic conditions in early spring, (2) comprehensive groundwater monitoring during spring to characterize the release of U(VI) from the lower vadose zone to the aquifer during water table rise and fall, (3) dynamic geophysical monitoring of salt-plume migration during summer, and (4) a U reactive tracer experiment (desorption) during the fall. Geophysical characterization of the well field was completed using the down-well Electrical Resistance Tomography (ERT) array, with results subjected to robust

  5. Multi-Scale Mass Transfer Processes Controlling Natural Attenuation and Engineered Remediation: An IFRC Focused on Hanford’s 300 Area Uranium Plume January 2010 to January 2011

    Energy Technology Data Exchange (ETDEWEB)

    Zachara, John M.; Bjornstad, Bruce N.; Christensen, John N.; Conrad, Mark S.; Fredrickson, Jim K.; Freshley, Mark D.; Haggerty, Roy; Hammond, Glenn E.; Kent, Douglas B.; Konopka, Allan; Lichtner, Peter C.; Liu, Chongxuan; McKinley, James P.; Murray, Christopher J.; Rockhold, Mark L.; Rubin, Yoram; Vermeul, Vincent R.; Versteeg, Roelof J.; Ward, Anderson L.; Zheng, Chunmiao

    2011-02-01

    The Integrated Field Research Challenge (IFRC) at the Hanford Site 300 Area uranium (U) plume addresses multi-scale mass transfer processes in a complex subsurface hydrogeologic setting where groundwater and riverwater interact. A series of forefront science questions on reactive mass transfer focus research. These questions relate to the effect of spatial heterogeneities; the importance of scale; coupled interactions between biogeochemical, hydrologic, and mass transfer processes; and measurements and approaches needed to characterize and model a mass-transfer dominated system. The project was initiated in February 2007, with CY 2007, CY 2008, and CY 2009 progress summarized in preceding reports. A project peer review was held in March 2010, and the IFRC project has responded to all suggestions and recommendations made in consequence by reviewers and SBR/DOE. These responses have included the development of “Modeling” and “Well-Field Mitigation” plans that are now posted on the Hanford IFRC web-site. The site has 35 instrumented wells, and an extensive monitoring system. It includes a deep borehole for microbiologic and biogeochemical research that sampled the entire thickness of the unconfined 300 A aquifer. Significant, impactful progress has been made in CY 2010 including the quantification of well-bore flows in the fully screened wells and the testing of means to mitigate them; the development of site geostatistical models of hydrologic and geochemical properties including the distribution of U; developing and parameterizing a reactive transport model of the smear zone that supplies contaminant U to the groundwater plume; performance of a second passive experiment of the spring water table rise and fall event with a associated multi-point tracer test; performance of downhole biogeochemical experiments where colonization substrates and discrete water and gas samplers were deployed to the lower aquifer zone; and modeling of past injection experiments for

  6. Multi-Scale Mass Transfer Processes Controlling Natural Attenuation and Engineered Remediation: An IFRC Focused on Hanford’s 300 Area Uranium Plume

    Energy Technology Data Exchange (ETDEWEB)

    Zachara, John M.; Bjornstad, Bruce N.; Christensen, John N.; Conrad, Mark E.; Fredrickson, Jim K.; Freshley, Mark D.; Haggerty, Roy; Hammon, Glenn; Kent, Douglas B.; Konopka, Allan; Lichtner, Peter C.; Liu, Chongxuan; McKinley, James P.; Murray, Christopher J.; Rockhold, Mark L.; Rubin, Yoram; Vermeul, Vincent R.; Versteeg, Roelof J.; Ward, Anderson L.; Zheng, Chunmiao

    2010-02-01

    The Integrated Field-Scale Subsurface Research Challenge (IFRC) at the Hanford Site 300 Area uranium (U) plume addresses multi-scale mass transfer processes in a complex hydrogeologic setting where groundwater and riverwater interact. A series of forefront science questions on mass transfer are posed for research which relate to the effect of spatial heterogeneities; the importance of scale; coupled interactions between biogeochemical, hydrologic, and mass transfer processes; and measurements and approaches needed to characterize and model a mass-transfer dominated system. The project was initiated in February 2007, with CY 2007 and CY 2008 progress summarized in preceding reports. The site has 35 instrumented wells, and an extensive monitoring system. It includes a deep borehole for microbiologic and biogeochemical research that sampled the entire thickness of the unconfined 300 A aquifer. Significant, impactful progress has been made in CY 2009 with completion of extensive laboratory measurements on field sediments, field hydrologic and geophysical characterization, four field experiments, and modeling. The laboratory characterization results are being subjected to geostatistical analyses to develop spatial heterogeneity models of U concentration and chemical, physical, and hydrologic properties needed for reactive transport modeling. The field experiments focused on: (1) physical characterization of the groundwater flow field during a period of stable hydrologic conditions in early spring, (2) comprehensive groundwater monitoring during spring to characterize the release of U(VI) from the lower vadose zone to the aquifer during water table rise and fall, (3) dynamic geophysical monitoring of salt-plume migration during summer, and (4) a U reactive tracer experiment (desorption) during the fall. Geophysical characterization of the well field was completed using the down-well Electrical Resistance Tomography (ERT) array, with results subjected to robust

  7. Cocaine-induced psychotic disorders: presentation, mechanism, and management.

    Science.gov (United States)

    Tang, Yilang; Martin, Nancy L; Cotes, Robert O

    2014-01-01

    Cocaine, the third mostly commonly used illicit drug in the United States, has a wide range of neuropsychiatric effects, including transient psychotic symptoms. When psychotic symptoms occur within a month of cocaine intoxication or withdrawal, the diagnosis is cocaine-induced psychotic disorder (CIPD). Current evidence suggests those with CIPD are likely to be male, have longer severity and duration of cocaine use, use intravenous cocaine, and have a lower body mass index. Differentiating CIPD from a primary psychotic disorder requires a detailed history of psychotic symptoms in relation to substance use and often a longitudinal assessment. Treatment includes providing a safe environment, managing agitation and psychosis, and addressing the underlying substance use disorder. This review begins with a clinical case and summarizes the literature on CIPD, including clinical presentation, differential diagnosis, mechanism and predictors of illness, and treatment.

  8. Cocaine addiction and family dysfunction: a case-control study in southern Brazil.

    Science.gov (United States)

    Pinheiro, Ricardo Tavares; Pinheiro, Karen Amaral Tavares; Magalhães, Pedro Vieira da Silva; Horta, Bernardo Lessa; da Silva, Ricardo Azevedo; Sousa, Paulo Luis Rosa; Fleming, Manuela

    2006-01-01

    Family-related factors play a crucial role in the onset, development, and maintenance of drug misuse and addiction. To investigate the hypothesis that families with a cocaine addicted son display more dysfunction than control families, we applied the Personal Authority in the Family System and the Self-Report Measure of Family Functioning to 67 case triads (child-father-mother) in which the son was an inpatient with a primary diagnosis of cocaine abuse or dependence and to 67 matched control triads from the community (Pelotas, Brazil) in 2000. Case children, mothers, and fathers were significantly more likely to present nuclear family triangulation than their matched control subjects. In addition, case triads had a significantly greater chance of perceiving family functioning as enmeshment. These results suggest both structural and functional differences in these families. We argue for the need of interventions in the family as a whole and for further research in this area.

  9. Neuropsychological and Emotional Correlates Involved in Cocaine Use: A Theoretical Review of New Findings

    Directory of Open Access Journals (Sweden)

    Juan Ramos-Cejudo

    2010-02-01

    Full Text Available Cocaine is being an alarming health problem in developed countries. This issue has important implications in economic, social and public health. Currently, efforts are focused on research in metabolic, neuropsychological and emotional changes, resulting from chronic use. However, theoretical work review on this critical area is not available. The aim of our study is to review and integrate the ultimate findings and results in terms of metabolic abnormalities, neuropsychological and emotional abuse of cocaine. The results show a significant impairment of dopaminergic pathways in the frontal lobe, both in the number of recipient and depletion of the neurotransmitter, as well as an important executive function deficit in response inhibition in attention and working memory. In addition, alterations in the ability in identifying emotions, impulsiveness, decision making, anxiety and depression are proved in different studies.

  10. Partial extinction of a conditioned context enhances preference for elements previously associated with cocaine but not with chocolate.

    Science.gov (United States)

    Orsini, C; Bonito-Oliva, A; Montanari, C; Conversi, D; Cabib, S

    2013-08-15

    Drug-associated stimuli are crucial to reinstatement of drug-seeking after periods of abstinence, representing a central problem in treatment of addiction. The present study investigated the influence of partial extinction of the conditioned context on the expression of conditioned place preference (CPP). Mice of the inbred DBA/2J strain were conditioned with cocaine or chocolate in a context identified by multiple elements (A+B) and subsequently CPP expression was evaluated in a context containing only one element (A or B) or both (A+B). Cocaine- and chocolate-conditioned mice showed CPP in presence of the original compound stimulus. However, cocaine-conditioned mice did not show CPP when tested in A or B context, while chocolate-conditioned mice did show CPP to single element context. After conditioning mice were exposed to extinction training of the context A or B and then tested for CPP 1 and 9 days after the end of the extinction (days 9 and 18). Cocaine-conditioned mice showed CPP 9 days after extinction while chocolate-conditioned mice were relatively insensitive to the extinction procedure on day 1 after extinction, but they did not show CPP for the partial or the original compound 9 days after extinction. Cocaine-conditioned mice not submitted to the extinction training (simple passage of time) or submitted to a Sham-extinction procedure (saline injections and confinement in a new environment) did not show CPP on day 9 or 18. Cocaine-conditioned mice exposed to extinction training showed increased c-Fos expression in several brain areas in comparison to mice exposed to Sham-extinction. The extinction procedure did not specifically reduce behavioral sensitization. The results suggest that extinction training involving only elements of a drug-associated context can result in increased associative strength of those elements. © 2013.

  11. Enhanced anxiety observed in cocaine withdrawn rats is associated with altered reactivity of the dorsomedial prefrontal cortex.

    Directory of Open Access Journals (Sweden)

    Cynthia El Hage

    Full Text Available Discontinuation of drug intake in cocaine abusers commonly produces a variety of adverse withdrawal symptoms among which anxiety and depression-related behavior are prevailing during the initial period of abstinence. The aim of this study was to provide further insight into the neurobiological dysregulations that might contribute to these pathological states. Rats were treated with cocaine or saline for 14 days (20 mg/kg; i.p and anxiety-related behavior was assessed in different paradigms (elevated plus-maze (EPM, confinement to an open arm of the EPM and shock-probe burying tests for up to 4 weeks after withdrawal. Depression-like behavior was assessed by the forced swim test and sucrose preference test. Altogether our results demonstrated that cocaine withdrawal induced persistent heightened levels of anxiety that last for at least 28 days but did not affect depression-like behavior. We then used Fos immunohistochemistry to map neuronal activation patterns in withdrawn rats confined to one open arm of an EPM, and a double labeling procedure using Fos immunohistochemistry and in situ hybridization of glutamic acid decarboxylase or vesicular glutamate transporter mRNAs to identify the phenotype of the activated neurons. Our data showed that the exacerbated anxiety observed in cocaine withdrawn rats exposed to an elevated open arm was accompanied by an altered reactivity of the dorsal part of the medial prefrontal cortex (anterior cingulate and dorsal prelimbic cortices, the paraventricular thalamic nucleus and the lateral and anterior areas of the hypothalamus. In the medial prefrontal cortex, we evidenced a negative correlation between Fos expression in its dorsal part and open arm-induced freezing in NaCl-treated rats but not in cocaine withdrawn rats. We also found that more than 65% of activated neurons were glutamatergic projection neurons. The present study provides new insights into the neuroanatomical regions and neuronal cell types

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

    Science.gov (United States)

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

    2017-08-30

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

  13. Effects of bingeing on fat during adolescence on the reinforcing effects of cocaine in adult male mice.

    Science.gov (United States)

    Blanco-Gandía, M Carmen; Cantacorps, Lídia; Aracil-Fernández, Auxiliadora; Montagud-Romero, Sandra; Aguilar, María A; Manzanares, Jorge; Valverde, Olga; Miñarro, José; Rodríguez-Arias, Marta

    2017-02-01

    Binge eating is a specific form of overeating characterized by intermittent excessive eating. In addition to altering the neurobiological reward system, several studies have highlighted that consumption of palatable food increases vulnerability to drug use. The aim of the present study was to evaluate the effects of a high-fat diet consumed in a binge pattern during adolescence on the reinforcing effects of cocaine. After 40 days of binge-eating for 2 h, three days a week (PND 29-69), the reinforcing effects of cocaine on conditioning place preference and intravenous self-administration paradigm were evaluated in adolescent male mice. Circulating leptin and ghrelin levels and the effects of bingeing on fat on CB1 mu opioid receptor (MOr) and ghrelin receptor (GHSR) gene expression in the Nucleus Accumbens (NAcc) and Ventral Tegmental Area (VTA) were also assessed. Our results showed a significant escalation in the consumption of a high-fat diet between the first and last week. High-fat binge (HFB) animals were more sensitive to the reinforcing effects of a subthreshold dose of cocaine in the paradigms assayed, and animals under fat withdrawal were more vulnerable to the reinstatement of conditioned place preference. HFB mice also showed enhanced cocaine self-administration. After fat withdrawal, exposure to a new fat binge reinstated cocaine seeking. Although HFB did not modify leptin levels, a decrease in plasmatic ghrelin was observed. Moreover, this pattern of fatty diet resulted in a reduction of MOr and CB1 gene expression in the NAcc and an increase in GHSR expression in the VTA. We propose that bingeing on fat during adolescence induces long-lasting changes in the brain through the sensitization of brain reward circuits, which predisposes individuals to seek cocaine during adulthood. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Terminal Dopamine Release Kinetics in the Accumbens Core and Shell Are Distinctly Altered after Withdrawal from Cocaine Self-Administration.

    Science.gov (United States)

    Saddoris, Michael P

    2016-01-01

    Repeated self-administration of cocaine is associated with impairments in motivated behaviors as well as alterations in both dopamine (DA) release and neural signaling within the nucleus accumbens (NAc). These impairments are present even after several weeks of abstinence from drug taking, suggesting that the self-administration experience induces long-lasting neuroplastic alterations in the mesolimbic DA circuit. To understand these changes at the terminal level, rats were allowed to self-administer either cocaine intravenously (∼1 mg/kg per infusion) or water to a receptacle (control) in 2-h sessions over 14 days, followed by 30 days of enforced abstinence. Fast-scan cyclic voltammetry was used to record real-time DA release in either NAc core or shell after electrical stimulations of the ventral tegmental area (VTA) in freely-moving animals. In controls, the kinetics of DA release in the core and shell strikingly differed, with shell displaying slower release and reuptake rates than core. However, cocaine experience differentially altered these signaling patterns by NAc subregion. In the shell, cocaine rats showed less sensitivity to the dynamic range of applied stimulations than controls. In the core, by contrast, cocaine rats displayed robustly reduced peak DA release given the same stimulation, while also showing slower release and reuptake kinetics. The differential effects of cocaine self-administration on terminal function between core and shell is consistent with a region-specific functional reorganization of the mesolimbic DA system after repeated exposure and may provide an anatomical substrate for altered cognitive function after chronic drug-taking and addiction.

  15. Glutamate and dopamine transmission from midbrain dopamine neurons share similar release properties but are differentially affected by cocaine.

    Science.gov (United States)

    Adrover, Martín F; Shin, Jung Hoon; Alvarez, Veronica A

    2014-02-26

    Synaptic transmission between ventral tegmental area and nucleus accumbens (NAc) is critically involved in reward-motivated behaviors and thought to be altered in addiction. In addition to dopamine (DA), glutamate is packaged and released by a subset of mesolimbic DA neurons, eliciting EPSCs onto medium spiny neurons in NAc. Little is known about the properties and modulation of glutamate release from DA midbrain terminals and the effect of cocaine. Using an optogenetic approach to selectively activate midbrain DA fibers, we compared the properties and modulation of DA transients and EPSCs measured using fast-scan cyclic voltammetry and whole-cell recordings in mouse brain slices. DA transients and EPSCs were inhibited by DA receptor D2R agonist and showed a marked paired-pulse depression that required 2 min for full recovery. Cocaine depressed EPSCs amplitude by 50% but enhanced the overall DA transmission from midbrain DA neurons. AMPA and NMDA receptor-mediated EPSCs were equally inhibited by cocaine, suggesting a presynaptic mechanism of action. Pharmacological blockage and genetic deletion of D2R in DA neurons prevented the cocaine-induced inhibition of EPSCs and caused a larger increase in DA transient peak, confirming the involvement of presynaptic D2R. These findings demonstrate that acute cocaine inhibits DA and glutamate release from midbrain DA neurons via presynaptic D2R but has differential overall effects on their transmissions in the NAc. We postulate that cocaine, by blocking DA reuptake, prolongs DA transients and facilitates the feedback inhibition of DA and glutamate release from these terminals.

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

    Science.gov (United States)

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

    2016-11-01

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

  17. 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.

  18. Neuroticism associated with cocaine-induced psychosis in cocaine-dependent patients: a cross-sectional observational study.

    Science.gov (United States)

    Roncero, Carlos; Daigre, Constanza; Barral, Carmen; Ros-Cucurull, Elena; Grau-López, Lara; Rodríguez-Cintas, Laia; Tarifa, Nuria; Casas, Miguel; Valero, Sergi

    2014-01-01

    Cocaine consumption can induce transient psychotic symptoms, which has been correlated with more severe addiction and aggressive behavior. However, little is known about the nature of the relationship between personality traits and psychotic symptoms in cocaine-dependent patients. This study examined the relationship between neuroticism and cocaine-induced psychosis. A total of 231 cocaine-dependent patients seeking treatment were recruited to the study. Personality was evaluated by the Zuckerman-Kuhlman Personality Questionnaire. Cocaine-induced psychosis questionnaire, SCID-I, and SCID-II were used to evaluate comorbidity and clinical characteristics. Data analysis was performed in three steps: descriptive, bivariate, and multivariate analyses. Cocaine-induced psychosis was reported in 65.4% of the patients and some personality disorder in 46.8%. Two personality dimensions (Neuroticism-Anxiety and Aggression-Hostility) presented a significant effect on the risk of experiencing psychotic symptoms (t(229) = 2.69, p = 0.008; t(229) = 2.06, p = 0.004), and patients with psychotic symptoms showed higher scores in both variables. On the multivariate analysis, only Neuroticism remained as a significant personality factor independently associated with psychotic symptoms (Wald = 7.44, pcocaine has been found, independently of other consumption variables. Personality dimensions should be evaluated in cocaine-dependent patients in order to detect high scores of neuroticism and warn patients about the risk of developing cocaine-induced psychotic symptoms.

  19. Genome-Environmental Risk Assessment of Cocaine Dependence

    Directory of Open Access Journals (Sweden)

    Changshuai eWei

    2012-05-01

    Full Text Available Cocaine-associated biomedical and psychosocial problems are substantial 21st century global burdens of disease. This burden is largely driven by a cocaine dependence process that becomes engaged with increasing occasions of cocaine product use. For this reason, the development of a risk prediction model for cocaine dependence may be of special value. Ultimately, success in building such a risk prediction model may help promote personalized cocaine dependence prediction, prevention, and treatment approaches not presently available. As an initial step toward this goal, we conducted a genome-environmental risk prediction study for cocaine dependence, simultaneously considering 948,658 single nucleotide polymorphisms (SNPs, six potentially cocaine-related facets of environment, and three personal characteristics. In this study, a novel statistical approach was applied to 1045 case-control samples from the Family Study of Cocaine Dependence. The results identify 330 low- to medium-effect size SNPs (i.e., those with a single locus p-value of less than 10-4 that made a substantial contribution to cocaine dependence risk prediction (AUC=0.718. Inclusion of six facets of environment and three personal characteristics yielded greater accuracy (AUC=0.809. Of special importance was childhood abuse (CA among trauma experiences, with a potentially important interaction of CA and the GBE1 gene in cocaine dependence risk prediction. Genome-environmental risk prediction models may become more promising in future risk prediction research, once a more substantial array of environmental facets are taken into account, sometimes with model improvement when gene-by-environment product terms are included as part of these risk predication models.

  20. NMDA receptors on non-dopaminergic neurons in the VTA support cocaine sensitization.

    Directory of Open Access Journals (Sweden)

    Yu Luo

    2010-08-01

    Full Text Available The initiation of behavioral sensitization to cocaine and other psychomotor stimulants is thought to reflect N-methyl-D-aspartate receptor (NMDAR-mediated synaptic plasticity in the mesolimbic dopamine (DA circuitry. The importance of drug induced NMDAR mediated adaptations in ventral tegmental area (VTA DA neurons, and its association with drug seeking behaviors, has recently been evaluated in Cre-loxp mice lacking functional NMDARs in DA neurons expressing Cre recombinase under the control of the endogenous dopamine transporter gene (NR1(DATCre mice.Using an additional NR1(DATCre mouse transgenic model, we demonstrate that while the selective inactivation of NMDARs in DA neurons eliminates the induction of molecular changes leading to synaptic strengthening, behavioral measures such as cocaine induced locomotor sensitization and conditioned place preference remain intact in NR1(DATCre mice. Since VTA DA neurons projecting to the prefrontal cortex and amygdala express little or no detectable levels of the dopamine transporter, it has been speculated that NMDA receptors in DA neurons projecting to these brain areas may have been spared in NR1(DATCre mice. Here we demonstrate that the NMDA receptor gene is ablated in the majority of VTA DA neurons, including those exhibiting undetectable DAT expression levels in our NR1(DATCre transgenic model, and that application of an NMDAR antagonist within the VTA of NR1(DATCre animals still blocks sensitization to cocaine.These results eliminate the possibility of NMDAR mediated neuroplasticity in the different DA neuronal subpopulations in our NR1(DATCre mouse model and therefore suggest that NMDARs on non-DA neurons within the VTA must play a major role in cocaine-related addictive behavior.

  1. Ghrelin receptor antagonism of hyperlocomotion in cocaine-sensitized mice requires βarrestin-2.

    Science.gov (United States)

    Toth, Krisztian; Slosky, Lauren M; Pack, Thomas F; Urs, Nikhil M; Boone, Peter; Mao, Lan; Abraham, Dennis; Caron, Marc G; Barak, Lawrence S

    2018-01-01

    The "brain-gut" peptide ghrelin, which mediates food-seeking behaviors, is recognized as a very strong endogenous modulator of dopamine (DA) signaling. Ghrelin binds the G protein-coupled receptor GHSR1a, and administration of ghrelin increases the rewarding properties of psychostimulants while ghrelin receptor antagonists decrease them. In addition, the GHSR1a signals through βarrestin-2 to regulate actin/stress fiber rearrangement, suggesting βarrestin-2 participation in the regulation of actin-mediated synaptic plasticity for addictive substances like cocaine. The effects of ghrelin receptor ligands on reward strongly suggest that modulation of ghrelin signaling could provide an effective strategy to ameliorate undesirable behaviors arising from addiction. To investigate this possibility, we tested the effects of ghrelin receptor antagonism in a cocaine behavioral sensitization paradigm using DA neuron-specific βarrestin-2 KO mice. Our results show that these mice sensitize to cocaine as well as wild-type littermates. The βarrestin-2 KO mice, however, no longer respond to the locomotor attenuating effects of the GHSR1a antagonist YIL781. The data presented here suggest that the separate stages of addictive behavior differ in their requirements for βarrestin-2 and show that pharmacological inhibition of βarrestin-2 function through GHSR1a antagonism is not equivalent to the loss of βarrestin-2 function achieved by genetic ablation. These data support targeting GHSR1a signaling in addiction therapy but indicate that using signaling biased compounds that modulate βarrestin-2 activity differentially from G protein activity may be required. © 2017 Wiley Periodicals, Inc.

  2. Reduction of Cocaine Self-Administration and D3 Receptor-Mediated Behavior by Two Novel Dopamine D3 Receptor-Selective Partial Agonists, OS-3-106 and WW-III-55

    Science.gov (United States)

    Cheung, Timothy H. C.; Loriaux, Amy L.; Weber, Suzanne M.; Chandler, Kayla N.; Lenz, Jeffrey D.; Schaan, Romina F.; Mach, Robert H.; Luedtke, Robert R.

    2013-01-01

    Dopamine D3 receptor (D3R)-selective compounds may be useful medications for cocaine dependence. In this study, we identified two novel arylamide phenylpiperazines, OS-3-106 and WW-III-55, as partial agonists at the D3R in the adenylyl cyclase inhibition assay. OS-3-106 and WW-III-55 have 115- and 862-fold D3R:D2 receptor (D2R) binding selectivity, respectively. We investigated their effects (0, 3, 5.6, or 10 mg/kg) on operant responding by using a multiple variable-interval (VI) 60-second schedule that alternated components with sucrose reinforcement and components with intravenous cocaine reinforcement (0.375 mg/kg). Additionally, we evaluated the effect of OS-3-106 (10 mg/kg) on the dose-response function of cocaine self-administration and the effect of WW-III-55 (0–5.6 mg/kg) on a progressive ratio schedule with either cocaine or sucrose reinforcement. Both compounds were also examined for effects on locomotion and yawning induced by a D3R agonist. OS-3-106 decreased cocaine and sucrose reinforcement rates, increased latency to first response for cocaine but not sucrose, and downshifted the cocaine self-administration dose-response function. WW-III-55 did not affect cocaine self-administration on the multiple-variable interval schedule, but it reduced cocaine and sucrose intake on the progressive ratio schedule. Both compounds reduced locomotion at doses that reduced responding, and both compounds attenuated yawning induced by low doses of 7-OH-DPAT (a D3R-mediated behavior), but neither affected yawning on the descending limb of the 7-OH-DPAT dose-response function (a D2R-mediated behavior). Therefore, both compounds blocked a D3R-mediated behavior. However, OS-3-106 was more effective in reducing cocaine self-administration. These findings support D3Rs, and possibly D2Rs, as targets for medications aimed at reducing the motivation to seek cocaine. PMID:24018640

  3. Purpura and leukopenia in a cocaine user.

    Science.gov (United States)

    Dezman, Zachary; Rimi, Barbara; McClain, Joshua

    2016-08-01

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

  4. Chest pain related to crack cocaine smoking

    International Nuclear Information System (INIS)

    Eurman, D.W.; Potash, H.I.; Eyler, W.R.; Beute, G.H.; Paganussi, P.

    1988-01-01

    The chest radiographs of 80 patients coming to emergency room because of chest pain and/or shortness of breath following the smoking of highly potent crack cocaine were retrospectively reviewed. Four showed intrathoracic free air (pneumomediastinum in two, hemopneumothorax in one, and pneumothorax in one). Four other patients showed subsegmental atelectasis or parenchymal infiltrate. Radiographic detection of these abnormalities was of importance in the clinical management of the patients. This spectrum of findings is presented with a discussion of the pathophysiologic mechanisms and other potential complications of this form of drug abuse

  5. 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.

  6. Brief intermittent cocaine self-administration and abstinence sensitizes cocaine effects on the dopamine transporter and increases drug seeking.

    Science.gov (United States)

    Calipari, Erin S; Siciliano, Cody A; Zimmer, Benjamin A; Jones, Sara R

    2015-02-01

    Although traditional sensitization paradigms, which result in an augmentation of cocaine-induced locomotor behavior and dopamine (DA) overflow following repeated experimenter-delivered cocaine injections, are often used as a model to study drug addiction, similar effects have been difficult to demonstrate following cocaine self-administration. We have recently shown that intermittent access (IntA) to cocaine can result in increased cocaine potency at the DA transporter (DAT); however, traditional sensitization paradigms often show enhanced effects following withdrawal/abstinence periods. Therefore, we determined a time course of IntA-induced sensitization by examining the effects of 1 or 3 days of IntA, as well as a 7-day abstinence period on DA function, cocaine potency, and reinforcement. Here we show that cocaine potency is increased following as little as 3 days of IntA and further augmented following an abstinence period. In addition, IntA plus abstinence produced greater evoked DA release in the presence of cocaine as compared with all other groups, demonstrating that following abstinence, both cocaine's ability to increase DA release and inhibit uptake at the DAT, two separate mechanisms for increasing DA levels, are enhanced. Finally, we found that IntA-induced sensitization of the DA system resulted in an increased reinforcing efficacy of cocaine, an effect that was augmented after the 7-day abstinence period. These results suggest that sensitization of the DA system may have an important role in the early stages of drug abuse and may drive the increased drug seeking and taking that characterize the transition to uncontrolled drug use. Human data suggest that intermittency, sensitization, and periods of abstinence have an integral role in the process of addiction, highlighting the importance of utilizing pre-clinical models that integrate these phenomena, and suggesting that IntA paradigms may serve as novel models of human addiction.

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

    Science.gov (United States)

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

    2018-04-01

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

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

    Directory of Open Access Journals (Sweden)

    Marina E Wolf

    2012-06-01

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

  9. Modafinil Reinstates a Cocaine Conditioned Place Preference Following Extinction in Rats

    OpenAIRE

    Bernardi, Rick E.; Lewis, Jason R.; Lattal, K. Matthew; Berger, S. Paul

    2009-01-01

    The current study examined whether modafinil would reinstate an extinguished cocaine conditioned place preference (CPP). Following extinction of a cocaine CPP, rats were administered modafinil (128mg/kg), cocaine (5mg/kg) or vehicle and given a 60-min reinstatement test. While the effect of cocaine was transient, modafinil robustly reinstated a cocaine CPP following extinction, suggesting that modafinil may induce relapse or increase the vulnerability of addicts to the reinforcing effects of ...

  10. The Effectiveness of Treatments for Cocaine Dependence in Schizophrenic Patients: A Systematic Review

    OpenAIRE

    Sabioni, Pamela; Ramos, Anna Carolina; Galduróz, Jose Carlos F.

    2013-01-01

    Objectives: To evaluate and compare the effectiveness of available treatments for cocaine dependence in schizophrenic patients. Method: We searched articles published between May 2002 and June 2012 in the following databases: Scopus, Pubmed and Web of Knowledge. The key words utilised were “schizophrenia”, "dementia praecox", "schizophrenic disorder", "cocaine related disorder", "cocaine abuse", "cocaine addiction", "cocaine dependence", “treatment”, “therapeutic”, and "drug therapy”. Selecti...

  11. Effects of anti-cocaine vaccine and viral gene transfer of cocaine hydrolase in mice on cocaine toxicity including motor strength and liver damage.

    Science.gov (United States)

    Gao, Yang; Geng, Liyi; Orson, Frank; Kinsey, Berma; Kosten, Thomas R; Shen, Xiaoyun; Brimijoin, Stephen

    2013-03-25

    In developing an vivo drug-interception therapy to treat cocaine abuse and hinder relapse into drug seeking provoked by re-encounter with cocaine, two promising agents are: (1) a cocaine hydrolase enzyme (CocH) derived from human butyrylcholinesterase and delivered by gene transfer; (2) an anti-cocaine antibody elicited by vaccination. Recent behavioral experiments showed that antibody and enzyme work in a complementary fashion to reduce cocaine-stimulated locomotor activity in rats and mice. Our present goal was to test protection against liver damage and muscle weakness in mice challenged with massive doses of cocaine at or near the LD50 level (100-120 mg/kg, i.p.). We found that, when the interceptor proteins were combined at doses that were only modestly protective in isolation (enzyme, 1mg/kg; antibody, 8 mg/kg), they provided complete protection of liver tissue and motor function. When the enzyme levels were ~400-fold higher, after in vivo transduction by adeno-associated viral vector, similar protection was observed from CocH alone. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  12. Oral methylphenidate normalizes cingulate activity in cocaine addiction during a salient cognitive task

    International Nuclear Information System (INIS)

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

    2010-01-01

    Anterior cingulate cortex (ACC) hypoactivations during cognitive demand are a hallmark deficit in drug addiction. Methylphenidate (MPH) normalizes cortical function, enhancing task salience and improving associated cognitive abilities, in other frontal lobe pathologies; however, in clinical trials, MPH did not improve treatment outcome in cocaine addiction. We hypothesized that oral MPH will attenuate ACC hypoactivations and improve associated performance during a salient cognitive task in individuals with cocaine-use disorders (CUD). In the current functional MRI study, we used a rewarded drug cue-reactivity task previously shown to be associated with hypoactivations in both major ACC subdivisions (implicated in default brain function) in CUD compared with healthy controls. The task was performed by 13 CUD and 14 matched healthy controls on 2 d: after ingesting a single dose of oral MPH (20 mg) or placebo (lactose) in a counterbalanced fashion. Results show that oral MPH increased responses to this salient cognitive task in both major ACC subdivisions (including the caudal-dorsal ACC and rostroventromedial ACC extending to the medial orbitofrontal cortex) in the CUD. These functional MRI results were associated with reduced errors of commission (a common impulsivity measure) and improved task accuracy, especially during the drug (vs. neutral) cue-reactivity condition in all subjects. The clinical application of such MPH-induced brain-behavior enhancements remains to be tested.

  13. High cocaine dosage decreases neurogenesis in the hippocampus and impairs working memory.

    Science.gov (United States)

    Sudai, Einav; Croitoru, Ofri; Shaldubina, Alona; Abraham, Lital; Gispan, Iris; Flaumenhaft, Yakov; Roth-Deri, Ilana; Kinor, Noa; Aharoni, Shai; Ben-Tzion, Moshe; Yadid, Gal

    2011-04-01

    Drug addiction is a chronic brain disorder, characterized by the loss of the ability to control drug consumption. The neurobiology of addiction is traditionally thought to involve the mesocorticolimbic system of the brain. However, the hippocampus has received renewed interest for its potential role in addiction. Part of this attention is because of the fact that drugs of abuse are potent negative regulators of neurogenesis in the adult hippocampus and may as a result impair learning and memory. We investigated the effects of different dosages of contingent cocaine on cell proliferation and neurogenesis in the dentate gyrus of the hippocampus and on working memory during abstinence, using the water T-maze test, in adult rats. We found that cocaine, in addition to the changes it produces in the reward system, if taken in high doses, can attenuate the production and development of new neurons in the hippocampus, and reduce working memory. © 2010 The Authors, Addiction Biology © 2010 Society for the Study of Addiction.

  14. Oral methylphenidate normalizes cingulate activity in cocaine addiction during a salient cognitive task

    Energy Technology Data Exchange (ETDEWEB)

    Goldstein, R.Z.; Goldstein, R.Z.; Woicik, P.A.; Maloney, T.; Tomasi, D.; Alia-Klein, N.; Shan, J.; Honorario, J.; Samaras, d.; Wang, R.; Telang, F.; Wang, G.-J.; Volkow, N.D.

    2010-09-21

    Anterior cingulate cortex (ACC) hypoactivations during cognitive demand are a hallmark deficit in drug addiction. Methylphenidate (MPH) normalizes cortical function, enhancing task salience and improving associated cognitive abilities, in other frontal lobe pathologies; however, in clinical trials, MPH did not improve treatment outcome in cocaine addiction. We hypothesized that oral MPH will attenuate ACC hypoactivations and improve associated performance during a salient cognitive task in individuals with cocaine-use disorders (CUD). In the current functional MRI study, we used a rewarded drug cue-reactivity task previously shown to be associated with hypoactivations in both major ACC subdivisions (implicated in default brain function) in CUD compared with healthy controls. The task was performed by 13 CUD and 14 matched healthy controls on 2 d: after ingesting a single dose of oral MPH (20 mg) or placebo (lactose) in a counterbalanced fashion. Results show that oral MPH increased responses to this salient cognitive task in both major ACC subdivisions (including the caudal-dorsal ACC and rostroventromedial ACC extending to the medial orbitofrontal cortex) in the CUD. These functional MRI results were associated with reduced errors of commission (a common impulsivity measure) and improved task accuracy, especially during the drug (vs. neutral) cue-reactivity condition in all subjects. The clinical application of such MPH-induced brain-behavior enhancements remains to be tested.

  15. Cocaine and other illicit drugs in airborne particulates in urban environments: A reflection of social conduct and population size

    Energy Technology Data Exchange (ETDEWEB)

    Viana, M., E-mail: mar.viana@idaea.csic.es [Institute for Environmental Assessment and Water Research (IDAEA-CSIC), C/Jordi Girona 18, 08034 Barcelona (Spain); Postigo, C., E-mail: cprqam@cid.csic.es [Institute for Environmental Assessment and Water Research (IDAEA-CSIC), C/Jordi Girona 18, 08034 Barcelona (Spain); Querol, X., E-mail: xavier.querol@idaea.csic.es [Institute for Environmental Assessment and Water Research (IDAEA-CSIC), C/Jordi Girona 18, 08034 Barcelona (Spain); Alastuey, A., E-mail: andres.alastuey@idaea.csic.es [Institute for Environmental Assessment and Water Research (IDAEA-CSIC), C/Jordi Girona 18, 08034 Barcelona (Spain); Lopez de Alda, M.J., E-mail: mlaqam@cid.csic.es [Institute for Environmental Assessment and Water Research (IDAEA-CSIC), C/Jordi Girona 18, 08034 Barcelona (Spain); Barcelo, D., E-mail: dbcqam@cid.csic.es [Institute for Environmental Assessment and Water Research (IDAEA-CSIC), C/Jordi Girona 18, 08034 Barcelona (Spain); King Saud University, Box 2454, Riyadh 11451 (Saudi Arabia); Artinano, B., E-mail: b.artinano@ciemat.es [Centre for Energy, Environment and Technology Research (CIEMAT), Av. Complutense 22, 28040 Madrid (Spain); Lopez-Mahia, P., E-mail: purmahia@udc.es [Department of Analytical Chemistry, University of A Coruna, Campus A Zapateira, 15071 A Coruna (Spain); Garcia Gacio, D., E-mail: dgarcia@udc.es [Department of Analytical Chemistry, University of A Coruna, Campus A Zapateira, 15071 A Coruna (Spain); Cots, N., E-mail: nuria.cots@gencat.ca [Department of the Environment, Catalonia Regional Government, Av. Diagonal 525, 08193 Barcelona (Spain)

    2011-05-15

    Levels of cocaine and other psychoactive substances in atmospheric particulate matter (PM) were determined in urban environments representing distinct social behaviours with regard to drug abuse: night-life, university and residential areas. Three cities (with population >1 million and <0.3 million inhabitants) were selected. Mean daily levels of drugs in PM were 11-336 pg/m{sup 3} for cocaine, 23-34 pg/m{sup 3} for cannabinoids, and 5-90 pg/m{sup 3} for heroin. The highest levels were recorded on weekends, with factors with respect to weekdays of 1-3 for cocaine, 1-2 for cannabinoids and 1.1-1.7 for heroin. Higher levels were detected in the night-life areas, pointing towards consumption and trafficking as major emission sources, and possibly ruling out drug manufacture. The similarities in temporal trends at all sites suggested a city-scale transport of psychoactive substances. Correlations were detected between cocaine and amphetamine consumption (r{sup 2} = 0.98), and between heroin and cannabinoids (r{sup 2}>0.82). - Highlights: > Cocaine, heroin, cannabis and related illicit drugs are found in detectable amounts in urban air. > Illicit drug consumption and small-scale trafficking are the major emission sources. > Illicit drugs remain in atmospheric particles and are transported across cities during at least 5 days. > Levels of illicit drugs increase from residential to night-life areas, and maximise on weekends. > Correlations between illicit drugs were detected, suggesting differences in consumer groups. - The presence of illicit drugs in atmospheric particles can be used to track illicit drug abuse.

  16. Pharmacological reduction of adult hippocampal neurogenesis modifies functional brain circuits in mice exposed to a cocaine conditioned place preference paradigm.

    Science.gov (United States)

    Castilla-Ortega, Estela; Blanco, Eduardo; Serrano, Antonia; Ladrón de Guevara-Miranda, David; Pedraz, María; Estivill-Torrús, Guillermo; Pavón, Francisco Javier; Rodríguez de Fonseca, Fernando; Santín, Luis J

    2016-05-01

    We investigated the role of adult hippocampal neurogenesis in cocaine-induced conditioned place preference (CPP) behaviour and the functional brain circuitry involved. Adult hippocampal neurogenesis was pharmacologically reduced with temozolomide (TMZ), and mice were tested for cocaine-induced CPP to study c-Fos expression in the hippocampus and in extrahippocampal addiction-related areas. Correlational and multivariate analysis revealed that, under normal conditions, the hippocampus showed widespread functional connectivity with other brain areas and strongly contributed to the functional brain module associated with CPP expression. However, the neurogenesis-reduced mice showed normal CPP acquisition but engaged an alternate brain circuit where the functional connectivity of the dentate gyrus was notably reduced and other areas (the medial prefrontal cortex, accumbens and paraventricular hypothalamic nucleus) were recruited instead of the hippocampus. A second experiment unveiled that mice acquiring the cocaine-induced CPP under neurogenesis-reduced conditions were delayed in extinguishing their drug-seeking behaviour. But if the inhibited neurons were generated after CPP acquisition, extinction was not affected but an enhanced long-term CPP retention was found, suggesting that some roles of the adult-born neurons may differ depending on whether they are generated before or after drug-contextual associations are established. Importantly, cocaine-induced reinstatement of CPP behaviour was increased in the TMZ mice, regardless of the time of neurogenesis inhibition. The results show that adult hippocampal neurogenesis sculpts the addiction-related functional brain circuits, and reduction of the adult-born hippocampal neurons increases cocaine seeking in the CPP model. © 2015 Society for the Study of Addiction.

  17. Individual differences in cocaine addiction: maladaptive behavioural traits.

    Science.gov (United States)

    Homberg, Judith R; Karel, Peter; Verheij, Michel M M

    2014-07-01

    Cocaine use leads to addiction in only a subset of individuals. Understanding the mechanisms underlying these individual differences in the transition from cocaine use to cocaine abuse is important to develop treatment strategies. There is agreement that specific behavioural traits increase the risk for addiction. As such, both high impulsivity and high anxiety have been reported to predict (compulsive) cocaine self-administration behaviour. Here, we set out a new view explaining how these two behavioural traits may affect addictive behaviour. According to psychological and psychiatric evolutionary views, organisms flourish well when they fit (match) their environment by trait and genotype. However, under non-fit conditions, the need to compensate the failure to deal with this environment increases, and, as a consequence, the functional use of rewarding drugs like cocaine may also increase. It suggests that neither impulsivity nor anxiety are bad per se, but that the increased risk to develop cocaine addiction is dependent on whether behavioural traits are adaptive or maladaptive in the environment to which the animals are exposed. This 'behavioural (mal)adaptation view' on individual differences in vulnerability to cocaine addiction may help to improve therapies for addiction. © 2013 The Authors, Addiction Biology © 2013 Society for the Study of Addiction.

  18. Cocaine-induced psychotic symptoms in clinical setting.

    Science.gov (United States)

    Vergara-Moragues, Esperanza; Araos Gómez, Pedro; González-Saiz, Francisco; Rodríguez-Fonseca, Fernando

    2014-06-30

    Cocaine use is significantly associated with psychiatric co-morbidities of which psychotic symptoms are the most typical. The primary goal of this study is to estimate the life-time prevalence of cocaine-induced psychotic symptoms (CIPS) in a sample of patients without a history of primary psychosis, who attended specific out-patient drug-dependence treatment centres (ODDTCs). This is an observational, cross-sectional design and a consecutive sampling technique. The Scale for Assessment of Positive Symptoms-Cocaine Induced Psychosis (SAPS-CIP) was used to interview 114 patients who request treatment at specific ODDTCs for problems related to cocaine use. Most patients, 89.5% (95% CIs: 83.8-95.2%) had dependence of cocaine and 84.2% (95% CIs: 77.5-90.9%) showed at least one CIPS. Patients with CIPS had used cocaine more times throughout their lives and had a more frequency of use during the period of higher abuse severity in the last year, had higher severity of dependence score and had fewer abstinence periods greater than 30 days compared with those without CIPS. Cocaine dependency severity scale scores were significantly greater in patients with CIPS compared with those without CIPS. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  19. Structural analysis of thermostabilizing mutations of cocaine esterase

    Energy Technology Data Exchange (ETDEWEB)

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

    2010-09-03

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

  20. Dopamine-beta hydroxylase polymorphism and cocaine addiction

    Directory of Open Access Journals (Sweden)

    Collier David

    2008-01-01

    Full Text Available Abstract Cocaine addiction involves a number of medical, psychological and social problems. Understanding the genetic aetiology of this disorder will be essential for design of effective treatments. Dopamine-beta hydroxylase (DbH catalyzes the conversion of dopamine to norepinephrine and could, therefore, have an influence on both cocaine action and the basal sensitivity of neurotransmitter systems to cocaine. Recently, the -1021C>T polymorphism have been found to strongly correlated with individual variation in plasma DbH activity. To test the influence of this polymorphism on the susceptibility of cocaine addiction, we decided to genotype it in a sample of 689 cocaine addicts and 832 healthy individuals. Genotypic and allelic analyses did not show any evidence of association with cocaine addiction, even after correcting for the effect of population stratification and other possible confounders. Our results do not support a major role of the -1021C>T polymorphism or the gene itself in the development of cocaine addiction but further examination of other variants within this gene will be necessary to completely rule out an effect.

  1. Comparison of oxymetazoline and lidocaine versus cocaine for outpatient dacryocystorhinostomy.

    Science.gov (United States)

    Meyer, D R

    2000-05-01

    To evaluate the effectiveness of oxymetazoline combined with lidocaine versus cocaine for outpatient dacryocystorhinostomy (DCR). Twenty-seven patients underwent DCR with a combination of oxymetazoline 0.05% nasal spray and lidocaine 4% spray/pledgetts (oxy/lido) and were compared with 28 patients who underwent DCR with cocaine 4% pledgetts for nasal anesthesia and vasoconstriction. Most of the patients underwent standard external approach DCR: five patients in the oxy/lido group and four patients in the cocaine group underwent endoscopic DCR. Patients in both groups reported being comfortable during and immediately after surgery. Visualization of the operative field was adequate, and surgery was successfully completed in all cases. Mean blood loss was 6.3 ml (+/-6.0) in the oxy/lido group and 7.3 ml (+/-6.4) in the cocaine group (p = 0.541). There were no cases of postoperative epistaxis requiring nasal packing or hospital admission in the oxy/lido group, whereas one patient in the cocaine group developed epistaxis 8 days after surgery, which required treatment. Success rate was similar in the two groups. The combination of oxymetazoline and lidocaine is effective for outpatient dacryocystorhinostomy. Patient comfort was adequate and blood loss not significantly different in comparison to cocaine. This combination provides effective nasal anesthesia and vasoconstriction, while avoiding the "hassle" and potentially greater risks associated with cocaine.

  2. The evaluation of evidence relating to traces of cocaine on banknotes.

    Science.gov (United States)

    Wilson, Amy; Aitken, Colin; Sleeman, Richard; Carter, James

    2014-03-01

    Banknotes can be seized from crime scenes as evidence for suspected association with illicit drug dealing. Tandem mass spectrometry data are available from banknotes seized in criminal investigations, as well as from banknotes from general circulation. The aim of the research is to evaluate the support provided by the data gathered in a criminal investigation for the proposition that the banknotes from which the data were obtained are associated with a person who is associated with a criminal activity related to cocaine in contrast to the proposition that the banknotes are associated with a person who is not associated with a criminal activity involving cocaine. The data considered are the peak area for the ion count for cocaine product ion m/z 105. Previous methods for assessment of the relative support for these propositions were concerned with the percentage of banknotes contaminated or assume independence of measurements of quantities between adjacent banknotes. Methods which account for an association of the quantity of drug on a banknote with that on adjacent banknotes are described. The methods are based on an autoregressive model of order one and on two versions of a nonparametric approach. The results are compared with a standard model which assumes measurements on individual banknotes are independent; there is no autocorrelation. Performance is assessed using rates of misleading evidence and a recommendation made as to which method to use. Copyright © 2014. Published by Elsevier Ireland Ltd.

  3. Electroacupuncture reduces cocaine-induced seizures and mortality in mice.

    Science.gov (United States)

    Chen, Yi-Hung; Ivanic, Boris; Chuang, Chieh-Min; Lu, Dah-Yuu; Lin, Jaung-Geng

    2013-01-01

    The aims of this study were to characterize the protective profile of electroacupuncture (EA) on cocaine-induced seizures and mortality in mice. Mice were treated with EA (2 Hz, 50 Hz, and 100 Hz), or they underwent needle insertion without anesthesia at the Dazhui (GV14) and Baihui (GV20) acupoints before cocaine administration. EA at 50 Hz applied to GV14 and GV20 significantly reduced the seizure severity induced by a single dose of cocaine (75 mg/kg; i.p.). Furthermore, needle insertion into GV14 and GV20 and EA at 2 Hz and 50 Hz at both acupoints significantly reduced the mortality rate induced by a single lethal dose of cocaine (125 mg/kg; i.p.). In the sham control group, EA at 50 Hz applied to bilateral Tianzong (SI11) acupoints had no protective effects against cocaine. In addition, EA at 50 Hz applied to GV14 and GV20 failed to reduce the incidence of seizures and mortality induced by the local anesthetic procaine. In an immunohistochemistry study, EA (50 Hz) pretreatment at GV14 and GV20 decreased cocaine (75 mg/kg; i.p.)-induced c-Fos expression in the paraventricular thalamus. While the dopamine D3 receptor antagonist, SB-277011-A (30 mg/kg; s.c), did not by itself affect cocaine-induced seizure severity, it prevented the effects of EA on cocaine-induced seizures. These results suggest that EA alleviates cocaine-induced seizures and mortality and that the dopamine D3 receptor is involved, at least in part, in the anticonvulsant effects of EA in mice.

  4. Electroacupuncture Reduces Cocaine-Induced Seizures and Mortality in Mice

    Directory of Open Access Journals (Sweden)

    Yi-Hung Chen

    2013-01-01

    Full Text Available The aims of this study were to characterize the protective profile of electroacupuncture (EA on cocaine-induced seizures and mortality in mice. Mice were treated with EA (2 Hz, 50 Hz, and 100 Hz, or they underwent needle insertion without anesthesia at the Dazhui (GV14 and Baihui (GV20 acupoints before cocaine administration. EA at 50 Hz applied to GV14 and GV20 significantly reduced the seizure severity induced by a single dose of cocaine (75 mg/kg; i.p.. Furthermore, needle insertion into GV14 and GV20 and EA at 2 Hz and 50 Hz at both acupoints significantly reduced the mortality rate induced by a single lethal dose of cocaine (125 mg/kg; i.p.. In the sham control group, EA at 50 Hz applied to bilateral Tianzong (SI11 acupoints had no protective effects against cocaine. In addition, EA at 50 Hz applied to GV14 and GV20 failed to reduce the incidence of seizures and mortality induced by the local anesthetic procaine. In an immunohistochemistry study, EA (50 Hz pretreatment at GV14 and GV20 decreased cocaine (75 mg/kg; i.p.-induced c-Fos expression in the paraventricular thalamus. While the dopamine D3 receptor antagonist, SB-277011-A (30 mg/kg; s.c, did not by itself affect cocaine-induced seizure severity, it prevented the effects of EA on cocaine-induced seizures. These results suggest that EA alleviates cocaine-induced seizures and mortality and that the dopamine D3 receptor is involved, at least in part, in the anticonvulsant effects of EA in mice.

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

    Science.gov (United States)

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

    2016-04-01

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

  6. Acute coronary syndrome after levamisole-adultered cocaine abuse.

    Science.gov (United States)

    Michaud, Katarzyna; Grabherr, Silke; Shiferaw, Kebede; Doenz, Franceso; Augsburger, Marc; Mangin, Patrice

    2014-01-01

    Cocaine is a well known trigger of acute coronary syndromes. Over the last 10 years levamisole, a veterinary anthelminthic drug has been increasingly used as an adulterant of cocaine. Levamisole was used to treat pediatric nephritic syndrome and rheumatoid arthritis before being withdrawn from the market due to its significant toxicity, i.e. hematological complications and vasculitis. The major complications of levamisole-adultered cocaine reported up to now are hematological and dermatological. The case reported here is of a 25 year old man with a history of cocaine abuse who died at home after complaining of retrosternal pain. Postmortem CT-angiography, autopsy, and chemical and toxicological analyses were performed. An eroded coronary artery plaque was found at the proximal segment of the left anterior descending coronary artery. Two myocardial infarct scars were present in the left ventricle. Microscopic examination of the coronary artery revealed infiltration of eosinophils into the adventitia and intima. Toxicological examination confirmed the presence of cocaine and its metabolites in the peripheral blood, and of levamisole in the urine and pericardial fluid. Eosinophilic inflammatory coronary artery pathologies have been clinically linked to coronary dissection, hypersensitivity coronary syndrome and vasospastic allergic angina. The coronary pathology in the presented case could be a complication of levamisole-adultered cocaine use, in which an allergic or immune-mediated mechanism might play a role. The rise in cocaine addiction worldwide and the increase of levamisole adulterated cocaine highlights the importance of updating our knowledge of the effects of adultered cocaine abuse. Copyright © 2013 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

  7. Cocaine and the AP-1 transcription factor complex.

    Science.gov (United States)

    Hope, B T

    1998-05-30

    Cocaine addition in humans develops gradually with repeated administrations and persists long after cocaine has cleared the body. The mechanisms underlying this persistent form of neuroplasticity are not understood and can involve both structural and biochemical mechanisms. The long time course for cocaine addiction in humans and for development of cocaine self-administration in animal models suggest the involvement of alterations in gene expression leading to altered signaling in the brain. In the striatum (Str) and nucleus accumbens (NAc) of rats. Pretreatment with repeated cocaine administrations downregulates the induction of various immediate early genes (IEGs) by a subsequent acute challenge with cocaine. Some of these downregulated IEGs encode Fos-related components of the activator protein-1 (AP-1) complex, which is likely re regulate a number of genes important for neuronal function. Interestingly, repeated cocaine administration induces novel delta FosB-related proteins (called chronic Fos-related antigens (Fras)) in the NAc and Str that replace the downregulated isoforms of Fos. Unlike the acutely induced, short-lasting isoforms of Fos and FosB, the chronic Fras persist long after the last cocaine administration. The known form of delta FosB per se lacks the domain required to activate transcription. If the chronic Fras are similar in structure to delta FosB, then the induction of chronic Fras likely leads to a blockade of AP-1-dependent transcription resulting in altered gene expression. We presently purifying the chronic Fras to obtain amino acid sequence in order to directly examine our hypothesis about the effects of repeated cocaine administration on AP-1 dependent transcription and gene expression in the brain

  8. Histone arginine methylation in cocaine action in the nucleus accumbens

    Science.gov (United States)

    Sun, HaoSheng; Scobie, Kimberly N.; Shao, Ningyi; Rabkin, Jaclyn; Dias, Caroline; Calipari, Erin S.; Maze, Ian; Pena, Catherine J.; Walker, Deena M.; Cahill, Michael E.; Chandra, Ramesh; Gancarz, Amy; Landry, Joseph A.; Cates, Hannah; Lobo, Mary-Kay; Dietz, David; Allis, C. David; Guccione, Ernesto; Turecki, Gustavo; Defilippi, Paola; Neve, Rachael L.; Hurd, Yasmin L.; Shen, Li; Nestler, Eric J.

    2016-01-01

    Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanisms—such as histone acetylation and methylation on Lys residues—have been linked to these lasting actions of cocaine. In contrast to Lys methylation, the role of histone Arg (R) methylation remains underexplored in addiction models. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to a