Cannabidiol Rescues Acute Hepatic Toxicity and Seizure Induced by Cocaine

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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.

Fatal cocaine intoxication in a body packer

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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.

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

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Siciliano, Cody A.; Fordahl, Steve C.

2016-01-01

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

Sensitivity to monetary reward is most severely compromised in recently abstaining cocaine addicted individuals: a cross-sectional ERP study.

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Parvaz, Muhammad A; Maloney, Thomas; Moeller, Scott J; Woicik, Patricia A; Alia-Klein, Nelly; Telang, Frank; Wang, Gene-Jack; Squires, Nancy K; Volkow, Nora D; Goldstein, Rita Z

2012-07-30

Recent studies suggest that drug-addicted individuals have a dampened cortical response to non-drug rewards. However, it remains unclear whether recency of drug use impacts this impairment. Therefore, in this event-related potential study, recency of cocaine use was objectively determined by measuring cocaine in urine on study day. Thirty-five individuals with current cocaine use disorder [CUD: 21 testing positive (CUD+) and 14 testing negative (CUD-) for cocaine in urine] and 23 healthy controls completed a sustained attention task with graded monetary incentives (0¢, 1¢ and 45¢). Unlike in controls, in both CUD subgroups P300 amplitude was not modulated by the varying amounts of money and the CUD- showed the most severe impairment as documented by the lowest P300 amplitudes and task accuracy. Moreover, while recency of drug use was associated with better accuracy and higher P300 amplitudes, chronic drug use was associated with lower sensitivity to money. These results extend our previous findings of decreased sustained sensitivity to monetary reward in CUD+ to recently abstaining individuals, where level of impairment was most severe. Taken together, these results support the self-medication hypothesis, where CUD may be self-administering cocaine to avoid or compensate for underlying cognitive and emotional difficulties albeit with a long-term detrimental effect on sensitivity to non-drug reward. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Sensitivity to monetary reward is most severely compromised in recently abstaining cocaine addicted individuals: A cross-sectional ERP study

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Parvaz, Muhammad A.; Maloney, Thomas; Moeller, Scott J.; Woicik, Patricia A.; Alia-Klein, Nelly; Telang, Frank; Wang, Gene-Jack; Squires, Nancy K.; Volkow, Nora D.; Goldstein, Rita Z.

2012-01-01

Recent studies suggest that drug addicted individuals have a dampened cortical response to non-drug rewards. However, it remains unclear whether recency of drug use impacts this impairment. Therefore, in this study, recency of cocaine use was objectively determined by measuring cocaine in urine on study day. Thirty-five individuals with current cocaine use disorder [CUD: 21 testing positive (CUD+) and 14 testing negative (CUD−) for cocaine in urine] and 23 healthy controls completed a sustained attention task with graded monetary incentives (0¢, 1¢ and 45¢). Unlike in controls, in both CUD subgroups P300 amplitude was not modulated by the varying amounts of money and the CUD− showed the most severe impairment as documented by the lowest P300 amplitudes and task accuracy. Moreover, while recency of drug use was associated with better accuracy and higher P300 amplitudes, chronic drug use was associated with lower sensitivity to money. These results extend our previous findings of decreased sustained sensitivity to monetary reward in CUD+ to recently abstaining individuals, where level of impairment was most severe. Taken together, these results support the self-medication hypothesis, where CUD may be self-administering cocaine to avoid or compensate for underlying cognitive and emotional difficulties albeit with a long-term detrimental effect on sensitivity to non-drug reward. PMID:22841343

Impaired insight in cocaine addiction: laboratory evidence and effects on cocaine-seeking behaviour

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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.

Impaired insight in cocaine addiction: laboratory evidence and effects on cocaine-seeking behaviour

Science.gov (United States)

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

2010-01-01

Neuropsychiatric disorders are often characterized by impaired insight into behaviour. Such an insight deficit has been suggested, but never directly tested, in drug addiction. Here we tested for the first time this impaired insight hypothesis in drug addiction, and examined its potential association with drug-seeking behaviour. We also tested potential modulation of these effects by cocaine urine status, an individual difference known to impact underlying cognitive functions and prognosis. Sixteen cocaine addicted individuals testing positive for cocaine in urine, 26 cocaine addicted individuals testing negative for cocaine in urine, and 23 healthy controls completed a probabilistic choice task that assessed objective preference for viewing four types of pictures (pleasant, unpleasant, neutral and cocaine). This choice task concluded by asking subjects to report their most selected picture type; correspondence between subjects’ self-reports with their objective choice behaviour provided our index of behavioural insight. Results showed that the urine positive cocaine subjects exhibited impaired insight into their own choice behaviour compared with healthy controls; this same study group also selected the most cocaine pictures (and fewest pleasant pictures) for viewing. Importantly, however, it was the urine negative cocaine subjects whose behaviour was most influenced by insight, such that impaired insight in this subgroup only was associated with higher cocaine-related choice on the task and more severe actual cocaine use. These findings suggest that interventions to enhance insight may decrease drug-seeking behaviour, especially in urine negative cocaine subjects, potentially to improve their longer-term clinical outcomes. PMID:20395264

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

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

2012-10-01

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

Cocaine use and the breastfeeding mother.

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Jones, Wendy

2015-01-01

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

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

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

2016-05-01

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

Cocaine-induced renal infarction: report of a case and review of the literature

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Nosrati Saeid M

2005-09-01

Full Text Available Abstract Background Cocaine abuse has been known to have detrimental effects on the cardiovascular system. Its toxicity has been associated with myocardial ischemia, cerebrovascular accidents and mesenteric ischemia. The pathophysiology of cocaine-related renal injury is multifactorial and involves renal hemodynamic changes, alterations in glomerular matrix synthesis, degradation and oxidative stress, and possibly induction of renal atherogenesis. Renal infarction as a result of cocaine exposure, however, is rarely reported in the literature. Case presentation A 48 year-old male presented with a four-day history of severe right flank pain following cocaine use. On presentation, he was tachycardic, febrile and had severe right costovertebral angle tenderness. He had significant proteinuria, leukocytosis and elevated serum creatinine and lactate dehydrogenase. Radiographic imaging studies as well as other screening tests for thromboembolic events, hypercoagulability states, collagen vascular diseases and lipid disorders were suggestive of Cocaine-Induced Renal Infarction (CIRI by exclusion. Conclusion In a patient with a history of cocaine abuse presenting with fevers and flank pain suggestive of urinary tract infection or nephrolithiasis, cocaine-induced renal infarction must be considered in the differential diagnosis. In this article, we discuss the prior reported cases of CIRI and thoroughly review the literature available on this disorder. This is important for several reasons. First, it will allow us to discuss and elaborate on the mechanism of renal injury caused by cocaine. In addition, this review will demonstrate the importance of considering the diagnosis of CIRI in a patient with documented cocaine use and an atypical presentation of acute renal injury. Finally, we will emphasize the need for a consensus on optimal treatment of this disease, for which therapy is not yet standardized.

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

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

2015-05-01

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

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 ...

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...

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.

Preventive Strength of Dyadic Social Interaction against Reacquisition/Reexpression of Cocaine Conditioned Place Preference.

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Bregolin, Tanja; Pinheiro, Barbara S; El Rawas, Rana; Zernig, Gerald

2017-01-01

The reorientation away from drugs of abuse and toward social interaction is a highly desirable but as yet elusive goal in the therapy of substance dependence. We could previously show that cocaine preferring Sprague-Dawley rats which engaged in only four 15 min episodes of dyadic social interaction (DSI) did not reacquire and reexpress cocaine conditioned place preference (CPP) after a single cocaine exposure. In the present study, we investigated how strong this preventive effect of DSI is. In corroboration of our previous findings in rats, four 15 min DSI episodes prevented the reacquisition/reexpression of cocaine CPP in mice. However, this effect was only observed if only one cocaine conditioning session (15 min) was used. If mice were counterconditioned with a total of four cocaine sessions, the cocaine CPP reemerged. Interestingly, the opposite also held true: in mice that had acquired/expressed cocaine CPP, one conditioning session with DSI did not prevent the persistence of cocaine CPP, whereas four DSI conditioning sessions reversed CPP for 15 mg/kg intraperitoneal cocaine. Of note, this cocaine dose was a strong reward in C57BL/6J mice, causing CPP in all tested animals. Our findings suggest that both the reversal (reconditioning) of CPP from cocaine to DSI as well as that from DSI to cocaine requires four conditioning sessions. As previously shown in C57BL/6 mice from the NIH substrain, mice from the Jackson substrain also showed a greater relative preference for 15 mg/kg intraperitoneal cocaine over DSI, whereas Sprague-Dawley rats were equally attracted to contextual stimuli associated with this cocaine dose and DSI. Also in corroboration of previous findings, both C57BL/6J mice and experimenters several generations removed from the original ones produced CPP for DSI to a lesser degree than Sprague-Dawley rats. Our findings demonstrate the robustness of our experimental model across several subject- and experimenter generations in two rodent genus (i

Preventive Strength of Dyadic Social Interaction against Reacquisition/Reexpression of Cocaine Conditioned Place Preference

Directory of Open Access Journals (Sweden)

Tanja Bregolin

2017-11-01

Full Text Available The reorientation away from drugs of abuse and toward social interaction is a highly desirable but as yet elusive goal in the therapy of substance dependence. We could previously show that cocaine preferring Sprague-Dawley rats which engaged in only four 15 min episodes of dyadic social interaction (DSI did not reacquire and reexpress cocaine conditioned place preference (CPP after a single cocaine exposure. In the present study, we investigated how strong this preventive effect of DSI is. In corroboration of our previous findings in rats, four 15 min DSI episodes prevented the reacquisition/reexpression of cocaine CPP in mice. However, this effect was only observed if only one cocaine conditioning session (15 min was used. If mice were counterconditioned with a total of four cocaine sessions, the cocaine CPP reemerged. Interestingly, the opposite also held true: in mice that had acquired/expressed cocaine CPP, one conditioning session with DSI did not prevent the persistence of cocaine CPP, whereas four DSI conditioning sessions reversed CPP for 15 mg/kg intraperitoneal cocaine. Of note, this cocaine dose was a strong reward in C57BL/6J mice, causing CPP in all tested animals. Our findings suggest that both the reversal (reconditioning of CPP from cocaine to DSI as well as that from DSI to cocaine requires four conditioning sessions. As previously shown in C57BL/6 mice from the NIH substrain, mice from the Jackson substrain also showed a greater relative preference for 15 mg/kg intraperitoneal cocaine over DSI, whereas Sprague-Dawley rats were equally attracted to contextual stimuli associated with this cocaine dose and DSI. Also in corroboration of previous findings, both C57BL/6J mice and experimenters several generations removed from the original ones produced CPP for DSI to a lesser degree than Sprague-Dawley rats. Our findings demonstrate the robustness of our experimental model across several subject- and experimenter generations in two

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

NARCIS (Netherlands)

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

2015-01-01

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

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

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.

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

Science.gov (United States)

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

2014-09-01

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

Error-related brain activity predicts cocaine use after treatment at 3-month follow-up.

Science.gov (United States)

Marhe, Reshmi; van de Wetering, Ben J M; Franken, Ingmar H A

2013-04-15

Relapse after treatment is one of the most important problems in drug dependency. Several studies suggest that lack of cognitive control is one of the causes of relapse. In this study, a relative new electrophysiologic index of cognitive control, the error-related negativity, is investigated to examine its suitability as a predictor of relapse. The error-related negativity was measured in 57 cocaine-dependent patients during their first week in detoxification treatment. Data from 49 participants were used to predict cocaine use at 3-month follow-up. Cocaine use at follow-up was measured by means of self-reported days of cocaine use in the last month verified by urine screening. A multiple hierarchical regression model was used to examine the predictive value of the error-related negativity while controlling for addiction severity and self-reported craving in the week before treatment. The error-related negativity was the only significant predictor in the model and added 7.4% of explained variance to the control variables, resulting in a total of 33.4% explained variance in the prediction of days of cocaine use at follow-up. A reduced error-related negativity measured during the first week of treatment was associated with more days of cocaine use at 3-month follow-up. Moreover, the error-related negativity was a stronger predictor of recent cocaine use than addiction severity and craving. These results suggest that underactive error-related brain activity might help to identify patients who are at risk of relapse as early as in the first week of detoxification treatment. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

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.

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.

Cocaine Allergy in Drug-Dependent Patients and Allergic People.

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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.

Demand curves for hypothetical cocaine in cocaine-dependent individuals.

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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.

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

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

2009-09-01

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

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

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

2011-01-01

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

Cocaine

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

Proteasome phosphorylation regulates cocaine-induced sensitization.

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

2018-04-01

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

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

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Liu, Yingxiong; Zhao, Qiang

2017-06-01

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

Sudden bilateral sensorineural hearing loss after intravenous cocaine injection: a case report and review of the literature.

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Stenner, Markus; Stürmer, Konrad; Beutner, Dirk; Klussmann, Jens Peter

2009-12-01

Little is known about the effects of intravenous abuse of cocaine, especially on the inner ear. We report on a 26-year-old man who presented to our outpatient department with a sudden severe hearing loss after intravenous injection of cocaine. The audiogram on admission showed symmetric air conduction levels up to 80 dB at 4 kHz. After treatment with intravenous sodium chloride, prednisolone, and pentoxifylline, the audiogram 2 days later showed a bilateral normacusis. A review of the literature on the topic is given and possible reasons for inner ear damages caused by cocaine are discussed.

Invasive aspergillosis in a user of inhaled cocaine: rhinosinusitis with bone and cartilage destruction

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Luna Azulay-Abulafia

2014-07-01

Full Text Available Aspergillosis is an infection caused by saprophytic fungi of the genus Aspergillus, which typically occurs in immunosuppressed individuals, but has also been reported in immunocompetent patients. The main routes of entry are the respiratory tract, skin, cornea, and ear, and the infection may be localized or disseminated by contiguity or vascular invasion. We report a severe case of rhinosinusitis with cutaneous involvement, caused by invasive aspergillosis, in an immunocompetent user of inhaled cocaine. Invasive aspergillosis related to cocaine abuse has not yet been reported in the literature. After itraconazole treatment and surgical debridement, complete clinical remission was achieved. Nasal reconstruction with a skin graft over a silicone prosthesis resulted in a satisfactory esthetic outcome.

Prenatal and postnatal cocaine exposure predict teen cocaine use

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

2015-01-01

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

Cocaine withdrawal causes delayed dysregulation of stress genes in the hippocampus.

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M Julia García-Fuster

Full Text Available Relapse, even following an extended period of withdrawal, is a major challenge in substance abuse management. Delayed neurobiological effects of the drug during prolonged withdrawal likely contribute to sustained vulnerability to relapse. Stress is a major trigger of relapse, and the hippocampus regulates the magnitude and duration of stress responses. Recent work has implicated hippocampal plasticity in various aspects of substance abuse. We asked whether changes in stress regulatory mechanisms in the hippocampus may participate in the neuroadaptations that occur during prolonged withdrawal. We therefore examined changes in the rat stress system during the course of withdrawal from extended daily access (5-hours of cocaine self-administration, an animal model of addiction. Tissue was collected at 1, 14 and 28 days of withdrawal. Plasma corticosterone levels were determined and corticosteroid receptors (GR, MR, MR/GR mRNA ratios and expression of other stress-related molecules (HSP90AA1 and HSP90AB1 mRNA were measured in hippocampal subfields using in situ hybridization. Results showed a delayed emergence of dysregulation of stress genes in the posterior hippocampus following 28 days of cocaine withdrawal. This included increased GR mRNA in DG and CA3, increased MR and HSP90AA1 mRNA in DG, and decreased MR/GR mRNA ratio in DG and CA1. Corticosterone levels progressively decreased during the course of withdrawal, were normalized following 28 days of withdrawal, and were correlated negatively with GR and positively with MR/GR mRNA ratio in DG. These results suggest a role for the posterior hippocampus in the neuroadaptations that occur during prolonged withdrawal, and point to a signaling partner of GR, HSP90AA1, as a novel dysregulated target during cocaine withdrawal. These delayed neurobiological effects of extended cocaine exposure likely contribute to sustained vulnerability to relapse.

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.

Smoked cocaine in socially-depressed areas

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Díaz Olga

2010-11-01

Full Text Available Abstract Background The main objectives of this study are to describe the smoked cocaine user's profile in socially-depressed areas and their needs from a harm-reduction perspective, to investigate their use of smoking crack and compare the acute effects between injecting and smoking consumption. Methods The study took place in SAPS, Barcelona, Spain. Two focus group sessions were undertaken with a total of 8 drug users. Secondly, the 8 participants answered a structured questionnaire and in the course of the sessions, as a snowball activity, were trained to survey 6 other crack smokers. Results We obtained 56 questionnaires. The majority of participants were from non-European Community countries (62.69%, 70.2% of participants referred to sharing the smoking equipment. The most frequent symptoms reported during smoked cocaine were mydriasis (83.33%, perspiration (72.92% and compulsive object search (70.83% During the group sessions, participants said that smoked cocaine is much more addictive than injected cocaine and causes more anxiety. Participants also reported the difficulty of changing from injected use to smoked use, due to the larger amount of cocaine needed to reach the same effects as when having injected. Conclusions We can conclude that the research, focused on achieving greater knowledge of the smoked cocaine user's profile, their usage of smoking crack, consumption patterns and acute effects, should be incorporated into substance misuse interventions.

Cigarette Cue Attentional Bias in Cocaine-Smoking and Non-Cocaine-Using Cigarette Smokers.

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Marks, Katherine R; Alcorn, Joseph L; Stoops, William W; Rush, Craig R

2016-09-01

Cigarette smoking in cocaine users is nearly four times higher than the national prevalence and cocaine use increases cigarette smoking. The mechanisms underlying cigarette smoking in cocaine-using individuals need to be identified to promote cigarette and cocaine abstinence. Previous studies have examined the salience of cigarette and cocaine cues separately. The present aim was to determine whether cigarette attentional bias (AB) is higher in cigarettes smokers who smoke cocaine relative to individuals who only smoke cigarettes. Twenty cigarette smokers who smoke cocaine and 20 non-cocaine-using cigarette smokers completed a visual probe task with eye-tracking technology. During this task, the magnitude of cigarette and cocaine AB was assessed through orienting bias, fixation time, and response time. Cocaine users displayed an orienting bias towards cigarette cues. Cocaine users also endorsed a more urgent desire to smoke to relieve negative affect associated with cigarette craving than non-cocaine users (g = 0.6). Neither group displayed a cigarette AB, as measured by fixation time. Cocaine users, but not non-cocaine users, displayed a cocaine AB as measured by orienting bias (g = 2.0) and fixation time (g = 1.2). There were no significant effects for response time data. Cocaine-smoking cigarettes smokers display an initial orienting bias toward cigarette cues, but not sustained cigarette AB. The incentive motivation underlying cigarette smoking also differs. Cocaine smokers report more urgent desire to smoke to relieve negative affect. Identifying differences in motivation to smoke cigarettes may provide new treatment targets for cigarette and cocaine use disorders. These results suggest that cocaine-smoking cigarette smokers display an initial orienting bias towards cigarette cues, but not sustained attention towards cigarette cues, relative to non-cocaine-using smokers. Smoked cocaine users also report a more urgent desire to smoke to relieve negative affect

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

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

2016-02-01

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

Cocaine

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

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

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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...

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

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Billing, Lawrence; Ersche, Karen D

2015-03-01

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

The drugs industry and peasant self-defence in a Peruvian cocaine enclave.

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van Dun, Mirella

2012-11-01

This article gives a detailed account of the cocaine industry and the related violence in the Peruvian Upper Huallaga. It is argued that in this cocaine producing region violence increased during state-led forced eradication operations of the coca plants. Most of the violent incidents were closely related to the diminishing cocaine industry, but they were also related to the actions of the state security forces. Instead of receiving support from the state's security apparatus, the population mobilized its own forces to fight the violence. As will be argued, the causes of violence in this cocaine enclave are part of a dynamic interaction amongst many factors - an interaction that is influenced by the local context, a partial state vacuum, and the social utility and the economic advantages of violence. One needs to be aware that motivations of those who engage in the violent behaviour can change over time, as underlying power structures are influenced by changes in local conditions. The study covers an in-depth account of events taking place in the Upper Huallaga during the years 2003-2007. The research material was collected by several ethnographical fieldwork methods. Copyright © 2012 Elsevier B.V. All rights reserved.

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

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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

Asthma associated with the use of cocaine, heroin, and marijuana: A review of the evidence.

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Self, Timothy H; Shah, Samarth P; March, Katherine L; Sands, Christopher W

2017-09-01

A review of the evidence was conducted regarding asthma associated with the use of cocaine, heroin, and marijuana. A search of the English literature was performed via PubMed/Medline and EMBASE using the search terms asthma AND cocaine, heroin, and marijuana. When pertinent articles were found, salient references in those articles were assessed. Due to the relatively small number of studies, we included all studies and cases. For several decades, case reports, retrospective studies, and laboratory investigations have demonstrated that inhalation of cocaine or heroin is associated with increased asthma symptoms and reduced pulmonary function. Smoking crack cocaine, nasal insufflation of cocaine or heroin, and smoking heroin increases the risk of emergency department visits and hospitalizations for asthma. Although frequent smoking of marijuana may cause symptoms of cough, sputum production, and wheezing in the general population, more studies are needed specifically in patients with asthma. Smoking marijuana with concomitant tobacco use is common and further worsens the respiratory symptoms. Use of cocaine and heroin in patients with asthma should be avoided. Pending further studies, it would be prudent for patients with asthma to avoid smoking marijuana. Clinicians need to be vigilant regarding use of these drugs in their patients with hyperreactive airway disease.

Neurotensin Agonist Attenuates Nicotine Potentiation to Cocaine Sensitization

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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.

Substance use - cocaine

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

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

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Boris B Quednow

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

Cocaine-induced encephalocele: case report and literature review.

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Albert, Ladislau; DeMattia, Joseph A

2011-01-01

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

Characterization of a high affinity cocaine binding site in rat brain

International Nuclear Information System (INIS)

Calligaro, D.; Eldefrawi, M.

1986-01-01

Binding of [ 3 H]cocaine to synaptic membranes from whole rat brain was reversible and saturable. Nonlinear regression analysis of binding isotherms indicated two binding affinities: one with k/sub d/ = 16 nM, B/sub max/ = 0.65 pmoles/mg protein and the other with K/sub d/ = 660 nM, B/sub max/ = 5.1 pmoles/mg protein. The high-affinity binding of [ 3 H]cocaine was sensitive to the actions of trypsin and chymotrypsin but not carboxypeptidase, and was eliminated by exposure of the membranes to 95 0 C for 5 min. Specific binding at 2 nM was higher at pH 8.8 than at pH 7.0. Binding of [ 3 H]cocaine (15 nM) was inhibited by increasing concentrations of Na + ions. Several cocaine analogues, neurotransmitter uptake inhibitors and local anesthetics displaced specific [ 3 H]cocaine binding at 2 nM with various potencies. The cocaine analogue (-)-norcocaine was the most potent (IC 50 = 10 nM), while the local anesthetic tetracaine was the least potent in inhibiting [ 3 H]cocaine binding. Several biogenic amine uptake inhibitors, including tricyclic antidepressants and phencyclidine, had IC 50 values below μM concentrations

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

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

2017-06-01

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

Adolescent cocaine exposure simplifies orbitofrontal cortical dendritic arbors

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Lauren M DePoy

2014-10-01

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

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

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

2014-04-01

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

Serotonin Syndrome in the Setting of Lamotrigine, Aripiprazole, and Cocaine Use

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Anupam Kotwal

2015-01-01

Full Text Available Serotonin syndrome is a potentially life-threatening condition associated with increased serotonergic activity in the central nervous system. It is classically associated with the simultaneous administration of two serotonergic agents, but it can occur after initiation of a single serotonergic drug or increasing the dose of a serotonergic drug in individuals who are particularly sensitive to serotonin. We describe a case of serotonin syndrome that occurred after ingestion of higher than prescribed doses of lamotrigine and aripiprazole, in addition to cocaine abuse. The diagnosis was established based on Hunter toxicity criteria and severity was classified as mild. The features of this syndrome resolved shortly after discontinuation of the offending agents. Serotonin syndrome is characterized by mental status changes, autonomic hyperactivity, and neuromuscular abnormalities along a spectrum ranging from mild to severe. Serotonin syndrome in our patient was most likely caused by the pharmacokinetic and pharmacodynamic interactions between lamotrigine, aripiprazole, and cocaine leading to increased CNS serotonergic activity.

Brain injury markers (S100B and NSE) in chronic cocaine dependents

OpenAIRE

Kessler, Felix Henrique Paim; Woody, George; Portela, Luís Valmor Cruz; Tort, Adriano Bretanha Lopes; De Boni, Raquel; Peuker, Ana Carolina Wolf Baldino; Genro, Vanessa; Diemen, Lísia von; Souza, Diogo Onofre Gomes de; Pechansky, Flavio

2007-01-01

OBJECTIVE: Studies have shown signs of brain damage caused by different mechanisms in cocaine users. The serum neuron specific enolase and S100B protein are considered specific biochemical markers of neuronal and glial cell injury. This study aimed at comparing blood levels of S100B and NSE in chronic cocaine users and in volunteers who did not use cocaine or other illicit drugs. METHOD: Twenty subjects dependent on cocaine but not on alcohol or marijuana, and 20 non-substance using controls ...

The effects of cocaine, alcohol and cocaine/alcohol combinations in conditioned taste aversion learning.

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Busse, Gregory D; Verendeev, Andrey; Jones, Jermaine; Riley, Anthony L

2005-09-01

We have recently reported that alcohol attenuates cocaine place preferences. Although the basis for this effect is unknown, alcohol may attenuate cocaine reward by potentiating its aversive effects. To examine this possibility, these experiments assessed the effects of alcohol on cocaine-induced taste aversions under conditions similar to those that resulted in attenuated place preferences. Specifically, Experiments 1 and 2 assessed the effects of alcohol (0.5 g/kg) on taste aversions induced by 20, 30 and 40 mg/kg cocaine. Experiment 3 examined the role of intertrial interval in the effects of alcohol (0.5 g/kg) on cocaine (30 mg/kg) taste aversions. In Experiments 1 and 2, cocaine was effective at conditioning aversions. Alcohol produced no measurable effect. Combining cocaine and alcohol produced no greater aversion than cocaine alone (and, in fact, weakened aversions at the lowest dose of cocaine). In Experiment 3, varying the intertrial interval from 3 days (as in the case of Experiments 1 and 2) to 1 day (a procedure identical to that in which alcohol attenuated cocaine place preferences) resulted in significant alcohol- and cocaine-induced taste aversions. Nonetheless, alcohol remained ineffective in potentiating cocaine aversions. Thus, under these conditions alcohol does not potentiate cocaine's aversiveness. These results were discussed in terms of their implication for the effects of alcohol on cocaine-induced place preferences. Further, the effects of alcohol on place preferences conditioned by cocaine were discussed in relation to other assessments of the effects of alcohol on the affective properties of cocaine and the implications of these interactions for alcohol and cocaine co-use.

Cocaine (Coke, Crack) Facts

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... 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 ...

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

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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.

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

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Sullivan Robin

2011-09-01

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

Alterations in tryptophan and purine metabolism in cocaine addiction: a metabolomic study.

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Patkar, Ashwin A; Rozen, Steve; Mannelli, Paolo; Matson, Wayne; Pae, Chi-Un; Krishnan, K Ranga; Kaddurah-Daouk, Rima

2009-10-01

Mapping metabolic "signatures" can provide new insights into addictive mechanisms and potentially identify biomarkers and therapeutic targets. We examined the differences in metabolites related to the tyrosine, tryptophan, purine, and oxidative stress pathways between cocaine-dependent subjects and healthy controls. Several of these metabolites serve as biological indices underlying the mechanisms of reinforcement, toxicity, and oxidative stress. Metabolomic analysis was performed in 18 DSM-IV-diagnosed cocaine-dependent individuals with at least 2 weeks of abstinence and ten drug-free controls. Plasma concentrations of 37 known metabolites were analyzed and compared using a liquid chromatography electrochemical array platform. Multivariate analyses were used to study the relationship between severity of drug use [Addiction Severity Index (ASI) scores] and biological measures. Cocaine subjects showed significantly higher levels of n-methylserotonin (p cocaine and control groups with no overlap. Alterations in the methylation processes in the serotonin pathways and purine metabolism seem to be associated with chronic exposure to cocaine. Given the preliminary nature and cross-sectional design of the study, the findings need to be confirmed in larger samples of cocaine-dependent subjects, preferably in a longitudinal design.

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...

Bilateral haemorrhagic infarction of the globus pallidus after cocaine and alcohol intoxication.

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Renard, Dimitri; Brunel, Hervé; Gaillard, Nicolas

2009-06-01

Cocaine is a risk factor for both ischemic and haemorrhagic stroke. We present the case of a 31-year-old man with bilateral ischemia of the globus pallidus after excessive alcohol and intranasal cocaine use. Drug-related globus pallidus infarctions are most often associated with heroin. Bilateral basal ganglia infarcts after the use of cocaine, without concurrent heroin use, have never been reported. In our patient, transient cardiac arrhythmia or respiratory dysfunction related to cocaine and/or ethanol use were the most likely causes of cerebral hypoperfusion.

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...... effects, suggesting that Y5 receptors could be a potential therapeutic target in cocaine addiction....

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

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

2015-12-01

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

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

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Hall, W; Carter, L

2004-08-01

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

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

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

2012-11-01

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

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

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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

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

Neural correlates of the severity of cocaine, heroin, alcohol, MDMA and cannabis use in polysubstance abusers: a resting-PET brain metabolism study.

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Laura Moreno-López

Full Text Available INTRODUCTION: Functional imaging studies of addiction following protracted abstinence have not been systematically conducted to look at the associations between severity of use of different drugs and brain dysfunction. Findings from such studies may be relevant to implement specific interventions for treatment. The aim of this study was to examine the association between resting-state regional brain metabolism (measured with 18F-fluorodeoxyglucose Positron Emission Tomography (FDG-PET and the severity of use of cocaine, heroin, alcohol, MDMA and cannabis in a sample of polysubstance users with prolonged abstinence from all drugs used. METHODS: Our sample consisted of 49 polysubstance users enrolled in residential treatment. We conducted correlation analyses between estimates of use of cocaine, heroin, alcohol, MDMA and cannabis and brain metabolism (BM (using Statistical Parametric Mapping voxel-based (VB whole-brain analyses. In all correlation analyses conducted for each of the drugs we controlled for the co-abuse of the other drugs used. RESULTS: The analysis showed significant negative correlations between severity of heroin, alcohol, MDMA and cannabis use and BM in the dorsolateral prefrontal cortex (DLPFC and temporal cortex. Alcohol use was further associated with lower metabolism in frontal premotor cortex and putamen, and stimulants use with parietal cortex. CONCLUSIONS: Duration of use of different drugs negatively correlated with overlapping regions in the DLPFC, whereas severity of cocaine, heroin and alcohol use selectively impact parietal, temporal, and frontal-premotor/basal ganglia regions respectively. The knowledge of these associations could be useful in the clinical practice since different brain alterations have been associated with different patterns of execution that may affect the rehabilitation of these patients.

Cocaine-Associated Myocardial Infarction: Should They All Be Stented?

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Sazzli Kasim

2011-01-01

Full Text Available Cocaine use is a known cause of chest pain and acute myocardial infarction and frequently leads to cardiac catheterization procedure. The treatment of cocaine-related acute coronary syndromes presents unique challenges because a variety of mechanisms including atherosclerotic plaque rupture, platelet activation, and coronary vasospasm may contribute to the pathogenesis. Our case highlights important considerations taken in dealing with this acute scenario

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

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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.

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

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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

Addiction-Related Effects of DOV 216,303 and Cocaine

DEFF Research Database (Denmark)

Sørensen, Gunnar; Husum, Henriette; Brennum, Lise T

2014-01-01

DOV 216,303, an inhibitor of serotonin, noradrenaline and dopamine reuptake, belongs to a new line of drugs called 'triple reuptake inhibitors' that have been proposed for treatment of depression. The addictive drug cocaine has similar mechanism of action and exerts rewarding effects by blocking...... of DOV 216,303, we conducted a comparative study of addiction-related effects of DOV 216,303 and cocaine in mice using acute self-administration, conditioned place preference (CPP) and drug-induced hyperlocomotion. Effects on accumbal extracellular dopamine levels were determined using microdialysis......, and we measured monoamine receptor occupancy as well as brain and plasma exposure. DOV 216,303 was self-administered acutely in the same dose range as cocaine. However, in the CPP model, DOV 216,303 did not induce place preference at doses where cocaine caused place preference. Higher doses of DOV 216...

Cocaine withdrawal

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

β-Blockers, Cocaine, and the Unopposed α-Stimulation Phenomenon.

Science.gov (United States)

Richards, John R; Hollander, Judd E; Ramoska, Edward A; Fareed, Fareed N; Sand, I Charles; Izquierdo Gómez, María Manuela; Lange, Richard A

2017-05-01

Cocaine abuse remains a significant worldwide health problem. Patients with cardiovascular toxicity from cocaine abuse frequently present to the emergency department for treatment. These patients may be tachycardic, hypertensive, agitated, and have chest pain. Several pharmacological options exist for treatment of cocaine-induced cardiovascular toxicity. For the past 3 decades, the phenomenon of unopposed α-stimulation after β-blocker use in cocaine-positive patients has been cited as an absolute contraindication, despite limited and inconsistent clinical evidence. In this review, the authors of the original studies, case reports, and systematic review in which unopposed α-stimulation was believed to be a factor investigate the pathophysiology, pharmacology, and published evidence behind the unopposed α-stimulation phenomenon. We also investigate other potential explanations for unopposed α-stimulation, including the unique and deleterious pharmacologic properties of cocaine in the absence of β-blockers. The safety and efficacy of the mixed β-/α-blockers labetalol and carvedilol are also discussed in relation to unopposed α-stimulation.

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.

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...

Dehydroepiandrosterone Attenuates Cocaine-Seeking Behaviour Independently of Corticosterone Fluctuations.

Science.gov (United States)

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

2015-11-01

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

Cocaine addiction: from habits to stereotypical-repetitive behaviors and punding.

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Fasano, Alfonso; Barra, Andrea; Nicosia, Paola; Rinaldi, Federica; Bria, Pietro; Bentivoglio, Anna Rita; Tonioni, Federico

2008-07-01

"Punding" is a stereotypical motor behavior characterized by an intense fascination with repetitive handling and examining of objects. Since its first description in amphetamine and cocaine addicts, data on punding has only derived from studies performed in patients with Parkinson's disease (PD). Punding is classifiable as the most severe form of Repetitive Reward-Seeking Behaviours (RRSB) syndromes. The aim of this study was to investigate the occurrence and phenomelogy of RRSB acutely induced by cocaine in order to determine the prevalence, severity and distinctive features discriminating "punders" from "non-punders". A consecutive sample of 50 cocaine addicts received a clinical psychiatric interview. RRSB diagnosis and severity were assessed using a modified version of a previous published questionnaire designed to identify punding in patients with PD. In the present series, 38% of the cocaine addicts met the proposed diagnostic criteria for a RRSB and 8% were considered punders. Subjects with vs. without RRSB did not differ in terms of sex ratio, age, education, occupation, predisposing habits, duration of cocaine use, hours of sleep, comorbid psychiatric disorders, and concomitant use of other drugs. These results and the observation that in the majority of cases RRSB started soon after first drug intake, strongly suggest that an underlying unknown predisposition led to the development of these behaviors. In conclusion, RRSB and punding is much more common than has been described previously and the resultant social disability is often overlooked.

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

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

2014-02-01

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

A review of instruments for screening and diagnosis of cocaine use

NARCIS (Netherlands)

Barrio, P.; López-Pelayo, H.; Schellekens, A.F.A.; Batalla, A.; Preedy, V.R.

2017-01-01

Cocaine is the second most used illicit drug worldwide. Identification of cocaine use disorders (CUD) and related aspects such as craving and CUD severity are relevant for clinical practice, public health programs, and research. There are a wide variety of instruments available for assessing CUD,

The Neuropsychology of Cocaine Addiction: Recent Cocaine Use Masks Impairment

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Woicik, Patricia A; Moeller, Scott J; Alia-Klein, Nelly; Maloney, Thomas; Lukasik, Tanya M; Yeliosof, Olga; Wang, Gene-Jack; Volkow, Nora D; Goldstein, Rita Z

2009-01-01

Individuals with current cocaine use disorders (CUD) form a heterogeneous group, making sensitive neuropsychological (NP) comparisons with healthy individuals difficult. The current study examined the effects on NP functioning of four factors that commonly vary among CUD: urine status for cocaine (positive vs negative on study day), cigarette smoking, alcohol consumption, and dysphoria. Sixty-four cocaine abusers were matched to healthy comparison subjects on gender and race; the groups also did not differ in measures of general intellectual functioning. All subjects were administered an extensive NP battery measuring attention, executive function, memory, facial and emotion recognition, and motor function. Compared with healthy control subjects, CUD exhibited performance deficits on tasks of attention, executive function, and verbal memory (within one standard deviation of controls). Although CUD with positive urine status, who had higher frequency and more recent cocaine use, reported greater symptoms of dysphoria, these cognitive deficits were most pronounced in the CUD with negative urine status. Cigarette smoking, frequency of alcohol consumption, and dysphoria did not alter these results. The current findings replicate a previously reported statistically significant, but relatively mild NP impairment in CUD as compared with matched healthy control individuals and further suggest that frequent/recent cocaine may mask underlying cognitive (but not mood) disturbances. These results call for development of pharmacological agents targeted to enhance cognition, without negatively impacting mood in individuals addicted to cocaine. PMID:18496524

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

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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.

Vascular disease in cocaine addiction.

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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.

[Cocaine - Characteristics and addiction].

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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.

Bowel ischaemia and cocaine consumption: case study and review of the literature

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Almudena Martínez-Vieira

2014-05-01

Full Text Available Background: Amongst others, cocaine consumption has a detrimental effect in the vascular supply to the mesenteric area causing abdominal ischemic changes. Early recognition of these changes and adequate treatment are essential to avoid serious complications and possible death of the patient from sepsis. Case report: In this case study, the subject is a 40-years-old gentleman presenting with acute abdominal pain due to multiple ischemic changes in both small bowel and sigmoid loops. The patient required emergency surgical intervention consisting of bowel resection and anastomosis. The pathologic analysis of the segment showed transmural necrosis and necrotizing phlebitis caused by the ingestion of drugs or toxic agents. The patient later confirmed the habitual consumption of cocaine. Discussion: The increase in cocaine consumption and other recreational toxins substructed from erythroyilon coca alcaloids amongst young people have generated a large number of admissions to Hospital Accident and Emergency Departments with patients complaining of acute abdominal pain. In many of these cases, surgical intervention is required and in some cases patients will sadly die without a proper diagnosis. Some of the most common effects of cocaine and its compounds includes; hollow viscus perforation, gastro-intestinal bleed, and other vascular problems such as enteritis and ischemic colitis. It appears clear that there is a great need for an advance history taking of these patients and their habit to cocaine and other drugs together with a urine test for drug screening. These together with a suspicion of a non- occlusive ischemic bowel caused by the effects of cocaine in young adults with no cardiac risk factors will guide clinicians and establish, and plan the correct treatment for these categories of patients.

Polysomnographic Sleep Dysregulation in Cocaine Dependence

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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.

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

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

2012-12-01

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

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

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

2002-06-01

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

[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

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

Science.gov (United States)

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

2012-01-01

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

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

Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity

Energy Technology Data Exchange (ETDEWEB)

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

2015-08-01

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

Prenatal IV Cocaine: Alterations in Auditory Information Processing

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Charles F. Mactutus

2011-06-01

Full Text Available One clue regarding the basis of cocaine-induced deficits in attentional processing is provided by the clinical findings of changes in the infants’ startle response; observations buttressed by neurophysiological evidence of alterations in brainstem transmission time. Using the IV route of administration and doses that mimic the peak arterial levels of cocaine use in humans, the present study examined the effects of prenatal cocaine on auditory information processing via tests of the acoustic startle response (ASR, habituation, and prepulse inhibition (PPI in the offspring. Nulliparous Long-Evans female rats, implanted with an IV access port prior to breeding, were administered saline, 0.5, 1.0, or 3.0 mg/kg/injection of cocaine HCL (COC from gestation day (GD8-20 (1x/day-GD8-14, 2x/day-GD15-20. COC had no significant effects on maternal/litter parameters or growth of the offspring. At 18-20 days of age, one male and one female, randomly selected from each litter displayed an increased ASR (>30% for males at 1.0 mg/kg and >30% for females at 3.0 mg/kg. When reassessed in adulthood (D90-100, a linear dose-response increase was noted on response amplitude. At both test ages, within-session habituation was retarded by prenatal cocaine treatment. Testing the females in diestrus vs. estrus did not alter the results. Prenatal cocaine altered the PPI response function across interstimulus interval (ISI and induced significant sex-dependent changes in response latency. Idazoxan, an alpha2-adrenergic receptor antagonist, significantly enhanced the ASR, but less enhancement was noted with increasing doses of prenatal cocaine. Thus, in utero exposure to cocaine, when delivered via a protocol designed to capture prominent features of recreational usage, causes persistent, if not permanent, alterations in auditory information processing, and suggests dysfunction of the central noradrenergic circuitry modulating, if not mediating, these responses.

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

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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

Clonidine blocks stress-induced craving in cocaine users.

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Jobes, Michelle L; Ghitza, Udi E; Epstein, David H; Phillips, Karran A; Heishman, Stephen J; Preston, Kenzie L

2011-11-01

Reactivity to stressors and environmental cues, a putative cause of relapse in addiction, may be a useful target for relapse-prevention medication. In rodents, alpha-2 adrenergic agonists such as clonidine block stress-induced reinstatement of drug seeking, but not drug cue-induced reinstatement. The objective of this study is to test the effect of clonidine on stress- and cue-induced craving in human cocaine users. Healthy, non-treatment-seeking cocaine users (n = 59) were randomly assigned to three groups receiving clonidine 0, 0.1, or 0.2 mg orally under double-blind conditions. In a single test session, each participant received clonidine or placebo followed 3 h later by exposure to two pairs of standardized auditory-imagery scripts (neutral/stress and neutral/drug). Subjective measures of craving were collected. Subjective responsivity ("crave cocaine" Visual Analog Scale) to stress scripts was significantly attenuated in the 0.1- and 0.2-mg clonidine groups; for drug-cue scripts, this attenuation occurred only in the 0.2-mg group. Other subjective measures of craving showed similar patterns of effects but Dose × Script interactions were not significant. Clonidine was effective in reducing stress-induced (and, at a higher dose, cue-induced) craving in a pattern consistent with preclinical findings, although this was significant on only one of several measures. Our results, though modest and preliminary, converge with other evidence to suggest that alpha-2 adrenergic agonists may help prevent relapse in drug abusers experiencing stress or situations that remind them of drug use.

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

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

2014-09-01

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

Immunization for prevention and treatment of cocaine abuse: legal and ethical implications.

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Cohen, P J

1997-12-15

A cocaine vaccine, currently under investigation by several laboratories, would be an innovative and exciting means of treating and preventing cocaine addiction. However, an approved vaccine will raise at least two major areas of concern. (1) Loss of privacy: cocaine antibodies might be used as a marker to identify, penalize, and stigmatize vaccinated individuals. (2) Selection for vaccination: should immunization be voluntary or compelled: should immunization be restricted to addicts, to those at risk of addiction, or should it be universal; should immunization be used in children? I propose to analogize cocaine addiction to an infectious disease which poses a major public health problem. This approach can provide an ethical and legal foundation on which we may begin to formulate a societal approach to the use of the cocaine vaccine.

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

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

2010-01-01

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

Persistence of drug use during imprisonment: relationship of drug type, recency of use and severity of dependence to use of heroin, cocaine and amphetamine in prison.

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Strang, John; Gossop, Michael; Heuston, Joan; Green, John; Whiteley, Christopher; Maden, Anthony

2006-08-01

To investigate the persistence of use of heroin, cocaine and amphetamine drugs during imprisonment, and to identify factors associated with increased levels of persistence. The use of heroin, cocaine and amphetamine by current prison inmates has been examined and, in particular, the relationship between drug use within prison and the type of drug used prior to imprisonment, recency of use and severity of dependence. A randomly selected sample of 1009 adult male prisoners in 13 prisons in England and Wales during 1994/95; structured confidential interviews conducted by independent research staff. Enquiry about prior use of heroin, cocaine or amphetamine focused on three time-periods (ever, last year and last month pre-prison) and the use of these drugs during the first month of imprisonment. A total of 557 (55%) of the 1009 prisoners had used previously one of the three drugs selected for study: 58% had used heroin, 69% cocaine and 75% amphetamine. More than half (59%; 327/557) had used these drugs in the month before the current imprisonment. Drug use in prisons was most likely to occur among those who had used in the month prior to imprisonment. The persistence of heroin use in prison occurred more frequently (70%) than use of cocaine (20%) or amphetamine (15%). Of those using heroin pre-imprisonment, 67% considered they were dependent, compared to 15% and 22%, respectively, for cocaine and amphetamine users. Changes in the drug-taking behaviour of drug users after imprisonment vary according to the type of drug being taken. Prisoners were much more likely to continue to use heroin than either cocaine or amphetamines while in prison. Heroin was most likely to be used by those who had been using heroin during the immediate pre-imprisonment period, and particularly by the two-thirds of heroin users who considered themselves dependent. In view of the high prevalence of prior use of these drugs by individuals currently imprisoned, continuing attention is required to

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

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

2015-01-01

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

Cocaine – Characteristics and addiction

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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

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

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Eirik Søvik

2014-11-01

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

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

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

2015-01-01

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

Interactive Effects of Cocaine on HIV Infection: Implication in HIV-Associated Neurocognitive Disorder and NeuroAIDS

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Santosh eDahal

2015-09-01

Full Text Available Substantial epidemiological studies suggest that not only, being one of the reasons for the transmission of the human immunodeficiency virus (HIV, but drug abuse also serves its role in determining the disease progression and severity among the HIV infected population. This article focuses on the drug cocaine, and its role in facilitating entry of HIV into the CNS and mechanisms of development of neurologic complications in infected individuals. Cocaine is a powerfully addictive central nervous system stimulating drug, which increases the level of neurotransmitter dopamine in the brain, by blocking the dopamine transporters (DAT which is critical for dopamine homeostasis and neurocognitive function. Tat protein of HIV acts as an allosteric modulator of DAT, where as cocaine acts as reuptake inhibitor. When macrophages in the CNS are exposed to dopamine, their number increases. These macrophages release inflammatory mediators and neurotoxins, causing chronic neuroinflammation. Cocaine abuse during HIV infection enhances the production of platelet monocyte complexes (PMCs, which may cross transendothelial barrier, and result in HIV-associated neurocognitive disorder (HAND. HAND is characterized by neuroinflammation, including astrogliosis, multinucleated giant cells, and neuronal apoptosis that is linked to progressive virus infection and immune deterioration. Cocaine and viral proteins are capable of eliciting signaling transduction pathways in neurons, involving in mitochondrial membrane potential loss, oxidative stress, activation of JNK, p38, and ERK/MAPK pathways, and results in downstream activation of NF-κB that leads to HAND. Tat-induced inflammation provokes permeability of the Blood Brain Barrier (BBB in the platelet dependent manner, which can potentially be the reason for progression to HAND during HIV infection. A better understanding on the role of cocaine in HIV infection can give a clue in developing novel therapeutic strategies

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.

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

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Jessica L. Bolton

2018-02-01

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

An exploratory study of information sources and key findings on UK cocaine-related deaths.

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Corkery, John M; Claridge, Hugh; Goodair, Christine; Schifano, Fabrizio

2017-08-01

Cocaine-related deaths have increased since the early 1990s in Europe, including the UK. Being multi-factorial, they are difficult to define, detect and record. The European Monitoring Centre for Drugs and Drug Addiction commissioned research to: describe trends reported to Special Mortality Registries and General Mortality Registers; provide demographic and drug-use characteristic information of cases; and establish how deaths are identified and classified. A questionnaire was developed and piloted amongst all European Monitoring Centre for Drugs and Drug Addiction Focal Point experts/Special Mortality Registries: 19 (63%) responded; nine countries provided aggregated data. UK General Mortality Registers use cause of death and toxicology to identify cocaine-related deaths. Categorisation is based on International Classification of Diseases codes. Special Mortality Registries use toxicology, autopsy, evidence and cause of death. The cocaine metabolites commonly screened for are: benzoylecgonine, ecgonine methyl ester, cocaethylene and ecgonine. The 2000s saw a generally accelerating upward trend in cases, followed by a decline in 2009. The UK recorded 2700-2900 deaths during 1998-2012. UK Special Mortality Registry data (2005-2009) indicate: 25-44 year-olds account for 74% of deaths; mean age=34 (range 15-81) years; 84% male. Cocaine overdoses account for two-thirds of cases; cocaine alone being mentioned/implicated in 23% in the UK. Opioids are involved in most (58%) cocaine overdose cases.

Effects of anti-cocaine vaccine and viral gene transfer of cocaine hydrolase in mice on cocaine toxicity including motor strength and liver damage.

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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.

Cocaine enhances the conditioned rewarding effects of MDMA in adolescent mice.

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Aguilar, M A; Roger-Sánchez, C; Rodríguez-Arias, M; Miñarro, J

2015-04-01

Although the consumption of cocaine is frequent in young users of MDMA (3,4-methylenedioxymethamphetamine), the influence of exposure to cocaine on the rewarding effects of MDMA in adolescents has not been studied. The purpose of the present work was to evaluate the effect of co-administration of cocaine (1 and 10 mg/kg) and a sub-threshold dose of MDMA (1.25 mg/kg) on the acquisition of conditioned place preference (CPP) (experiment 1). In addition, the effect of pre-treatment with cocaine on MDMA-induced CPP was evaluated (experiment 2). Levels of monoamines in striatum, hippocampus and cortex were measured in both experiments. Our hypotheses were that cocaine co-administration or pre-treatment would increase the rewarding effects of MDMA, and that these effects would be related with changes in brain monoamine levels. Our results showed that cocaine potentiated the rewarding effects of MDMA, since a sub-threshold dose of MDMA, which did not induce CPP by itself, induced a significant CPP in adolescent mice when administered along with cocaine during conditioning (experiment 1). Moreover, pre-treatment with cocaine several days before conditioning also increased the rewarding effects of MDMA (experiment 2). No significant changes in the levels of biogenic amines, which correlated with these behavioural effects, were observed. Our results confirm the involvement of the dopaminergic system in MDMA-induced CPP in adolescent mice and suggest that combined consumption with or pre-exposure to cocaine increases the conditioned rewarding effects of MDMA, which may enhance the capacity of MDMA to induce dependence. Copyright © 2015 Elsevier Inc. All rights reserved.

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

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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.

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

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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).

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

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

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

2017-06-01

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

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.

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

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

2016-05-01

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

Attention deficit hyperactivity disorder in cocaine-dependent adults: a psychiatric comorbidity analysis.

Science.gov (United States)

Daigre, Constanza; Roncero, Carlos; Grau-López, Lara; Martínez-Luna, Nieves; Prat, Gemma; Valero, Sergi; Tejedor, Rosa; Ramos-Quiroga, Josep A; Casas, Miguel

2013-01-01

Attention deficit hyperactivity disorder (ADHD) is highly prevalent among drug abusers. We studied the psychiatric comorbidity and characteristics of cocaine use in relation to the presence of ADHD among patients with cocaine dependence. A total of 200 cocaine-dependent patients attending an Outpatient Drug Clinic participated in the study. A systematic evaluation of ADHD (CAADID-II), the severity of addiction (EuropASI) and other axes I and II psychiatric disorders was made (SCID-I and SCID-II). A descriptive, bivariate, and multivariate analysis of the data was performed. In the multivariate analysis, the identified risk factors for the development of ADHD were a history of behavioral disorder in childhood (OR: 3.04), a lifetime history of cannabis dependence in the course of life (OR: 2.68), and age at the start of treatment (OR: 1.08). The bivariate analysis showed ADHD to be associated with other factors such as male gender, age at start of cocaine use and dependence, the amount of cocaine consumed weekly, increased occupational alteration, alcohol consumption, general psychological discomfort, depressive disorder, and antisocial personality disorder. We conclude that ADHD is associated with increased psychiatric comorbidity and greater severity of addiction. Copyright © American Academy of Addiction Psychiatry.

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

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

2016-01-01

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

Manipulating a "cocaine engram" in mice.

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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.

Characterization of differential cocaine metabolism in mouse and rat through metabolomics-guided metabolite profiling.

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Yao, Dan; Shi, Xiaolei; Wang, Lei; Gosnell, Blake A; Chen, Chi

2013-01-01

Rodent animal models have been widely used for studying neurologic and toxicological events associated with cocaine abuse. It is known that the mouse is more susceptible to cocaine-induced hepatotoxicity (CIH) than the rat. However, the causes behind this species-dependent sensitivity to cocaine have not been elucidated. In this study, cocaine metabolism in the mouse and rat was characterized through LC-MS-based metabolomic analysis of urine samples and were further compared through calculating the relative abundance of individual cocaine metabolites. The results showed that the levels of benzoylecgonine, a major cocaine metabolite from ester hydrolysis, were comparable in the urine from the mice and rats treated with the same dose of cocaine. However, the levels of the cocaine metabolites from oxidative metabolism, such as N-hydroxybenzoylnorecgonine and hydroxybenzoylecgonine, differed dramatically between the two species, indicating species-dependent cocaine metabolism. Subsequent structural analysis through accurate mass analysis and LC-MS/MS fragmentation revealed that N-oxidation reactions, including N-demethylation and N-hydroxylation, are preferred metabolic routes in the mouse, while extensive aryl hydroxylation reactions occur in the rat. Through stable isotope tracing and in vitro enzyme reactions, a mouse-specific α-glucoside of N-hydroxybenzoylnorecgonine and a group of aryl hydroxy glucuronides high in the rat were identified and structurally elucidated. The differences in the in vivo oxidative metabolism of cocaine between the two rodent species were confirmed by the in vitro microsomal incubations. Chemical inhibition of P450 enzymes further revealed that different P450-mediated oxidative reactions in the ecgonine and benzoic acid moieties of cocaine contribute to the species-dependent biotransformation of cocaine.

Sensing cocaine in saliva with infrared laser spectroscopy

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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.

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

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

2010-12-01

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

Mirtazapine attenuates cocaine seeking in rats.

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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.

Reduced frontal brain volume in non-treatment-seeking cocaine-dependent individuals: exploring the role of impulsivity, depression, and smoking.

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

2014-01-01

In cocaine-dependent patients, gray matter (GM) volume reductions have been observed in the frontal lobes that are associated with the duration of cocaine use. Studies are mostly restricted to treatment-seekers and studies in non-treatment-seeking cocaine abusers are sparse. Here, we assessed GM volume differences between 30 non-treatment-seeking cocaine-dependent individuals and 33 non-drug using controls using voxel-based morphometry. Additionally, within the group of non-treatment-seeking cocaine-dependent individuals, we explored the role of frequently co-occurring features such as trait impulsivity (Barratt Impulsivity Scale, BIS), smoking, and depressive symptoms (Beck Depression Inventory), as well as the role of cocaine use duration, on frontal GM volume. Smaller GM volumes in non-treatment-seeking cocaine-dependent individuals were observed in the left middle frontal gyrus. Moreover, within the group of cocaine users, trait impulsivity was associated with reduced GM volume in the right orbitofrontal cortex, the left precentral gyrus, and the right superior frontal gyrus, whereas no effect of smoking severity, depressive symptoms, or duration of cocaine use was observed on regional GM volumes. Our data show an important association between trait impulsivity and frontal GM volumes in cocaine-dependent individuals. In contrast to previous studies with treatment-seeking cocaine-dependent patients, no significant effects of smoking severity, depressive symptoms, or duration of cocaine use on frontal GM volume were observed. Reduced frontal GM volumes in non-treatment-seeking cocaine-dependent subjects are associated with trait impulsivity and are not associated with co-occurring nicotine dependence or depression.

Location-specific immunodetection of cocaine on banknotes.

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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.

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

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

2013-12-01

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

Reversal of Cocaine-Associated Synaptic Plasticity in Medial Prefrontal Cortex Parallels Elimination of Memory Retrieval.

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Otis, James M; Mueller, Devin

2017-09-01

Addiction is characterized by abnormalities in prefrontal cortex that are thought to allow drug-associated cues to drive compulsive drug seeking and taking. Identification and reversal of these pathologic neuroadaptations are therefore critical for treatment of addiction. Previous studies using rodents reveal that drugs of abuse cause dendritic spine plasticity in prelimbic medial prefrontal cortex (PL-mPFC) pyramidal neurons, a phenomenon that correlates with the strength of drug-associated memories in vivo. Thus, we hypothesized that cocaine-evoked plasticity in PL-mPFC may underlie cocaine-associated memory retrieval, and therefore disruption of this plasticity would prevent retrieval. Indeed, using patch clamp electrophysiology we find that cocaine place conditioning increases excitatory presynaptic and postsynaptic transmission in rat PL-mPFC pyramidal neurons. This was accounted for by increases in excitatory presynaptic release, paired-pulse facilitation, and increased AMPA receptor transmission. Noradrenergic signaling is known to maintain glutamatergic plasticity upon reactivation of modified circuits, and we therefore next determined whether inhibition of noradrenergic signaling during memory reactivation would reverse the cocaine-evoked plasticity and/or disrupt the cocaine-associated memory. We find that administration of the β-adrenergic receptor antagonist propranolol before memory retrieval, but not after (during memory reconsolidation), reverses the cocaine-evoked presynaptic and postsynaptic modifications in PL-mPFC and causes long-lasting memory impairments. Taken together, these data reveal that cocaine-evoked synaptic plasticity in PL-mPFC is reversible in vivo, and suggest a novel strategy that would allow normalization of prefrontal circuitry in addiction.

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

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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.

Recurrent Levamisole-Induced Agranulocytosis Complicated by Bowel Ischemia in a Cocaine User.

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Khan, Mohammad Saud; Khan, Zubair; Khateeb, Faisal; Moustafa, Abdelmoniem; Taleb, Mohammad; Yoon, Youngsook

2018-06-01

BACKGROUND Levamisole is a common adulterant of cocaine and up to 69% of seized cocaine in United States contains levamisole. It is a synthetic imidazothiazole derivative which was previously used as an immunomodulating agent for treatment of various connective tissue disorders and colorectal carcinoma. However, it was withdrawn later from the market due to significant toxicity associated with it. CASE REPORT We present the case of a 59-year-old male patient with a history of active cocaine use who presented to the hospital with febrile neutropenia and agranulocytosis. He underwent extensive work-up for neutropenia and was suspected to have it secondary to levamisole-adulterated cocaine. He was treated with antibiotics and granulocyte-stimulating factor. His white cell count improved and he was discharged home. He continued to use cocaine after discharge from the hospital. He returned to the hospital 3 weeks later with recurrent neutropenia and agranulocytosis complicated by septic shock and bowel necrosis which required prolonged antibiotics and a bowel resection. CONCLUSIONS Levamisole-induced agranulocytosis should be considered in patients who present with neutropenia and a history of cocaine use. Physicians should have high clinical suspicion and consider it a potential etiology of agranulocytosis when other causes have been excluded.

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

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

2014-03-01

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

Evidence on unusual way of cocaine smuggling: cocaine-polymethyl methacrylate (PMMA) solid solution--study of clandestine laboratory samples.

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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

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

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

2011-05-01

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

Cocaine in the UK--1991.

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Strang, J; Johns, A; Caan, W

1993-01-01

More than 100 years after Freud's original endorsement of the drug, the use of cocaine is a problem for both users and for society, which struggles to organise effective responses to the epidemic of the last decade. During the 1980s the rapid spread of smokeable cocaine (including 'crack') was seen in the Americas (particularly the US). The initial simple predictions of an identical European epidemic were mistaken. The available data on the extent of cocaine use and of cocaine problems in the UK are examined. New forms of cocaine have been developed by black-market entrepreneurs ('freebase' and 'crack'), and new technologies have emerged for their use; with these new technologies have come new effects and new problems. The general psychiatrist now needs a knowledge of directly and indirectly related psychopathology which has an increasing relevance to the diagnosis and management of the younger patient.

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

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

2012-06-01

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

Hormones, Nicotine and Cocaine: Clinical Studies

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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

Signs of Cocaine Abuse and Addiction

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... Used Drugs in the Past Drug Use Prevention Phone Numbers and Websites Search Share You are here Home » Drugs That People Abuse » Cocaine (Coke, Crack) Facts » Signs of Cocaine Use and Addiction Signs of Cocaine Use and Addiction Listen ©istock. ...

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

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Alireza Hosseinnezhad

2011-05-01

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

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

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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.

Reduced attentional scope in cocaine polydrug users.

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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.

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

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

2011-03-01

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

Crack/cocaine users show more family problems than other substance users

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Helena Ferreira Moura

2014-07-01

Full Text Available OBJECTIVES:To evaluate family problems among crack/cocaine users compared with alcohol and other substance users.METHODS:A cross-sectional multi-center study selected 741 current adult substance users from outpatient and inpatient Brazilian specialized clinics. Subjects were evaluated with the sixth version of the Addiction Severity Index, and 293 crack users were compared with 126 cocaine snorters and 322 alcohol and other drug users.RESULTS:Cocaine users showed more family problems when compared with other drug users, with no significant difference between routes of administration. These problems included arguing (crack 66.5%, powder cocaine 63.3%, other drugs 50.3%, p= 0.004, having trouble getting along with partners (61.5%×64.6%×48.7%, p= 0.013, and the need for additional childcare services in order to attend treatment (13.3%×10.3%×5.1%, p= 0.002. Additionally, the majority of crack/cocaine users had spent time with relatives in the last month (84.6%×86.5%×76.6%, p= 0.011.CONCLUSIONS:Brazilian treatment programs should enhance family treatment strategies, and childcare services need to be included.

Multiple Gastrointestinal Complications of Crack Cocaine Abuse

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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.

The role of acetylcholine in cocaine addiction.

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Williams, Mark J; Adinoff, Bryon

2008-07-01

Central nervous system cholinergic neurons arise from several discrete sources, project to multiple brain regions, and exert specific effects on reward, learning, and memory. These processes are critical for the development and persistence of addictive disorders. Although other neurotransmitters, including dopamine, glutamate, and serotonin, have been the primary focus of drug research to date, a growing preclinical literature reveals a critical role of acetylcholine (ACh) in the experience and progression of drug use. This review will present and integrate the findings regarding the role of ACh in drug dependence, with a primary focus on cocaine and the muscarinic ACh system. Mesostriatal ACh appears to mediate reinforcement through its effect on reward, satiation, and aversion, and chronic cocaine administration produces neuroadaptive changes in the striatum. ACh is further involved in the acquisition of conditional associations that underlie cocaine self-administration and context-dependent sensitization, the acquisition of associations in conditioned learning, and drug procurement through its effects on arousal and attention. Long-term cocaine use may induce neuronal alterations in the brain that affect the ACh system and impair executive function, possibly contributing to the disruptions in decision making that characterize this population. These primarily preclinical studies suggest that ACh exerts a myriad of effects on the addictive process and that persistent changes to the ACh system following chronic drug use may exacerbate the risk of relapse during recovery. Ultimately, ACh modulation may be a potential target for pharmacological treatment interventions in cocaine-addicted subjects. However, the complicated neurocircuitry of the cholinergic system, the multiple ACh receptor subtypes, the confluence of excitatory and inhibitory ACh inputs, and the unique properties of the striatal cholinergic interneurons suggest that a precise target of cholinergic

Cardiotoxic effects of cocaine and anabolic-androgenic steroids in the athlete.

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Welder, A A; Melchert, R B

1993-04-01

Cocaine and anabolic-androgenic steroid abuse have become major drug problems in the United States. Cocaine has been designated as "the drug of greatest national health concern" while as many as 1 million Americans have used or are currently using anabolic-androgenic steroids to promote athletic performance and/or improve physical appearance. Unfavorable cardiovascular events have been linked to both cocaine and anabolic-androgenic steroid abuse in healthy, physically active individuals. Deaths of several United States athletes in 1986 focused attention on the life-threatening cardiovascular consequences of cocaine abuse. Reports of myocardial injury with anabolic-androgenic steroid abuse are anecdotal. Nevertheless, case reports have illustrated the alarming cardiotoxic potential of these steroids in athletes. Anabolic-androgenic steroids were correlated to myocardial infarction in weight lifters and cardiomyopathy in a former professional football player. From the total emergency room episodes where cocaine was mentioned in 1990, approximately 66% of these episodes occurred in young individuals 18-29 years of age. Over 500,000 of the individuals currently taking anabolic-androgenic steroids for nonmedical purposes are high-school children. Because cocaine and anabolic-androgenic steroids are used improperly, more focus needs to be paid to the toxic mechanisms of their adverse effects. Therefore, the purpose of this review is to discuss mechanisms whereby exercise and/or exercise training may alter the cardiovascular responses to these drugs. Furthermore, we would like to illustrate that contrary to the popular belief, acute and chronic abuse of cocaine and anabolic-androgenic steroids have a negative impact on exercise performance.

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

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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.

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

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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.

[Sucrose reward promotes rats' motivation for cocaine].

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Li, Yan-Qing; LE, Qiu-Min; Yu, Xiang-Chen; Ma, Lan; Wang, Fei-Fei

2016-06-25

Caloric diet, such as fat and sugar intake, has rewarding effects, and has been indicated to affect the responses to addictive substances in animal experiments. However, the possible association between sucrose reward and the motivation for addictive drugs remains to be elucidated. Thus, we carried out behavioral tests after sucrose self-administration training to determine the effects of sucrose experience on rats' motivation for cocaine, locomotor sensitivity to cocaine, basal locomotor activity, anxiety level, and associative learning ability. The sucrose-experienced (sucrose) group exhibited higher lever press, cocaine infusion and break point, as well as upshift of cocaine dose-response curve in cocaine self-administration test, as compared with the control (chow) group. Additionally, despite similar locomotor activity in open field test and comparable score in cocaine-induced conditioned place preference, the sucrose group showed higher cocaine-induced locomotor sensitivity as compared with the chow group. The anxiety level and the performance in vocal-cue induced fear memory were similar between these two groups in elevated plus maze and fear conditioning tests, respectively. Taken together, our work indicates that sucrose experience promotes the rats' motivation for cocaine.

Functions of microRNA in response to cocaine stimulation.

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Xu, L-F; Wang, J; Lv, F B; Song, Q

2013-12-04

MicroRNAs (miRNAs) are a type of non-protein-coding single-stranded RNA, which are typically 20-25 nt in length. miRNAs play important roles in various biological processes, including development, cell proliferation, differentiation, and apoptosis. We aimed to detect the miRNA response to cocaine stimulations and their target genes. Using the miRNA expression data GSE21901 downloaded from the Gene Expression Omnibus database, we screened out the differentially expressed miRNA after short-term (1 h) and longer-term (6 h) cocaine stimulations based on the fold change >1.2. Target genes of differentially expressed miRNAs were retrieved from TargetScan database with the context score -0.3. Functional annotation enrichment analysis was performed for all the target genes with DAVID. A total of 121 differentially expressed miRNAs between the 1-h treatment and the control samples, 58 between the 6-h treatment and the control samples, and 69 between the 1-h and the 6-h treatment samples. Among them, miR-212 results of particular interest, since its expression level was constantly elevated responding to cocaine treatment. After functional and pathway annotations of target genes, we proved that miR-212 was a critical element in cocaine-addiction, because of its involvement in regulating several important cell cycle events. The results may pave the way for further understanding the regulatory mechanisms of cocaine-response in human bodies.

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

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

2016-08-01

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

MDMA reinstates cocaine-seeking behaviour in mice.

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Trigo, José Manuel; Orejarena, Maria Juliana; Maldonado, Rafael; Robledo, Patricia

2009-06-01

MDMA effects are mediated by monoaminergic systems, which seem to play a central role in cocaine craving and relapse. CD1 mice trained to self-administer cocaine (1 mg/kg/infusion) underwent an extinction procedure in which the cues contingent with drug self-administration remained present. Mice achieving extinction were injected with MDMA (10 mg/kg), d-amphetamine (1 and 2 mg/kg) or saline and tested for reinstatement. Acute MDMA, but not d-amphetamine or saline reinstated cocaine-seeking behaviour in mice in which cocaine self-administration and contingent cues were previously extinguished. Acute MDMA can reinstate cocaine-seeking behaviour in mice.

Cocaine

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Malignant hypertension-associated thrombotic microangiopathy following cocaine use.

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Lamia, Rais; El Ati, Zohra; Ben Fatma, Lilia; Zouaghi, Karim; Smaoui, Wided; Rania, Khedher; Krid, Madiha; Ben Hmida, Fathi; Béji, Soumaya; Ben Moussa, Fatma

2016-01-01

Cocaine is one of the most commonly used illicit drugs with distribution and consumption throughout the world. Acute renal failure associated with rhabdomyolysis, direct vasoconstriction and hemodynamic alteration is well described in patients with cocaine intoxication. Cocaine use is associated with high blood pressure and may rarely induce malignant hypertension associated with thrombotic microangiopathy. We report the case of a patient who developed malignant hypertension associated with thrombotic microangiopathy after chronic consumption of cocaine. A kidney biopsy revealed thrombotic microangiopathy with fibrinoid necrosis of arterioles and glomerular tufts. He required dialysis sessions. Cocaine-mediated endothelial injury and platelet activation may play important pathogenetic roles in cocaine abusers who develop malignant hypertension associated with thrombotic microangiopathy. Clinicians need to be aware of this rare feature of cocaine intoxication.

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

[Substance use and risk behaviors of out-of-treatment cocaine base paste and cocaine hydrochloride users].

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Santis B, Rodrigo; Hidalgo C, Carmen Gloria; Hayden C, Viviana; Anselmo M, Enzo; Rodríguez T, Jorge; Cartajena de la M, Fernando; Dreyse D, Jorge; Torres B, Rafael

2007-01-01

In Chile, cocaine base paste (CBP) is the illegal substance that produces the highest rate of addiction. Nonetheless, a marginal number of users receive treatment each year. To compare the consumption patterns and risk behavior of CBP and cocaine hydrochloride (CH) users who do not attend rehabilitation services. In a prospective research design, through a study methodology called Privileged Access Interview of hidden populations, 28 surveyors recruited 231 CBP users (group 1) and 236 CH users (group 2). The Risk Behavior Questionnaire was applied in four communities of Metropolitan Santiago, that have the highest prevalence of PBC and CH use. CBP users showed higher schools drop-out and unemployment rates. Subjects of both groups were predominantly polysubstance and polyaddicted users. The severity of addiction to CBP of group 1 was significantly higher than the severity of addiction to CH of group 2 (5.5 versus 5.1: psexual risk behaviors, antisocial behavior, self infliction of injuries, suicide attempt and child neglect. A higher vulnerability was shown for users of CBP than those of CH. Attention is drawn to the need for developing community interventions in order to alter substance abuse and the risk behavior of these vulnerable groups.

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

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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

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

[Sigmund Freud and cocaine].

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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.

Bioavailability and Pharmacokinetics of Oral Cocaine in Humans.

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

2018-06-01

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

Effect of GABA agonists and GABA-A receptor modulators on cocaine- and food-maintained responding and cocaine discrimination in rats.

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Barrett, Andrew C; Negus, S Stevens; Mello, Nancy K; Caine, S Barak

2005-11-01

Recent studies indicate that GABAergic ligands modulate abuse-related effects of cocaine. The goal of this study was to evaluate the effects of a mechanistically diverse group of GABAergic ligands on the discriminative stimulus and reinforcing effects of cocaine in rats. One group of rats was trained to discriminate 5.6 mg/kg cocaine from saline in a two-lever, food-reinforced, drug discrimination procedure. In two other groups, responding was maintained by cocaine (0-3.2 mg/kg/injection) or liquid food (0-100%) under a fixed ratio 5 schedule. Six GABA agonists were tested: the GABA-A receptor agonist muscimol, the GABA-B receptor agonist baclofen, the GABA transaminase inhibitor gamma-vinyl-GABA (GVG), and three GABA-A receptor modulators (the barbiturate pentobarbital, the high-efficacy benzodiazepine midazolam, and the low-efficacy benzodiazepine enazenil). When tested alone, none of the compounds substituted fully for the discriminative stimulus effects of cocaine. As acute pretreatments, select doses of midazolam and pentobarbital produced 2.2- to 3.6-fold rightward shifts in the cocaine dose-effect function. In contrast, muscimol, baclofen, GVG, and enazenil failed to alter the discriminative stimulus effects of cocaine. In assays of cocaine- and food-maintained responding, midazolam and pentobarbital decreased cocaine self-administration at doses 9.6- and 3.3-fold lower, respectively, than those that decreased food-maintained responding. In contrast, muscimol, baclofen, and GVG decreased cocaine self-administration at doses that also decreased food-maintained responding. Enazenil failed to alter cocaine self-administration. Together with previous studies, these data suggest that among mechanistically diverse GABA agonists, high-efficacy GABA-A modulators may be the most effective for modifying the abuse-related effects of cocaine.

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

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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.

Cocaine and Pavlovian fear conditioning: dose-effect analysis.

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

2007-01-25

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

Drug smuggling using clothing impregnated with cocaine.

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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.

Effects of Methylphenidate on Resting-State Functional Connectivity of the Mesocorticolimbic Dopamine Pathways in Cocaine Addiction

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Konova, Anna B.; Moeller, Scott J.; Tomasi, Dardo; Volkow, Nora D.; Goldstein, Rita Z.

2013-08-01

Cocaine addiction is associated with altered resting-state functional connectivity among regions of the mesocorticolimbic dopamine pathways. Methylphenidate hydrochloride, an indirect dopamine agonist, normalizes task-related regional brain activity and associated behavior in cocaine users; however, the neural systems–level effects of methylphenidate in this population have not yet been described. To use resting-state functional magnetic resonance imaging to examine changes in mesocorticolimbic connectivity with methylphenidate and how connectivity of affected pathways relates to severity of cocaine addiction.

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

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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.

Effects of cocaine hydrochloride on the male reproductive system

International Nuclear Information System (INIS)

Berul, C.I.; Harclerode, J.E.

1989-01-01

The reproductive system effects of cocaine were studied in male rats. The analysis included measurements of circulating levels of luteinizing hormone (LH) and testosterone (T) by radioimmunoassay (RIA). The weights of the testes and sex accessory organs were also assessed and compared with control animals. Dosage level, duration of treatment, and interval between injection and sacrifice were the parameters examined. Following a single intraperitoneal (IP) injection, LH levels decreased over a 3-hour period. At a high dosage, cocaine caused a significant elevation in serum T followed by a significant depression of T for at least 2 hours. When administered chronically for 15 days, the low dose group did not vary significantly from the vehicle controls. However, the high dose group had lower LH and T levels, as well as correspondingly lighter weight seminal vesicles and epididymus. No changes were noted in the weights of the ventral prostate or testes. This research suggests that cocaine acts primarily at the hypothalamic-hypophyseal axis with a possible secondary action at the gonadal level

Cardiovascular Mitochondrial Dysfunction Induced by Cocaine: Biomarkers and Possible Beneficial Effects of Modulators of Oxidative Stress

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Manuela Graziani

2017-01-01

Full Text Available Cocaine abuse has long been known to cause morbidity and mortality due to its cardiovascular toxic effects. The pathogenesis of the cardiovascular toxicity of cocaine use has been largely reviewed, and the most recent data indicate a fundamental role of oxidative stress in cocaine-induced cardiovascular toxicity, indicating that mitochondrial dysfunction is involved in the mechanisms of oxidative stress. The comprehension of the mechanisms involving mitochondrial dysfunction could help in selecting the most appropriate mitochondria injury biological marker, such as superoxide dismutase-2 activity and glutathionylated hemoglobin. The potential use of modulators of oxidative stress (mitoubiquinone, the short-chain quinone idebenone, and allopurinol in the treatment of cocaine cardiotoxic effects is also suggested to promote further investigations on these potential mitochondria-targeted antioxidant strategies.

Peripheral afferent mechanisms underlying acupuncture inhibition of cocaine behavioral effects in rats.

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Seol Ah Kim

Full Text Available Administration of cocaine increases locomotor activity by enhancing dopamine transmission. To explore the peripheral mechanisms underlying acupuncture treatment for drug addiction, we developed a novel mechanical acupuncture instrument (MAI for objective mechanical stimulation. The aim of this study was to evaluate whether acupuncture inhibition of cocaine-induced locomotor activity is mediated through specific peripheral nerves, the afferents from superficial or deep tissues, or specific groups of nerve fibers. Mechanical stimulation of acupuncture point HT7 with MAI suppressed cocaine-induced locomotor activity in a stimulus time-dependent manner, which was blocked by severing the ulnar nerve or by local anesthesia. Suppression of cocaine-induced locomotor activity was elicited after HT7 stimulation at frequencies of either 50 (for Meissner corpuscles or 200 (for Pacinian corpuscles Hz and was not affected by block of C/Aδ-fibers in the ulnar nerve with resiniferatoxin, nor generated by direct stimulation of C/Aδ-fiber afferents with capsaicin. These findings suggest that HT7 inhibition of cocaine-induced locomotor activity is mediated by A-fiber activation of ulnar nerve that originates in superficial and deep tissue.

Development of a translational model to screen medications for cocaine use disorder II: Choice between intravenous cocaine and money in humans

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Lile, Joshua A.; Stoops, William W.; Rush, Craig R.; Negus, S. Stevens; Glaser, Paul E. A.; Hatton, Kevin W.; Hays, Lon R.

2016-01-01

Background A medication for treating cocaine use disorder has yet to be approved. Laboratory-based evaluation of candidate medications in animals and humans is a valuable means to demonstrate safety, tolerability and initial efficacy of potential medications. However, animal-to-human translation has been hampered by a lack of coordination. Therefore, we designed homologous cocaine self-administration studies in rhesus monkeys (see companion article) and human subjects in an attempt to develop linked, functionally equivalent procedures for research on candidate medications for cocaine use disorder. Methods Eight (N=8) subjects with cocaine use disorder completed 12 experimental sessions in which they responded to receive money ($0.01, $1.00 and $3.00) or intravenous cocaine (0, 3, 10 and 30 mg/70 kg) under independent, concurrent progressive-ratio schedules. Prior to the completion of 9 choice trials, subjects sampled the cocaine dose available during that session and were informed of the monetary alternative value. Results The allocation of behavior varied systematically as a function of cocaine dose and money value. Moreover, a similar pattern of cocaine choice was demonstrated in rhesus monkeys and humans across different cocaine doses and magnitudes of the species-specific alternative reinforcers. The subjective and cardiovascular responses to IV cocaine were an orderly function of dose, although heart rate and blood pressure remained within safe limits. Conclusions These coordinated studies successfully established drug vs. non-drug choice procedures in humans and rhesus monkeys that yielded similar cocaine choice behavior across species. This translational research platform will be used in future research to enhance the efficiency of developing interventions to reduce cocaine use. PMID:27269368

Cocaine

Science.gov (United States)

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

Prefrontal Neuronal Excitability Maintains Cocaine-Associated Memory During Retrieval

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James M. Otis

2018-06-01

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

Opponent process properties of self-administered cocaine.

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Ettenberg, Aaron

2004-01-01

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

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)

Community Reinforcement Approach (CRA) for cocaine dependence in the Spanish public health system: 1 year outcome.

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Secades-Villa, Roberto; Sánchez-Hervás, Emilio; Zacarés-Romaguera, Francisco; García-Rodríguez, Olaya; Santonja-Gómez, Francisco J; García-Fernández, Gloria

2011-11-01

The development and dissemination of effective treatments for cocaine dependence is an important public health priority in Europe, and especially in Spain, given the increase in treatment demand over recent years. The aim of this study was to determine the effectiveness of the Community Reinforcement Approach (CRA) for cocaine dependents at an outpatient clinic within the Spanish public health system. A total of 82 cocaine-dependent patients were randomly assigned to one of two treatment conditions: Standard Treatment (n = 35) or CRA (n = 47). Dependent variables were treatment retention, cocaine abstinence and composite scores from the European version of the Addiction Severity Index at 12 month follow up. Of the patients who received CRA, 55% completed 6 months of treatment, versus 40% who received Standard Treatment. At the 12 month follow up, patients assigned to the CRA condition achieved higher rates of abstinence (95.2%) by comparison with Standard Treatment (69.2%). In the CRA group, 27% of the patients achieved continuous cocaine abstinence, versus 21% in the Standard Treatment group. The CRA group also obtained lower scores than the Standard Treatment group in all Addiction Severity Index composite scores. This study showed that CRA is a feasible treatment for cocaine addiction in a public community setting in Spain. © 2010 Australasian Professional Society on Alcohol and other Drugs.

CRF1 receptor-deficiency increases cocaine reward.

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

2017-05-01

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

Cocaine addiction: the hidden dimension.

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Oswald, L M

1989-06-01

There is growing awareness within the nursing profession that nurses need to expand their knowledge about addiction and develop expertise in providing care for substance abusing clients. This report presents a discussion about cocaine abuse that is focused on evolving knowledge about the physiology of addiction. Researchers have recently described cocaine-induced neurochemical changes in the brain that may form the underpinnings for the behavioral manifestations and symptomatology that have been associated with cocaine addiction. These neurochemical alterations are described at the cellular level, and treatment implications for nurses are presented.

Dopaminergic sensitivity and cocaine abuse: response to apomorphine.

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Hollander, E; Nunes, E; DeCaria, C M; Quitkin, F M; Cooper, T; Wager, S; Klein, D F

1990-08-01

Ten male patients with chronic cocaine abuse received a single dose of the dopamine agonist apomorphine. Self-ratings of cocaine craving, depression, and anxiety decreased in response to apomorphine. Neuroendocrine response was consistent with central dopaminergic stimulation. Patients in the "craving" phase of the cocaine abuse cycle differed in behavioral but not neuroendocrine response to apomorphine from patients in the "crash" phase. Decrease in cocaine craving correlated with decrease in plasma homovanillic acid (pHVA). Total cocaine consumption correlated negatively with baseline prolactin and pHVA levels and inversely with peak change in prolactin following apomorphine. Patients had blunted neuroendocrine response to apomorphine in comparison to historical normal controls. Implications for the "dopamine" hypothesis of cocaine abuse are discussed.

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...

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

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

2015-01-01

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

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

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

2013-01-01

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

Anticonvulsants for cocaine dependence.

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

2015-04-17

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

Pulmonary talc granulomatosis in a cocaine sniffer.

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Oubeid, M; Bickel, J T; Ingram, E A; Scott, G C

1990-07-01

The development of pulmonary granulomatosis following intravenous injection of medications intended for oral use has been well described previously. Talc is the most commonly implicated agent. We present a case of talc granulomatosis which developed in a patient following cocaine sniffing and suggest that this may be the cause of development of granulomata in drug addicts who deny any history of intravenous drug abuse.

Cocaine-Associated Seizures and Incidence of Status Epilepticus

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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.

Electrochemistry of norcocaine nitroxide and related compounds: implications for cocaine hepatotoxicity.

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Charkoudian, J C; Shuster, L

1985-08-15

Norcocaine nitroxide, a free radical metabolite of cocaine, displays a reversible one-electron cyclic voltammogram which is abolished by the addition of reduced glutathione. The corresponding nitrosonium ion was synthesized. It showed the same electrochemical characteristics as the nitroxide. The spin label 4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl (TEMPOL) and its nitrosonium ion behaved like morcocaine nitroxide and its nitrosonium ion. The nitrosonium ion of TEMPOL caused hemolysis of red blood cells, but TEMPOL did not. These observations suggest that the highly reactive nitrosonium ion may be involved in the production of cocaine-induced hepatic necrosis in mice.

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

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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.

Clinical ratings and plasma HVA during cocaine abstinence.

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

1989-08-01

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

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

Fetal cocaine exposure: analysis of vernix caseosa.

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

1996-10-01

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

The effects of prenatal cocaine, post-weaning housing and sex on conditioned place preference in adolescent rats.

Science.gov (United States)

Dow-Edwards, Diana; Iijima, Maiko; Stephenson, Stacy; Jackson, April; Weedon, Jeremy

2014-04-01

Gestational exposure to cocaine now affects several million people including adolescents and young adults. Whether prenatal drug exposures alter an individual's tendency to take and/or abuse drugs is still a matter of debate. This study sought to answer the question "Does prenatal exposure to cocaine, in a dose-response fashion, alter the rewarding effects of cocaine using a conditioned place preference (CPP) procedure during adolescence in the rat?" Further, we wanted to assess the possible sex differences and the role of being raised in an enriched versus impoverished environment. Virgin female Sprague-Dawley rats were dosed daily with cocaine at 30 mg/kg (C30), 60 mg/kg (C60), or vehicle intragastrically prior to mating and throughout gestation. Pups were culled, fostered and, on postnatal day (PND) 23, placed into isolation cages or enriched cages with three same-sex littermates and stimulus objects. On PND43-47, CPP was determined across a range of cocaine doses. C30 exposure increased sensitivity to the rewarding effects of cocaine in adolescent males, and being raised in an enriched environment further enhanced this effect. Rats exposed to C60 resembled the controls in cocaine CPP. Overall, females were modestly affected by prenatal cocaine and enrichment. These data support the unique sensitivity of males to the effects of gestational cocaine, that moderate prenatal cocaine doses produce greater effects on developing reward circuits than high doses and that housing condition interacts with prenatal treatment and sex such that enrichment increases cocaine CPP mostly in adolescent males prenatally exposed to moderate cocaine doses.

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

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Bradberry, Charles W

2011-02-01

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

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

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Ken Taro Wakabayashi

2015-02-01

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

Kalrn promoter usage and isoform expression respond to chronic cocaine exposure

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Ma Xin-Ming

2011-02-01

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

Prenatal Cocaine Exposure and Infant Cortisol Reactivity

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

2009-01-01

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

Relapse to cocaine seeking in an invertebrate.

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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.

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

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

2013-09-01

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

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

International Nuclear Information System (INIS)

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

2004-01-01

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

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

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Ramesh B Badisa

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

Psychiatric comorbidity in a sample of cocaine-dependent outpatients seen in the Community of Madrid drug addiction care network.

Science.gov (United States)

Martínez-Gras, Isabel; Ferre Navarrete, Francisco; Pascual Arriazu, Jesús; Peñas Pascual, José; de Iceta Ruiz de Gauna, Mariano; Fraguas Herráez, David; Rubio Valladolid, Gabriel

2016-03-02

The objective of this study was to estimate the current prevalence of psychiatric disorders in cocaine-dependent patients who attend different treatment centres in the Community of Madrid. A prospective multicentre study was used, and a total of 197 cocaine-dependent subjects were assessed. The assessment instrument used for diagnosis was the Psychiatric Research Interview for Substance and Mental Disorders (PRISM-IV). The main findings of this study were a high prevalence of psychiatric comorbidity in cocaine-dependent patients seeking treatment (64.0%). The most common Non Substance Use Disorders found were attention-deficit/hyperactivity Disorders (34.5%) and depressive disorders (13.7%). The most common Substance Use Disorder was alcohol dependence (28.4%). Cocaine-dependent patients who had a depressive disorder and were alcohol dependent presented a more severe clinical profile and a higher degree of psychopathology, measured using different assessment tools, than the patients who were only cocaine dependent. These data suggest that the presence of psychiatric comorbidity could constitute a risk factor associated with the severity of cocaine dependence. The clinical heterogeneity found also indicates the need to search for individualised treatments that more specifically fit the needs of this population.

N-Acetylcysteine Reverses Cocaine Induced Metaplasticity

OpenAIRE

Moussawi, Khaled; Pacchioni, Alejandra; Moran, Megan; Olive, M. Foster; Gass, Justin T.; Lavin, Antonieta; Kalivas, Peter W

2009-01-01

Cocaine addiction is characterized by an impaired ability to develop adaptive behaviors that can compete with cocaine seeking, implying a deficit in the ability to induce plasticity in cortico-accumbens circuitry critical for regulating motivated behavior. RWe found that rats withdrawn from cocaine self-administration had a marked in vivo deficit in the ability to develop long-term potentation (LTP) and depression (LTD) in the nucleus accumbens core subregion following stimulation of prefront...

Estradiol increases choice of cocaine over food in male rats.

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

2017-10-19

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

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

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

2016-02-01

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

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

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...

Dyadic social interaction as an alternative reward to cocaine.

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Zernig, Gerald; Kummer, Kai K; Prast, Janine M

2013-09-12

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. This 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.

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.

Effects of Trace Amine-associated Receptor 1 Agonists on the Expression, Reconsolidation, and Extinction of Cocaine Reward Memory.

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Liu, Jian-Feng; Thorn, David A; Zhang, Yanan; Li, Jun-Xu

2016-07-01

As a modulator of dopaminergic system, trace amine-associated receptor 1 has been shown to play a critical role in regulating the rewarding properties of additive drugs. It has been demonstrated that activation of trace amine-associated receptor 1 decreased the abuse-related behaviors of cocaine in rats. However, the role of trace amine-associated receptor 1 in specific stages of cocaine reward memory is still unclear. Here, using a cocaine-induced conditioned place preference model, we tested the effects of a selective trace amine-associated receptor 1 agonist RO5166017 on the expression, reconsolidation, and extinction of cocaine reward memory. We found that RO5166017 inhibited the expression but not retention of cocaine-induced conditioned place preference. RO5166017 had no effect on the reconsolidation of cocaine reward memory. Pretreatment with RO5166017 before extinction hindered the formation of extinction long-term memory. RO5166017 did not affect the movement during the conditioned place preference test, indicating the inhibitory effect of RO5166017 on the expression of cocaine-induced conditioned place preference was not caused by locomotion inhibition. Using a cocaine i.v. self-administration model, we found that the combined trace amine-associated receptor 1 partial agonist RO5263397 with extinction had no effect on the following cue- and drug-induced reinstatement of cocaine-seeking behavior. Repeated administration of the trace amine-associated receptor 1 agonist during extinction showed a continually inhibitory effect on the expression of cocaine reward memory both in cocaine-induced conditioned place preference and cocaine self-administration models. Taken together, these results indicate that activation of trace amine-associated receptor 1 specifically inhibited the expression of cocaine reward memory. The inhibitory effect of trace amine-associated receptor 1 agonists on cocaine reward memory suggests that trace amine-associated receptor 1

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

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Ramesh eChandra

2013-05-01

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

WITHDRAWN: Carbamazepine for cocaine dependence.

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Lima Reisser, Anelise A R L; Silva de Lima, Mauricio; Soares, Bernardo Garcia de Oliveira; Farrell, Michael

2009-01-21

Cocaine dependence has become a public health problem, developing a significant number of medical, psychological and social problems. Although there is no consensus regarding how to treat cocaine dependence, effective pharmacotherapy has a potentially major role to play as part of a broader treatment milieu. The anti-convulsant carbamazepine, a tricyclic medication that is widely used to treat a variety of neurological and psychiatric disorders, has been used for treatment of cocaine dependence, although its effectiveness has not been established. To determine whether carbamazepine is effective for the treatment of cocaine dependence. We searched: Cochrane Controlled Trials Register (Cochrane Library issue 1, 1999), MEDLINE (f1966 - October 1997), EMBASE (1980 - October 1997), PsycLIT (1974 - July 1997), Biological Abstracts and LILACS (1982 - 1997); scan of reference list of relevant articles; personal communication; conference abstracts; unpublished trials from pharmaceutical industry; book chapters on treatment of cocaine dependence. The specialised register of trials of Cochrane Group on Drugs and Alcohol until February 2003. All randomised controlled trials focused on the use of carbamazepine versus placebo on the treatment of cocaine dependence. Trials including patients with additional diagnosis such as opiate dependence were also eligible. The reviewers extracted the data independently, Odds Ratios, weighted mean difference and number needed to treat were estimated. Qualitative assessments of the methodology of eligible studies were carried out using validated checklists. The reviewers assumed that people who died or dropped out had no improvement and tested the sensitivity of the final results to this assumption. Where possible analysis was carried out according to the "intention to treat" principles. 5 studies were included (455 participants). No differences regarding positive urine sample for cocaine metabolites. Scores on Spielberg State Anxiety

Cocaine and crack cocaine abuse by pregnant or lactating mothers and analysis of its biomarkers in meconium and breast milk by LC-MS-A review.

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D'Avila, Felipe Bianchini; Limberger, Renata Pereira; Fröehlich, Pedro Eduardo

2016-09-01

Abusive use of drugs is a public health problem worldwide. The use of these substances by pregnant or lactating women can have many serious side effects in newborns. Among the commonest causes of addiction in drug users is cocaine in powdered form, inhaled, intravenously injected or smoked form (crack). Fast screening and a confirmation test using high specificity and sensitivity instruments such as LC-MS or GC/MS, can provide data to qualify and quantify chemical substances present in biological samples such as breast milk or meconium. Cocaine and/or crack can be detected through biomarkers or the unchanged molecule, enabling the form of cocaine use to be distinguished through the analytes. These methods must be carefully developed and validated according to internationally recognized guidelines. Thus, the study of biological matrices in which it can be detected through the development of simple and quick analytical methods can help prevent intoxication and diagnose the symptoms of dependency such as seizures, especially in babies, providing appropriate medical care. Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

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

International Nuclear Information System (INIS)

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

1988-01-01

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

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

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

2017-08-14

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

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

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

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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.

Limitations to the Generality of Cocaine Locomotor Sensitization

OpenAIRE

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

2008-01-01

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

COCAINE AND PAVLOVIAN FEAR CONDITIONING: DOSE-EFFECT ANALYSIS

OpenAIRE

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

2006-01-01

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

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

Directory of Open Access Journals (Sweden)

Kimberly H LeBlanc

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

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

Science.gov (United States)

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

2013-01-01

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

Basolateral amygdalar D2 receptor activation is required for the companions-exerted suppressive effect on the cocaine conditioning.

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Tzeng, Wen-Yu; Cherng, Chian-Fang G; Yu, Lung; Wang, Ching-Yi

2017-01-01

The presence of companions renders decreases in cocaine-stimulated dopamine release in the nucleus accumbens and cocaine-induced conditioned place preference (CPP) magnitude. Limbic systems are widely believed to underlie the modulation of accumbal dopamine release and cocaine conditioning. Thus, this study aimed to assess whether intact basolateral nucleus of amygdala (BLA), dorsal hippocampus (DH), and dorsolateral striatum (DLS) is required for the companions-exerted suppressive effect on the cocaine-induced CPP. Three cage mates, serving as companions, were arranged to house with the experimental mice in the cocaine conditioning compartment throughout the cocaine conditioning sessions. Approximately 1week before the conditioning procedure, intracranial ibotenic acid infusions were done in an attempt to cause excitotoxic lesions targeting bilateral BLA, DH and DLS. Albeit their BLA, DH, and DLS lesions, the lesioned mice exhibited comparable cocaine-induced CPP magnitudes compared to the intact and sham lesion controls. Bilateral BLA, but not DH or DLS, lesions abolished the companions-exerted suppressive effect on the cocaine-induced CPP. Intact mice receiving intra-BLA infusion of raclopride, a selective D2 antagonist, 30min prior to the cocaine conditioning did not exhibit the companions-exerted suppressive effect on the cocaine-induced CPP. Intra-BLA infusion of Sch23390, a selective D1 antagonist, did not affect the companions-exerted suppressive effect on the CPP. These results, taken together, prompt us to conclude that the intactness of BLA is required for the companions-exerted suppressive effect on the cocaine-induced CPP. Importantly, activation of D2 receptor in the BLA is required for such suppressive effect on the CPP. Copyright © 2016 Elsevier Inc. All rights reserved.

[Cutaneous and mucosal manifestations associated with cocaine use].

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Imbernón-Moya, Adrián; Chico, Ricardo; Aguilar-Martínez, Antonio

2016-06-17

Complications due to cocaine are a public health problem. The typical cutaneous disease is leukocytoclastic vasculitis and/or thrombotic vasculopathy affecting mainly the ears. No intense systemic involvement is usually present, but there may be several cutaneous, mucosal and systemic manifestations. Other findings associated as arthralgia, neutropaenia or agranulocytosis, low titer positive antinuclear antibodies, antiphospholipid antibody positivity and neutrophil cytoplasmic antibodies against multiple antigens help the diagnosis. This disease requires a clinical suspicion with a clinical history, a complete physical examination and a broad differential diagnosis for an early and correct diagnosis. The course is usually self-limited. In most cases the only treatment is to discontinue the use of cocaine associated with symptomatic treatment, no proven benefit of systemic corticosteroids. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

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

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

Energy Technology Data Exchange (ETDEWEB)

Clow, D.W.; Hammer, R.P. Jr. (Univ. of Hawaii School of Medicine, Honolulu (USA))

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.

Effects of GABA(B) receptor agents on cocaine priming, discrete contextual cue and food induced relapses.

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Filip, Małgorzata; Frankowska, Małgorzata

2007-10-01

following the GABA(B) receptor agonists or the allosteric positive modulator, however, doses of baclofen and SKF 97541 that inhibited cocaine-seeking were only threefold lower of those that inhibited food-seeking. In addition, the direct GABA(B) receptor agonists and the allosteric positive modulator cause decreases in cocaine or food self-administration (Filip et al., submitted for publication), indicating their nonspecific effects on relapse to drug-seeking and drug-taking behavior. In conclusion, the GABA(B) receptor antagonist SCH 50911 seems to be viable treatment for reducing cocaine craving and preventing relapse, while the GABA(B) receptor allosteric positive modulator CGP 7930 may hold the highest promise for attenuating cue-evoked relapses to cocaine as well as the direct rewarding properties of cocaine.

Overlapping patterns of brain activation to food and cocaine cues in cocaine abusers: association to striatal D2/D3 receptors

OpenAIRE

Tomasi, Dardo; Wang, Gene-Jack; Wang, Ruiliang; Caparelli, Elisabeth C.; Logan, Jean; Volkow, Nora D.

2014-01-01

Cocaine, through its activation of dopamine (DA) signaling, usurps pathways that process natural rewards. However, the extent to which there is overlap between the networks that process natural and drug rewards and whether DA signaling associated with cocaine abuse influences these networks have not been investigated in humans. We measured brain activation responses to food and cocaine cues with fMRI, and D2/D3 receptors in the striatum with [11C]raclopride and PET in 20 active cocaine abuser...

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

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Ruan, Hongyu; Yao, Wei-Dong

2017-01-25

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

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

Science.gov (United States)

2011-01-01

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

Gender differences in cocaine pharmacokinetics in CF-1 mice.

Science.gov (United States)

Visalli, Thomas; Turkall, Rita; Abdel-Rahman, Mohamed S

2005-01-15

Hepatocellular damage is thought to occur as a result of cytochrome P450-mediated oxidation of cocaine to norcocaine (NC), a precursor of the hepatotoxic nitrosonium ion. However, this damage occurs only in male mice, with females exhibiting minimal biochemical and histological signs of hepatocellular stress. The objective of this study was to determine the plasma time course and tissue disposition of cocaine and its metabolites to further investigate the role that metabolism may play in the gender difference observed. Male and female CF-1 mice were orally administered 20mg/kg cocaine hydrochloride once daily for 7 days. Blood samples were withdrawn at various time points post-injection and analyzed for cocaine and its metabolites benzoylecgonine (BE), norcocaine, ecgonine methyl ester (EME), and ecgonine (E). In addition, tissue concentrations of cocaine and its metabolites were determined in liver, heart, brain, and kidney tissue. The results demonstrated that the plasma elimination half-life of cocaine is nearly three times longer in males versus females. Non-hepatotoxic hydrolysis metabolites BE, EME, and E were higher in female tissues while norcocaine was detected in tissues of male animals only. This study revealed that differences in cocaine pharmacokinetics and the resultant differences in the biodisposition of cocaine and its metabolites in tissues contribute to the mechanism of gender difference seen in cocaine hepatotoxicity.

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

Cdk5 modulates cocaine reward, motivation, and striatal neuron excitability.

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Benavides, David R; Quinn, Jennifer J; Zhong, Ping; Hawasli, Ammar H; DiLeone, Ralph J; Kansy, Janice W; Olausson, Peter; Yan, Zhen; Taylor, Jane R; Bibb, James A

2007-11-21

Cyclin-dependent kinase 5 (Cdk5) regulates dopamine neurotransmission and has been suggested to serve as a homeostatic target of chronic psychostimulant exposure. To study the role of Cdk5 in the modulation of the cellular and behavioral effects of psychoactive drugs of abuse, we developed Cre/loxP conditional knock-out systems that allow temporal and spatial control of Cdk5 expression in the adult brain. Here, we report the generation of Cdk5 conditional knock-out (cKO) mice using the alphaCaMKII promoter-driven Cre transgenic line (CaMKII-Cre). In this model system, loss of Cdk5 in the adult forebrain increased the psychomotor-activating effects of cocaine. Additionally, these CaMKII-Cre Cdk5 cKO mice show enhanced incentive motivation for food as assessed by instrumental responding on a progressive ratio schedule of reinforcement. Behavioral changes were accompanied by increased excitability of medium spiny neurons in the nucleus accumbens (NAc) in Cdk5 cKO mice. To study NAc-specific effects of Cdk5, another model system was used in which recombinant adeno-associated viruses expressing Cre recombinase caused restricted loss of Cdk5 in NAc neurons. Targeted knock-out of Cdk5 in the NAc facilitated cocaine-induced locomotor sensitization and conditioned place preference for cocaine. These results suggest that Cdk5 acts as a negative regulator of neuronal excitability in the NAc and that Cdk5 may govern the behavioral effects of cocaine and motivation for reinforcement.

Financing Cocaine Use in a Homeless Population

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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.

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

Directory of Open Access Journals (Sweden)

Yuji Takahashi

2007-12-01

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

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.

Responses to Novelty and Vulnerability to Cocaine Addiction: Contribution of a Multi-Symptomatic Animal Model

Science.gov (United States)

Belin, David; Deroche-Gamonet, Véronique

2012-01-01

Epidemiological studies have revealed striking associations between several distinct behavioral/personality traits and drug addiction, with a large emphasis on the sensation-seeking trait and the associated impulsive dimension of personality. However, in human studies, it is difficult to identify whether personality/behavioral traits actually contribute to increased vulnerability to drug addiction or reflect psychobiological adaptations to chronic drug exposure. Here we show how animal models, including the first multi-symptomatic model of addiction in the rat, have contributed to a better understanding of the relationships between different subdimensions of the sensation-seeking trait and different stages of the development of cocaine addiction, from vulnerability to initiation of cocaine self-administration to the transition to compulsive drug intake. We argue that sensation seeking predicts vulnerability to use cocaine, whereas novelty seeking, akin to high impulsivity, predicts instead vulnerability to shift from controlled to compulsive cocaine use, that is, addiction. PMID:23125204

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.

Investigation of degradation products of cocaine and benzoylecgonine in the aquatic environment

International Nuclear Information System (INIS)

Bijlsma, Lubertus; Boix, Clara; Niessen, Wilfried M.A.; Ibáñez, María; Sancho, Juan V.; Hernández, Félix

2013-01-01

In this work, ultra-high-performance liquid chromatography (UHPLC) coupled to a hybrid quadrupole time-of-flight mass spectrometer (QTOF MS) has allowed the discovery and elucidation of degradation products of cocaine and its main metabolite benzoylecgonine (BE) in water. Spiked surface water was subjected to hydrolysis, chlorination and photo-degradation (both ultraviolet irradiation and simulated sunlight). After degradation of cocaine, up to sixteen compounds were detected and tentatively identified (1 resulting from hydrolysis; 8 from chlorination; 7 from photo-degradation), three of which are well known cocaine metabolites (BE, norbenzoylecgonine and norcocaine). Regarding BE degradation, up to ten compounds were found (3 from chlorination; 7 from photo-degradation), including one known metabolite (norbenzoylecgonine). Since reference standards were available for the major metabolites, they could be confirmed using information on retention time and fragment ions. The other degradates resulted from chlorination, dealkylation, hydroxylation and nitration, or from a combination of these processes. Several influent and effluent sewage water, and surface water samples were then screened for the identified compounds (known and unknown) using UHPLC–tandem MS with triple quadrupole. BE, norcocaine and norbenzoylecgonine were identified in these samples as major metabolites. Four previously unreported degradates were also found in some of the samples under study, illustrating the usefulness and applicability of the degradation experiments performed in this work. Highlights: ► Cocaine and benzoylecgonine degradation/transformation products investigated in water ► Hydrolysis, chlorination and photo degradation studied under laboratory conditions ► Several TPs discovered and tentatively elucidated by high resolution MS ► Structures of non-previously reported TPs have been suggested. ► Several reported/known TPs but also new TPs were found in sewage and surface

Investigation of degradation products of cocaine and benzoylecgonine in the aquatic environment

Energy Technology Data Exchange (ETDEWEB)

Bijlsma, Lubertus; Boix, Clara [Research Institute for Pesticides and Water, University Jaume I, Avda. Sos Baynat, E-12071 Castellón (Spain); Niessen, Wilfried M.A. [hyphen MassSpec, Leiden (Netherlands); Ibáñez, María; Sancho, Juan V. [Research Institute for Pesticides and Water, University Jaume I, Avda. Sos Baynat, E-12071 Castellón (Spain); Hernández, Félix, E-mail: felix.hernandez@uji.es [Research Institute for Pesticides and Water, University Jaume I, Avda. Sos Baynat, E-12071 Castellón (Spain)

2013-01-15

In this work, ultra-high-performance liquid chromatography (UHPLC) coupled to a hybrid quadrupole time-of-flight mass spectrometer (QTOF MS) has allowed the discovery and elucidation of degradation products of cocaine and its main metabolite benzoylecgonine (BE) in water. Spiked surface water was subjected to hydrolysis, chlorination and photo-degradation (both ultraviolet irradiation and simulated sunlight). After degradation of cocaine, up to sixteen compounds were detected and tentatively identified (1 resulting from hydrolysis; 8 from chlorination; 7 from photo-degradation), three of which are well known cocaine metabolites (BE, norbenzoylecgonine and norcocaine). Regarding BE degradation, up to ten compounds were found (3 from chlorination; 7 from photo-degradation), including one known metabolite (norbenzoylecgonine). Since reference standards were available for the major metabolites, they could be confirmed using information on retention time and fragment ions. The other degradates resulted from chlorination, dealkylation, hydroxylation and nitration, or from a combination of these processes. Several influent and effluent sewage water, and surface water samples were then screened for the identified compounds (known and unknown) using UHPLC–tandem MS with triple quadrupole. BE, norcocaine and norbenzoylecgonine were identified in these samples as major metabolites. Four previously unreported degradates were also found in some of the samples under study, illustrating the usefulness and applicability of the degradation experiments performed in this work. Highlights: ► Cocaine and benzoylecgonine degradation/transformation products investigated in water ► Hydrolysis, chlorination and photo degradation studied under laboratory conditions ► Several TPs discovered and tentatively elucidated by high resolution MS ► Structures of non-previously reported TPs have been suggested. ► Several reported/known TPs but also new TPs were found in sewage and surface

Environmental enrichment facilitates cocaine abstinence in an animal conflict model.

Science.gov (United States)

Ewing, Scott; Ranaldi, Robert

2018-03-01

In this study, we sought to discover if housing in an enriched environment (EE) is an efficacious intervention for encouraging abstinence from cocaine seeking in an animal "conflict" model of abstinence. Sixteen Long-Evans rats were trained in 3-h daily sessions to self-administer a cocaine solution (1 mg/kg/infusion) until each demonstrated a stable pattern of drug-seeking. Afterward, half were placed in EE cages equipped with toys, obstacles, and a running wheel, while the other half were given clean, standard laboratory housing. All rats then completed daily 30-min sessions during which the 2/3 of flooring closest to the self-administration levers was electrified, causing discomfort should they approach the levers; current strength (mA) was increased after every day of drug seeking until the rat ceased activity on the active lever for 3 consecutive sessions (abstinence). Rats housed in EE abstained after fewer days and at lower current strengths than rats in standard housing. These results support the idea that EE administered after the development of a cocaine-taking habit may be an effective strategy to facilitate abstinence. Copyright © 2018 Elsevier Inc. All rights reserved.

Biomarkers for Success: Using Neuroimaging to Predict Relapse and Develop Brain Stimulation Treatments for Cocaine-Dependent Individuals.

Science.gov (United States)

Hanlon, C A; Dowdle, L T; Jones, J L

2016-01-01

Cocaine dependence is one of the most difficult substance use disorders to treat. While the powerful effects of cocaine use on behavior were documented in the 19th century, it was not until the late 20th century that we realized cocaine use was affecting brain tissue and function. Following a brief introduction (Section 1), this chapter will summarize our current knowledge regarding alterations in neural circuit function typically observed in chronic cocaine users (Section 2) and highlight an emerging body of literature which suggests that pretreatment limbic circuit activity may be a reliable predictor of clinical outcomes among individuals seeking treatment for cocaine (Section 3). Finally, as the field of addiction research strives to translate this neuroimaging data into something clinically meaningful, we will highlight several new brain stimulation approaches which utilize functional brain imaging data to design noninvasive brain stimulation interventions for individuals seeking treatment for substance dependence disorders (Section 4). © 2016 Elsevier Inc. All rights reserved.

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

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

N-Acetylcysteine Reverses Cocaine Induced Metaplasticity

Science.gov (United States)

Moussawi, Khaled; Pacchioni, Alejandra; Moran, Megan; Olive, M. Foster; Gass, Justin T.; Lavin, Antonieta; Kalivas, Peter W

2009-01-01

Cocaine addiction is characterized by an impaired ability to develop adaptive behaviors that can compete with cocaine seeking, implying a deficit in the ability to induce plasticity in cortico-accumbens circuitry critical for regulating motivated behavior. RWe found that rats withdrawn from cocaine self-administration had a marked in vivo deficit in the ability to develop long-term potentation (LTP) and depression (LTD) in the nucleus accumbens core subregion following stimulation of prefrontal cortex. N-acetylcysteine treatment prevents relapse in animal models and craving in humans by activating cystine-glutamate exchange and thereby stimulating extrasynaptic metabotropic glutamate receptors (mGluR). N-acetylcysteine treatment restored the ability to induce LTP and LTD by indirectly stimulating mGluR2/3 and mGluR5, respectively. Cocaine self-administration induces metaplasticity that inhibits the further induction of synaptic plasticity, and this impairment can be reversed by N-acetylcysteine, a drug that also prevents relapse. PMID:19136971

N-Acetylcysteine reverses cocaine-induced metaplasticity.

Science.gov (United States)

Moussawi, Khaled; Pacchioni, Alejandra; Moran, Megan; Olive, M Foster; Gass, Justin T; Lavin, Antonieta; Kalivas, Peter W

2009-02-01

Cocaine addiction is characterized by an impaired ability to develop adaptive behaviors that can compete with cocaine seeking, implying a deficit in the ability to induce plasticity in cortico-accumbens circuitry crucial for regulating motivated behavior. We found that rats withdrawn from cocaine self-administration had a marked in vivo deficit in the ability to develop long-term potentiation (LTP) and long-term depression (LTD) in the nucleus accumbens core subregion after stimulation of the prefrontal cortex. N-acetylcysteine (NAC) treatment prevents relapse in animal models and craving in humans by activating cystine-glutamate exchange and thereby stimulating extrasynaptic metabotropic glutamate receptors (mGluR). NAC treatment of rats restored the ability to induce LTP and LTD by indirectly stimulating mGluR2/3 and mGluR5, respectively. Our findings show that cocaine self-administration induces metaplasticity that inhibits further induction of synaptic plasticity, and this impairment can be reversed by NAC, a drug that also prevents relapse.

Chronic orbital inflammatory disease and optic neuropathy associated with long-term intranasal cocaine abuse: 2 cases and literature review.

Science.gov (United States)

Siemerink, Martin J; Freling, Nicole J M; Saeed, Peerooz

2017-10-01

Orbital inflammatory disease and secondary optic neuropathy is a rare but devastating complication of long-term intranasal cocaine abuse. We describe 2 patients with a history of intranasal cocaine consumption who presented with subacute onset of unilateral vision loss from optic neuropathy and limitation of abduction in the affected eye. Magnetic resonance imaging findings included an orbital mass in combination with absent nasal septum and partial destruction of the paranasal sinuses. Biopsies and histopathologic examination of the nasal cavity and the orbital mass revealed chronic inflammation. Both patients were treated with oral corticosteroids, ocular movements completely normalized but no improvement of visual acuity was noted. Intranasal cocaine abuse can cause orbital complications from chronic sinonasal inflammatory disease and these patients are at risk to develop optic neuropathy. Optic neuropathy may be caused by compression, infiltration, or ischaemia.

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.

Peripheral benzodiazepine receptors are decreased during cocaine withdrawal in humans.

Science.gov (United States)

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

1994-07-01

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

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

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

2016-09-01

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

Cocaine is pharmacologically active in the nonhuman primate fetal brain

DEFF Research Database (Denmark)

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

2010-01-01

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

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...

Optogenetic Central Amygdala Stimulation Intensifies and Narrows Motivation for Cocaine.

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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

Measuring Outcome in the Treatment of Cocaine Dependence

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

2015-01-01

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

Clinical and forensic signs related to cocaine abuse.

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Dinis-Oliveira, Ricardo Jorge; Carvalho, Félix; Duarte, José Alberto; Proença, Jorge Brandão; Santos, Agostinho; Magalhães, Teresa

2012-03-01

Good laboratory practice in toxicological analysis requires pre-analytical steps for collection of detailed information related to the suspected poisoning episodes, including biological and non-biological circumstantial evidences, which should be carefully scrutinized. This procedure provides great help to unveil the suspected cause of poisoning, to select the appropriate and correct samples to be analyzed and can facilitate the decision about the analytical techniques to perform. This implies a good knowledge of the signs related to acute and chronic intoxications by drugs of abuse. In this manuscript we highlight and discuss clinical and forensic imaging related to cocaine abuse, namely the midline destructive lesion, dental health, pseudoscleradermatous triad and crack hands, necrosis and gangrene of extremities and several other skin manifestations, reticular purpura, intracerebral and peripheral hemorrhages, angioneurotic edema, rhabdomyolysis, and crack lung. For this purpose, the state of the art on this topic is discussed, using clinical and forensic cases from our professional database in complement to images and mechanistic data from literature.

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.

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

Science.gov (United States)

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

2017-01-01

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

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)

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

Directory of Open Access Journals (Sweden)

Meriem Gaval-Cruz

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

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

Science.gov (United States)

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

2012-01-01

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

A Conceptual Model for Maternal Behavior Among Polydrug Cocaine-Using Mothers: The Role of Postnatal Cocaine Use and Maternal Depression

OpenAIRE

Eiden, Rina D.; Stevens, Arianne; Schuetze, Pamela; Dombkowski, Laura E.

2006-01-01

This study examined the association between maternal cocaine use and maternal behavior and tested a conceptual model predicting maternal insensitivity during mother–infant interactions. Participants included 130 mother–infant dyads (68 cocaine-exposed and 62 noncocaine-exposed) who were recruited after birth and assessed at 4–8 weeks of infant age. Results of model testing indicated that when the effects of prenatal cocaine use were examined in the context of polydrug use, maternal psychopath...

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

Science.gov (United States)

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

1989-12-01

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

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

Science.gov (United States)

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

2012-04-01

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

Cocaine/levamisole-induced systemic vasculitis with retiform purpura and pauci-immune glomerulonephritis.

Science.gov (United States)

Veronese, F V; Dode, R S O; Friderichs, M; Thomé, G G; da Silva, D R; Schaefer, P G; Sebben, V C; Nicolella, A R; Barros, E J G

2016-01-01

Levamisole has been increasingly used as an adulterant of cocaine in recent years, emerging as a public health challenge worldwide. Levamisole-associated toxicity manifests clinically as a systemic vasculitis, consisting of cutaneous, hematological, and renal lesions, among others. Purpura retiform, cutaneous necrosis, intravascular thrombosis, neutropenia, and less commonly crescentic nephritis have been described in association with anti-neutrophil cytoplasmic antibodies (ANCAs) and other autoantibodies. Here we report the case of a 49-year-old male who was a chronic cocaine user, and who presented spontaneous weight loss, arthralgia, and 3 weeks before admission purpuric skin lesions in the earlobes and in the anterior thighs. His laboratory tests on admission showed serum creatinine of 4.56 mg/dL, white blood count 3,800/μL, hemoglobin 7.3 g/dL, urinalysis with 51 white blood cells/μL and 960 red blood cells/μL, and urine protein-to-creatinine ratio 1.20. Serum ANCA testing was positive (>1:320), as well as serum anti-myeloperoxidase and anti-proteinase 3 antibodies. Urine toxicology screen was positive for cocaine and levamisole, with 62.8% of cocaine, 32.2% of levamisole, and 5% of an unidentified substance. Skin and renal biopsies were diagnostic for leukocytoclastic vasculitis and pauci-immune crescentic glomerulonephritis, respectively. The patient showed a good clinical response to cocaine abstinence, and use of corticosteroids and intravenous cyclophosphamide. Last serum creatinine was 1.97 mg/dL, white blood cell count 7,420/μL, and hemoglobin level 10.8 g/dL. In levamisole-induced systemic vasculitis, the early institution of cocaine abstinence, concomitant with the use of immunosuppressive drugs in severe cases, may prevent permanent end organ damage and associate with better clinical outcomes.

Cocaine/levamisole-induced systemic vasculitis with retiform purpura and pauci-immune glomerulonephritis

Directory of Open Access Journals (Sweden)

F.V. Veronese

2016-01-01

Full Text Available Levamisole has been increasingly used as an adulterant of cocaine in recent years, emerging as a public health challenge worldwide. Levamisole-associated toxicity manifests clinically as a systemic vasculitis, consisting of cutaneous, hematological, and renal lesions, among others. Purpura retiform, cutaneous necrosis, intravascular thrombosis, neutropenia, and less commonly crescentic nephritis have been described in association with anti-neutrophil cytoplasmic antibodies (ANCAs and other autoantibodies. Here we report the case of a 49-year-old male who was a chronic cocaine user, and who presented spontaneous weight loss, arthralgia, and 3 weeks before admission purpuric skin lesions in the earlobes and in the anterior thighs. His laboratory tests on admission showed serum creatinine of 4.56 mg/dL, white blood count 3,800/μL, hemoglobin 7.3 g/dL, urinalysis with 51 white blood cells/μL and 960 red blood cells/μL, and urine protein-to-creatinine ratio 1.20. Serum ANCA testing was positive (>1:320, as well as serum anti-myeloperoxidase and anti-proteinase 3 antibodies. Urine toxicology screen was positive for cocaine and levamisole, with 62.8% of cocaine, 32.2% of levamisole, and 5% of an unidentified substance. Skin and renal biopsies were diagnostic for leukocytoclastic vasculitis and pauci-immune crescentic glomerulonephritis, respectively. The patient showed a good clinical response to cocaine abstinence, and use of corticosteroids and intravenous cyclophosphamide. Last serum creatinine was 1.97 mg/dL, white blood cell count 7,420/μL, and hemoglobin level 10.8 g/dL. In levamisole-induced systemic vasculitis, the early institution of cocaine abstinence, concomitant with the use of immunosuppressive drugs in severe cases, may prevent permanent end organ damage and associate with better clinical outcomes.

Just showing up is not enough: Homework adherence and outcome in cognitive-behavioral therapy for cocaine dependence.

Science.gov (United States)

Decker, Suzanne E; Kiluk, Brian D; Frankforter, Tami; Babuscio, Theresa; Nich, Charla; Carroll, Kathleen M

2016-10-01

Homework in cognitive-behavioral therapy (CBT) provides opportunities to practice skills. In prior studies, homework adherence was associated with improved outcome across a variety of disorders. Few studies have examined whether the relationship between homework adherence and outcome is maintained after treatment end or is independent of treatment attendance. This study combined data from 4 randomized clinical trials of CBT for cocaine dependence to examine relationships among homework adherence, participant variables, and cocaine use outcomes during treatment and at follow-up. The data set included only participants who attended at least 2 CBT sessions to allow for assignment and return of homework (N = 158). Participants returned slightly less than half (41.1%) of assigned homework. Longitudinal random effects regression suggested a greater reduction in cocaine use during treatment and through 12-month follow-up for participants who completed half or more of assigned homework (3-way interaction), F(2, 910.69) = 4.28, p = .01. In multiple linear regression, the percentage of homework adherence was associated with greater number of cocaine-negative urine toxicology screens during treatment, even when accounting for baseline cocaine use frequency and treatment attendance; at 3 months follow-up, multiple logistic regression indicated homework adherence was associated with cocaine-negative urine toxicology screen, controlling for baseline cocaine use and treatment attendance. These results extend findings from prior studies regarding the importance of homework adherence by demonstrating associations among homework and cocaine use outcomes during treatment and up to 12 months after, independent of treatment attendance and baseline cocaine use severity. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

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

Energy Technology Data Exchange (ETDEWEB)

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

1995-07-01

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

Stability of cocaine impurity profiles during 12 months of storage

DEFF Research Database (Denmark)

Nielsen, Louise Stride; Villesen, Palle; Lindholst, Christian

2016-01-01

During the lifetime of a cocaine batch from production end to consumption, several alterations may occur, leading to possible changes in the original impurity profile. Such profile changes may eventually result in erroneous forensic evaluations. In the present study, the stability of both...... the alkaloid and the residual solvent impurity profiles of cocaine were evaluated over a period of 12 months under different storage conditions (temperature, purity and weight) using GC-MS and HS-GC-MS, respectively. The sample purity (p ... profile. The most significant change was observed in low purity samples stored at 37 °C. In contrast, no changes were observed in the residual solvent profile at all storage conditions for the entire 12-month study period. This finding indicates...

Cocaine Hydrolase Gene Transfer Demonstrates Cardiac Safety and Efficacy against Cocaine-Induced QT Prolongation in Mice

OpenAIRE

Murthy, Vishakantha; Reyes, Santiago; Geng, Liyi; Gao, Yang; Brimijoin, Stephen

2016-01-01

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...

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.

Cocaine induces astrocytosis through ER stress-mediated activation of autophagy

Science.gov (United States)

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

2016-01-01

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

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

Science.gov (United States)

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

2015-01-01

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

Synthesis of deuterium labelled cocaine and pseudococaine

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Casale, J.F.; Raney, H.T. (State Bureau of Investigation, Raleigh, NC (USA). Drug Chemistry Lab.); Lewin, A.H. (Research Triangle Inst., Research Triangle Park, NC (USA)); Cooper, D.A. (Drug Enforcement Administration, McLean, VA (USA))

1991-03-01

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-({sup 2}H)-, 4,4-({sup 2}H2)-, and 1,5,6,6,7,7-({sup 2}H6)-cocaine and 3-({sup 2}H)-, 4,4-({sup 2}H2)-, and 1,5,6,6,7,7-({sup 2}H6)-pseudococaine, while that of 3-({sup 2}H)-cocaine exceeded 90%. (author).

Dopamine D3 receptors regulate reconsolidation of cocaine memory.

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Yan, Y; Kong, H; Wu, E J; Newman, A H; Xu, M

2013-06-25

Memories of learned associations between the rewarding properties of drugs of abuse and environmental cues contribute to craving and relapse in humans. Disruption of reconsolidation dampens or even erases previous memories. Dopamine (DA) mediates the acquisition of reward memory and drugs of abuse can pathologically change related neuronal circuits in the mesolimbic DA system. Previous studies showed that DA D3 receptors are involved in cocaine-conditioned place preference (CPP) and reinstatement of cocaine-seeking behavior. However, the role of D3 receptors in reconsolidation of cocaine-induced reward memory remains unclear. In the present study, we combined genetic and pharmacological approaches to investigate the role of D3 receptors in reconsolidation of cocaine-induced CPP. We found that the mutation of the D3 receptor gene weakened reconsolidation of cocaine-induced CPP in mice triggered by a 3-min (min) retrieval. Furthermore, treatment of a selective D3 receptor antagonist PG01037 immediately following the 3-min retrieval disrupted reconsolidation of cocaine-induced CPP in wild-type mice and such disruption remained at least 1 week after the 3-min retrieval. These results suggest that D3 receptors play a key role in reconsolidation of cocaine-induced CPP in mice, and that pharmacological blockade of these receptors may be therapeutic for the treatment of cocaine craving and relapse in clinical settings. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Target-responsive aptamer release from manganese dioxide nanosheets for electrochemical sensing of cocaine with target recycling amplification.

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Chen, Zongbao; Lu, Minghua

2016-11-01

A novel electrochemical sensing platform based on manganese dioxide (MnO2) nanosheets was developed for sensitive screening of target cocaine with the signal amplification. Ferrocene-labeled cocaine aptamers were initially immobilized onto MnO2 nanosheets-modified screen-printed carbon electrode because of π-stacking interaction between nucleobases and nanosheets. The immobilized ferrocene-aptamer activated the electrical contact with the electrode, thereby resulting in the sensor circuit to switch on. Upon target cocaine introduction, the analyte reacted with the aptamer and caused the dissociation of ferrocene-aptamer from the electrode, thus giving rise to the detection circuit to switch off. The released aptamer was cleaved by DNase I with target recycling. Under optimal conditions, the decreasing percentage of the electronic signal relative to background current increased with the increasing cocaine concentration in the dynamic range of 0.1-20nM, and the detection limit was 32pM. The reproducibility, selectivity and method accuracy were acceptable. Importantly, this concept offers promise for rapid, simple, and cost-effective analysis of cocaine biological samples without the needs of sample separation and multiple washing steps. Copyright © 2016 Elsevier B.V. All rights reserved.

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

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

2013-01-01

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

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

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

2002-10-01

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

Cocaine influences alcohol-seeking behavior and relapse drinking in alcohol-preferring (P) rats.

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Hauser, Sheketha R; Wilden, Jessica A; Deehan, Gerald A; McBride, William J; Rodd, Zachary A

2014-10-01

The results of several studies suggest that there may be common neurocircuits regulating drug-seeking behaviors. Common biological pathways regulating drug-seeking would explain the phenomenon that seeking for 1 drug can be enhanced by exposure to another drug of abuse. The objective of this study was to assess the time course effects of acute cocaine administration on ethanol (EtOH) seeking and relapse. Alcohol-preferring (P) rats were allowed to self-administer 15% EtOH and water. EtOH-seeking was assessed through the use of the Pavlovian spontaneous recovery (PSR) model, while EtOH-relapse drinking was assessed through the use of the alcohol-deprivation effect. Cocaine (0, 1, or 10 mg/kg), injected immediately, 30 minutes, or 4 hours prior to the first PSR testing session, dose-dependently increased responding on the EtOH lever compared to extinction responses and responding by saline controls. Under relapse conditions, cocaine given immediately prior to the relapse session had no effect (1 mg/kg) or reduced responding (10 mg/kg). In contrast, cocaine given 4 hours prior to the relapse session markedly enhanced EtOH responding compared to saline. The enhanced expression of EtOH-seeking and EtOH-relapse behaviors may be a result of a priming effect of cocaine on neuronal circuits mediating these behaviors. The effect of cocaine on EtOH-relapse drinking is indicative of the complex interactions that can occur between drugs of abuse; production of conflicting behaviors (immediate), and priming of relapse/seeking (4-hour delay). Copyright © 2014 by the Research Society on Alcoholism.

Cilioretinal artery occlusion following intranasal cocaine insufflations

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Balaji Kannan

2011-01-01

Full Text Available Cocaine is used to produce a euphoric effect by abusers, who may be unaware of the devastating systemic and ocular side effects of this drug. We describe the first known case of cilioretinal artery occlusion after intranasal cocaine abuse.

Melatonin reduces motivation for cocaine self-administration and prevents relapse-like behavior in rats.

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Takahashi, Tatiane T; Vengeliene, Valentina; Spanagel, Rainer

2017-06-01

Melatonin is a hormone involved in the entrainment of circadian rhythms, which appears dysregulated in drug users. Further, it has been demonstrated that melatonin can modulate the reinforcing effects of several drugs of abuse and may therefore play a role in drug addiction. Here, we investigated whether administration of melatonin reduces relapse-like behavior and the motivation to seek cocaine in rats. Male Sprague-Dawley rats were submitted to long-term cocaine self-administration training. Thereafter, melatonin effects were assessed on: (1) the motivation to work for cocaine in the break point test, (2) the relapse-like behavior in the cue-induced reinstatement test, (3) the distance traveled in the open field test, and (4) sucrose preference in a two-bottle choice paradigm. Melatonin, 25 or 50 mg/kg, was injected 3-4 h after the dark phase onset, 30 min prior to each test. Both doses of melatonin decreased the number of active pokes in both break point and cue-induced reinstatement tests, demonstrating that melatonin can reduce the cocaine-seeking behavior and the motivation to work for cocaine. Administration of the higher dose of this hormone, however, significantly reduced the number of inactive pokes during the cue-induced reinstatement test and tended to reduce animals' locomotor activity in the open field test. Sucrose preference was unchanged in both vehicle- and melatonin-treated animal groups. Our data suggest that melatonin administration may lower the risk of relapse triggered by cues in cocaine-experienced animals.

Roentgenographical detection of cocaine smuggling in the alimentary tract

International Nuclear Information System (INIS)

Kersschot, E.A.J.; Beaucourt, L.E.A.; Degryse, H.R.M.; Schepper, A.M.A.P. de; Academisch Ziekenhuis Antwerpen, Edegem

1985-01-01

We report five cases of cocaine smuggling, by hiding multiple drug-filled foreign bodies in the colon, either after oral ingestion or by placing them in the colon per rectum. Several smuggling methods in the gastrointestinal (GI) tract and their radiological findings on abdominal plain film are presented. Computed tomography (CT) is found to be a more accurate method in the detection of the drug-filled bags, because of its improved contrast resolution and the absence of projections of overlapping structures on the transversal sections. Subsequently, CT is highly recommended in cases of negative or doubtful findings on conventional abdominal radiographs. In all cases conservative management was used and the drug-filled capsules and condoms passed spontaneously. No complications, such as intestinal obstruction by the bags of cocaine or intoxication by rupture of their wall were observed. (orig.) [de

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

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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.

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

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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

The Effects of Excitatory and Inhibitory Social Cues on Cocaine-Seeking Behavior

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Mark Andrew Smith

2016-11-01

Full Text Available Social partners influence the likelihood of using drugs, developing a substance use disorder, and relapse to drug use after a period of abstinence. Preclinical studies report that social cues influence the acquisition of cocaine use, the escalation of cocaine use over time, and the compulsive patterns of cocaine use that emerge during an extended binge. The purpose of this study was to examine the effects of social cues on the reinstatement of cocaine-seeking behavior after a period of abstinence. Male rats were obtained at weaning, assigned to triads (3 rats/cage, reared to adulthood, and implanted with intravenous catheters. Rats from each triad were then assigned to one of three conditions: (1 test rats were trained to self-administer cocaine and were tested for reinstatement, (2 cocaine partners were trained to self-administer cocaine and were predictive of response-contingent cocaine delivery, and (3 abstinent partners were not given access to cocaine and were predictive of extinction. Test rats alternated social partners every 5 days for 20 days such that responding was reinforced with cocaine in the presence of the cocaine partner (S+ for 10 days and not reinforced with cocaine in the presence of the abstinent partner (S- for 10 days. Responding of the test rats was then extinguished over 7 days under isolated conditions. Tests of reinstatement were then conducted in the presence of the cocaine partner and abstinent partner under extinction conditions. Neither social partner reinstated responding relative to that observed on the final day of extinction; however, responding was greater in the presence of the cocaine partner (S+ than the abstinent partner (S- during the reinstatement test. These data fail to demonstrate that a social partner reinstates cocaine-seeking behavior after a period of abstinence, but they do indicate that social partners can serve as either excitatory or inhibitory discriminative stimuli to influence drug

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

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

2013-02-01

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

Quality of Web-based information on cocaine addiction.

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Khazaal, Yasser; Chatton, Anne; Cochand, Sophie; Zullino, Daniele

2008-08-01

To evaluate the quality of web-based information on cocaine use and addiction and to investigate potential content quality indicators. Three keywords: cocaine, cocaine addiction and cocaine dependence were entered into two popular World Wide Web search engines. Websites were assessed with a standardized proforma designed to rate sites on the basis of accountability, presentation, interactivity, readability and content quality. "Health on the Net" (HON) quality label, and DISCERN scale scores aiding people without content expertise to assess quality of written health publication were used to verify their efficiency as quality indicators. Of the 120 websites identified, 61 were included. Most were commercial sites. The results of the study indicate low scores on each of the measures including content quality. A global score (the sum of accountability, interactivity, content quality and aesthetic criteria) appeared as a good content quality indicator. While cocaine education websites for patients are widespread, their global quality is poor. There is a need for better evidence-based information about cocaine use and addiction on the web. The poor and variable quality of web-based information and its possible impact on physician-patient relationship argue for a serious provider for patient talk about the health information found on Internet. Internet sites could improve their content using the global score as a quality indicator.

Cocaine-induced behavioral sensitization decreases the expression of endocannabinoid signaling-related proteins in the mouse hippocampus.

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Blanco, Eduardo; Galeano, Pablo; Palomino, Ana; Pavón, Francisco J; Rivera, Patricia; Serrano, Antonia; Alen, Francisco; Rubio, Leticia; Vargas, Antonio; Castilla-Ortega, Estela; Decara, Juan; Bilbao, Ainhoa; de Fonseca, Fernando Rodríguez; Suárez, Juan

2016-03-01

In the reward mesocorticolimbic circuits, the glutamatergic and endocannabinoid systems are implicated in neurobiological mechanisms underlying cocaine addiction. However, the involvement of both systems in the hippocampus, a critical region to process relational information relevant for encoding drug-associated memories, in cocaine-related behaviors remains unknown. In the present work, we studied whether the hippocampal gene/protein expression of relevant glutamate signaling components, including glutamate-synthesizing enzymes and metabotropic and ionotropic receptors, and the hippocampal gene/protein expression of cannabinoid type 1 (CB1) receptor and endocannabinoid metabolic enzymes were altered following acute and/or repeated cocaine administration resulting in conditioned locomotion and locomotor sensitization. Results showed that acute cocaine administration induced an overall down-regulation of glutamate-related gene expression and, specifically, a low phosphorylation level of GluA1. In contrast, locomotor sensitization to cocaine produced an up-regulation of several glutamate receptor-related genes and, specifically, an increased protein expression of the GluN1 receptor subunit. Regarding the endocannabinoid system, acute and repeated cocaine administration were associated with an increased gene/protein expression of CB1 receptors and a decreased gene/protein expression of the endocannabinoid-synthesis enzymes N-acyl phosphatidylethanolamine D (NAPE-PLD) and diacylglycerol lipase alpha (DAGLα). These changes resulted in an overall decrease in endocannabinoid synthesis/degradation ratios, especially NAPE-PLD/fatty acid amide hydrolase and DAGLα/monoacylglycerol lipase, suggesting a reduced endocannabinoid production associated with a compensatory up-regulation of CB1 receptor. Overall, these findings suggest that repeated cocaine administration resulting in locomotor sensitization induces a down-regulation of the endocannabinoid signaling that could

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

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

2017-07-01

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

Cocaine- and amphetamine-regulated transcript peptide in the nucleus accumbens shell inhibits cocaine-induced locomotor sensitization to transient over-expression of α-Ca2+ /calmodulin-dependent protein kinase II.

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Xiong, Lixia; Meng, Qing; Sun, Xi; Lu, Xiangtong; Fu, Qiang; Peng, Qinghua; Yang, Jianhua; Oh, Ki-Wan; Hu, Zhenzhen

2018-01-04

Cocaine- and amphetamine-regulated transcript (CART) peptide is a widely distributed neurotransmitter that attenuates cocaine-induced locomotor activity when injected into the nucleus accumbens (NAc). Our previous work first confirmed that the inhibitory mechanism of the CART peptide on cocaine-induced locomotor activity is related to a reduction in cocaine-enhanced phosphorylated Ca 2+ /calmodulin-dependent protein kinaseIIα (pCaMKIIα) and the enhancement of cocaine-induced D3R function. This study investigated whether CART peptide inhibited cocaine-induced locomotor activity via inhibition of interactions between pCaMKIIα and the D3 dopamine receptor (D3R). We demonstrated that lentivirus-mediated gene transfer transiently increased pCaMKIIα expression, which peaked at 10 days after microinjection into the rat NAc shell, and induced a significant increase in Ca 2+ influx along with greater behavioral sensitivity in the open field test after intraperitoneal injections of cocaine (15 mg/kg). However, western blot analysis and coimmunoprecipitation demonstrated that CART peptide treatment in lentivirus-transfected CaMKIIα-over-expressing NAc rat tissues or cells prior to cocaine administration inhibited the cocaine-induced Ca 2+ influx and attenuated the cocaine-increased pCaMKIIα expression in lentivirus-transfected CaMKIIα-over-expressing cells. CART peptide decreased the cocaine-enhanced phosphorylated cAMP response element binding protein (pCREB) expression via inhibition of the pCaMKIIα-D3R interaction, which may account for the prolonged locomotor sensitization induced by repeated cocaine treatment in lentivirus-transfected CaMKIIα-over-expressing cells. These results provide strong evidence for the inhibitory modulation of CART peptide in cocaine-induced locomotor sensitization. © 2018 International Society for Neurochemistry.

Probing cocaine-antibody interactions in buffer and human serum.

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Muthu Ramakrishnan

Full Text Available Despite progress in cocaine immunotherapy, the kinetic and thermodynamic properties of antibodies which bind to cocaine and its metabolites are not well understood. It is also not clear how the interactions between them differ in a complex matrix such as the serum present in the human body. In the present study, we have used microscale thermophoresis (MST, isothermal titration calorimetry (ITC, and surface plasmon resonance (SPR we have evaluated the affinity properties of a representative mouse monoclonal (mAb08 as well as those of polyclonal antibodies purified from vaccinated mouse and human patient serum.MST analysis of fluorescently tagged mAb08 binding to cocaine reveals an approximately 15 fold decrease in its equilibrium dissociation constant in 20-50% human serum compared with that in saline buffer. A similar trend was also found using enriched polyclonal antibodies purified from vaccinated mice and patient serum, for which we have used fluorescently tagged bovine serum albumin conjugated to succinyl norcocaine (BSA-SNC. This conjugate closely mimics both cocaine and the hapten used to raise these antibodies. The ITC data also revealed that cocaine has a moderate affinity of about 2 µM to 20% human serum and very little interaction with human serum albumin or nonspecific human IgG at that concentration range. In a SPR inhibition experiment, the binding of mAb08 to immobilized BSA-SNC was inhibited by cocaine and benzoylecgonine in a highly competitive manner, whereas the purified polyclonal antibodies from vaccinated humans and mice, revealed preferential selectivity to pharmacologically active cocaine but not to the inactive metabolite benzoylecgonine. We have also developed a simple binding model to simulate the challenges associated with cocaine immunotherapy using the variable quantitative and kinetic properties of the antibodies.High sensitivity calorimetric determination of antibody binding to cocaine and its metabolites provide

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

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Greenwald, Mark K.; Steinmiller, Caren L.

2017-01-01

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

Cocaine and metabolites in waste and surface water across Belgium

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Nuijs, Alexander L.N. van [Toxicological Centre, Department of Pharmaceutical Sciences, University of Antwerp (Ukraine), Universiteitsplein 1, 2610 Antwerp (Belgium)], E-mail: alexander.vannuijs@ua.ac.be; Pecceu, Bert [Laboratory for Ecophysiology, Biochemistry and Toxicology, Department of Biology, University of Antwerp (Ukraine), Groenenborgerlaan 171, 2020 Antwerp (Belgium); Theunis, Laetitia; Dubois, Nathalie; Charlier, Corinne [Laboratory of Clinical, Forensic and Environmental Toxicology, University of Liege, (ULg), CHU Sart-Tilman, 4000 Liege (Belgium); Jorens, Philippe G. [Department of Clinical Pharmacology/Clinical Toxicology, University of Antwerp (Ukraine), University Hospital of Antwerp, Universiteitsplein 1, 2610 Antwerp (Belgium); Bervoets, Lieven; Blust, Ronny [Laboratory for Ecophysiology, Biochemistry and Toxicology, Department of Biology, University of Antwerp (Ukraine), Groenenborgerlaan 171, 2020 Antwerp (Belgium); Neels, Hugo [Toxicological Centre, Department of Pharmaceutical Sciences, University of Antwerp (Ukraine), Universiteitsplein 1, 2610 Antwerp (Belgium); Laboratory of Toxicology, ZNA Stuivenberg, Lange Beeldekensstraat 267, 2060 Antwerp (Belgium); Covaci, Adrian [Toxicological Centre, Department of Pharmaceutical Sciences, University of Antwerp (Ukraine), Universiteitsplein 1, 2610 Antwerp (Belgium); Laboratory for Ecophysiology, Biochemistry and Toxicology, Department of Biology, University of Antwerp (Ukraine), Groenenborgerlaan 171, 2020 Antwerp (Belgium)

2009-01-15

Cocaine abuse, a growing social problem, is currently estimated from population surveys, consumer interviews and crime statistics. A new approach based on the analysis of cocaine (COC) and metabolites, benzoylecgonine (BE) and ecgonine methyl ester (EME), in water samples was applied to 28 rivers and 37 waste water treatment plants in Belgium using solid-phase extraction and liquid chromatography coupled to tandem mass spectrometry. While EME was undetectable, COC and BE were detectable with concentrations ranging from <1 to 753 ng/L and <1 to 2258 ng/L, respectively. BE concentrations were employed to calculate the local amount of abused cocaine. The highest values (up to 1.8 g/day cocaine per 1000 inhabitants) were found in large cities and during weekends. The estimation of cocaine abuse through water analysis can be executed on regular basis without cooperation of patients. It also gives clear geographical information, while prevention campaigns can easily be implemented and evaluated. - Cocaine consumption can be evaluated through analysis of waste and surface water.

Cocaine and metabolites in waste and surface water across Belgium

International Nuclear Information System (INIS)

Nuijs, Alexander L.N. van; Pecceu, Bert; Theunis, Laetitia; Dubois, Nathalie; Charlier, Corinne; Jorens, Philippe G.; Bervoets, Lieven; Blust, Ronny; Neels, Hugo; Covaci, Adrian

2009-01-01

Cocaine abuse, a growing social problem, is currently estimated from population surveys, consumer interviews and crime statistics. A new approach based on the analysis of cocaine (COC) and metabolites, benzoylecgonine (BE) and ecgonine methyl ester (EME), in water samples was applied to 28 rivers and 37 waste water treatment plants in Belgium using solid-phase extraction and liquid chromatography coupled to tandem mass spectrometry. While EME was undetectable, COC and BE were detectable with concentrations ranging from <1 to 753 ng/L and <1 to 2258 ng/L, respectively. BE concentrations were employed to calculate the local amount of abused cocaine. The highest values (up to 1.8 g/day cocaine per 1000 inhabitants) were found in large cities and during weekends. The estimation of cocaine abuse through water analysis can be executed on regular basis without cooperation of patients. It also gives clear geographical information, while prevention campaigns can easily be implemented and evaluated. - Cocaine consumption can be evaluated through analysis of waste and surface water

The binding sites for cocaine and dopamine in the dopamine transporter overlap

DEFF Research Database (Denmark)

Beuming, Thijs; Kniazeff, Julie; Bergmann, Marianne L

2008-01-01

Cocaine is a widely abused substance with psychostimulant effects that are attributed to inhibition of the dopamine transporter (DAT). We present molecular models for DAT binding of cocaine and cocaine analogs constructed from the high-resolution structure of the bacterial transporter homolog Leu......T. Our models suggest that the binding site for cocaine and cocaine analogs is deeply buried between transmembrane segments 1, 3, 6 and 8, and overlaps with the binding sites for the substrates dopamine and amphetamine, as well as for benztropine-like DAT inhibitors. We validated our models by detailed...... inhibition of dopamine transport by cocaine....

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

International Nuclear Information System (INIS)

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

1995-01-01

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

The effects of diazepam and zolpidem on cocaine- and amphetamine-induced place preference.

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Meririnne, E; Kankaanpää, A; Lillsunde, P; Seppälä, T

1999-01-01

Drugs such as benzodiazepines, which enhance the effects of inhibitory neurotransmitter gamma-amino butyric acid (GABA), are known to modulate the mesocorticolimbic dopaminergic system, which is considered to mediate the rewarding effects of psychostimulants. The effects of diazepam, a benzodiazepine that binds unspecifically to omega 1- (omega1-) and omega2-receptors, and zolpidem, a nonbenzodiazepine drug that binds preferentially to omega1-receptors, on cocaine- and amphetamine-induced place preference were evaluated in Wistar rats. In tests using the counterbalanced method, neither diazepam (0.2, 1, and 5 mg/kg) nor zolpidem (2.5, 5, and 10 mg/kg) alone induced place preference or place aversion. Diazepam pretreatment prevented both cocaine- and amphetamine-induced (15 and 9 mg/kg, respectively) place preference; however, at doses that were earlier shown to cause sedation and amnesia, zolpidem failed to prevent either cocaine- or amphetamine-induced place preference. These results suggest that diazepam interferes with the rewarding properties of the psychostimulants, whereas zolpidem is less effective in this respect, possibly due to differential distribution of omega1- and omega2-receptors in the brain.

Cocaine Dysregulates Opioid Gating of GABA Neurotransmission in the Ventral Pallidum

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

2014-01-01

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

Cocaine Use and Risk of Ischemic Stroke in Young Adults.

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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.

A cocaine context renews drug seeking preferentially in a subset of individuals.

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Saunders, Benjamin T; O'Donnell, Elizabeth G; Aurbach, Elyse L; Robinson, Terry E

2014-11-01

Addiction is characterized by a high propensity for relapse, in part because cues associated with drugs can acquire Pavlovian incentive motivational properties, and acting as incentive stimuli, such cues can instigate and invigorate drug-seeking behavior. There is, however, considerable individual variation in the propensity to attribute incentive salience to reward cues. Discrete and localizable reward cues act as much more effective incentive stimuli in some rats ('sign-trackers', STs), than others ('goal-trackers', GTs). We asked whether similar individual variation exists for contextual cues associated with cocaine. Cocaine context conditioned motivation was quantified in two ways: (1) the ability of a cocaine context to evoke conditioned hyperactivity and (2) the ability of a context in which cocaine was previously self-administered to renew cocaine-seeking behavior. Finally, we assessed the effects of intra-accumbens core flupenthixol, a nonselective dopamine receptor antagonist, on context renewal. In contrast to studies using discrete cues, a cocaine context spurred greater conditioned hyperactivity, and more robustly renewed extinguished cocaine seeking in GTs than STs. In addition, cocaine context renewal was blocked by antagonism of dopamine receptors in the accumbens core. Thus, contextual cues associated with cocaine preferentially acquire motivational control over behavior in different individuals than do discrete cues, and in these individuals the ability of a cocaine context to create conditioned motivation for cocaine requires dopamine in the core of the nucleus accumbens. We speculate that different individuals may be preferentially sensitive to different 'triggers' of relapse.

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

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Ream eAl-Hasani

2013-08-01

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

Cocaine users manifest impaired prosodic and cross-modal emotion processing

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Lea M Hulka

2013-09-01

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

Subchronic administration of atomoxetine causes an enduring reduction in context-induced relapse to cocaine seeking without affecting impulsive decision making.

Science.gov (United States)

Broos, Nienke; Loonstra, Rhianne; van Mourik, Yvar; Schetters, Dustin; Schoffelmeer, Anton N M; Pattij, Tommy; De Vries, Taco J

2015-07-01

Previous work has established a robust relationship between impulsivity and addiction, and revealed that impulsive decision making predisposes the vulnerability to cocaine-seeking behavior in rats. An important next step is to assess whether elevated relapse vulnerability can be treated via the reduction of impulsive decision making. Therefore, this study explored whether subchronic atomoxetine treatment can reduce relapse vulnerability by reducing impulsive decision making. Rats were trained in the delayed reward task and were subjected to 3 weeks of cocaine self-administration. Following drug self-administration, animals were divided to different experimental groups and received the noradrenaline transporter inhibitor and attention-deficit/hyperactivity disorder drug atomoxetine or vehicle subchronically for 20 days. On days 1 and 10 after treatment cessation, a context-induced reinstatement test was performed. Throughout the entire experiment, changes in impulsive decision making were continuously monitored. Subchronic treatment with atomoxetine reduced context-induced reinstatement both 1 and 10 days after treatment cessation, only in animals receiving no extinction training. Interestingly, neither subchronic nor acute atomoxetine treatments affected impulsive decision making. Our data indicate that the enduring reduction in relapse sensitivity by atomoxetine occurred independent of a reduction in impulsive decision making. Nonetheless, repeated atomoxetine administration seems a promising pharmacotherapeutical strategy to prevent relapse to cocaine seeking in abstinent drug-dependent subjects. © 2014 Society for the Study of Addiction.

The Role of Accumbal Hypoactivity in Cocaine Addiction.

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L. L. Peoples

2007-01-01

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

Aerobic exercise decreases the positive-reinforcing effects of cocaine.

Science.gov (United States)

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

2008-11-01

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

Social defeat alters the acquisition of cocaine self-administration in rats: role of individual differences in cocaine-taking behavior.

Science.gov (United States)

Kabbaj, M; Norton, C S; Kollack-Walker, S; Watson, S J; Robinson, T E; Akil, H

2001-12-01

It is known that social defeat can modulate cocaine self-administration. However, it is unclear whether this psychosocial stressor affects drug-taking behavior to the same extent across all individual animals, particularly those with differing propensities to self-administer psychostimulants. This study examined the effect of social defeat on cocaine self-administration in animals that differ in novelty-seeking behavior that predicts differences in drug self-administration. Male Sprague-Dawley rats were first classified into high-responder (HR) and low-responder (LR) groups. HR and LR rats were categorized based on their locomotor activity in a novel environment, with HR rats exhibiting higher locomotor activity than LR rats. Then, male rats were exposed on four occasions to an aggressive Long Evans male rat over the course of 4 days. Control rats were not exposed to the social defeat. All rats were subsequently implanted with jugular catheters and 3 days later placed into the self-administration box to study the acquisition of cocaine self-administration (0.25 mg per infusion). HR non-defeated animals self-administered more cocaine than the LR non-defeated animals. Following social defeat, the acquisition of cocaine self-administration is significantly delayed in HR rats and enhanced in LR rats. CONCLUSION The unique patterns of responsiveness in the HR and LR animals suggest that social defeat plays a role of equalizer of individual differences in drug-taking behavior.

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

Science.gov (United States)

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

2018-01-16

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

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

Estrogen protects against the synergistic toxicity by HIV proteins, methamphetamine and cocaine

Directory of Open Access Journals (Sweden)

Wise Phyllis M

2001-03-01

Full Text Available Abstract Background Human immunodeficiency virus (HIV infection continues to increase at alarming rates in drug abusers, especially in women. Drugs of abuse can cause long-lasting damage to the brain and HIV infection frequently leads to a dementing illness.To determine how these drugs interact with HIV to cause CNS damage, we used an in vitro human neuronal culture characterized for the presence of dopaminergic receptors, transporters and estrogen receptors. We determined the combined effects of dopaminergic drugs, methamphetamine, or cocaine with neurotoxic HIV proteins, gp120 and Tat. Results Acute exposure to these substances resulted in synergistic neurotoxic responses as measured by changes in mitochondrial membrane potential and neuronal cell death. Neurotoxicity occurred in a sub-population of neurons. Importantly, the presence of 17beta-estradiol prevented these synergistic neurotoxicities and the neuroprotective effects were partly mediated by estrogen receptors. Conclusion Our observations suggest that methamphetamine and cocaine may affect the course of HIV dementia, and additionally suggest that estrogens modify the HIV-drug interactions.

Prenatal cocaine exposure and neonatal/infant outcomes.

Science.gov (United States)

Cambell, Shelly

2003-01-01

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

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

OpenAIRE

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

2008-01-01

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

Cocaine serves as a peripheral interoceptive conditioned stimulus for central glutamate and dopamine release.

Directory of Open Access Journals (Sweden)

Roy A Wise

Full Text Available Intravenous injections of cocaine HCl are habit-forming because, among their many actions, they elevate extracellular dopamine levels in the terminal fields of the mesocorticolimbic dopamine system. This action, thought to be very important for cocaine's strong addiction liability, is believed to have very short latency and is assumed to reflect rapid brain entry and pharmacokinetics of the drug. However, while intravenous cocaine HCl has almost immediate effects on behavior and extracellular dopamine levels, recent evidence suggests that its central pharmacological effects are not evident until 10 or more seconds after IV injection. Thus the immediate effects of a given intravenous cocaine injection on extracellular dopamine concentration and behavior appear to occur before there is sufficient time for cocaine to act centrally as a dopamine uptake inhibitor. To explore the contribution of peripheral effects of cocaine to the early activation of the dopamine system, we used brain microdialysis to measure the effects of cocaine methiodide (MI--a cocaine analogue that does not cross the blood brain barrier--on glutamate (excitatory input to the dopamine cells. IP injections of cocaine MI were ineffective in cocaine-naïve animals but stimulated ventral tegmental glutamate release in rats previously trained to lever-press for cocaine HCl. This peripherally triggered glutamate input was sufficient to reinstate cocaine-seeking in previously trained animals that had undergone extinction of the habit. These findings offer an explanation for short-latency behavioral responses and immediate dopamine elevations seen following cocaine injections in cocaine-experienced but not cocaine-naïve animals.

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

Science.gov (United States)

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

2014-01-01

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

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

Role of glucocorticoid receptor-mediated mechanisms in cocaine memory enhancement.

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Stringfield, S J; Higginbotham, J A; Wang, R; Berger, A L; McLaughlin, R J; Fuchs, R A

2017-09-01

The basolateral amygdala (BLA) is a critical site for the reconsolidation of labile contextual cocaine memories following retrieval-induced reactivation/destabilization. Here, we examined whether glucocorticoid receptors (GR), which are abundant in the BLA, mediate this phenomenon. Rats were trained to lever press for cocaine reinforcement in a distinct environmental context, followed by extinction training in a different context. Rats were then briefly exposed to the cocaine-paired context (to elicit memory reactivation and reconsolidation) or their home cages (no reactivation control). Exposure to the cocaine-paired context elicited greater serum corticosterone concentrations than home cage stay. Interestingly, the GR antagonist, mifepristone (3-10 ng/hemisphere), administered into the BLA after memory reactivation produced a further, dose-dependent increase in serum corticosterone concentrations during the putative time of cocaine-memory reconsolidation but produced an inverted U-shaped dose-effect curve on subsequent cocaine-seeking behavior 72 h later. This effect was anatomically selective, dependent on memory reactivation (i.e., not observed after home cage exposure), and did not reflect protracted hyperactivity. However, the effect was also observed when mifepristone was administered after novelty stress that mimics drug context-induced hypothalamic-pituitary-adrenal (HPA) axis activation without explicit memory reactivation. Together, these findings suggest that, similar to explicit memory retrieval, a stressful event is sufficient to destabilize cocaine memories and permit their manipulation. Furthermore, BLA GR stimulation exerts inhibitory feedback upon HPA axis activation and thus suppresses cocaine-memory reconsolidation. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

OpenAIRE

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

2005-01-01

In rats, acute administration of SB-277011A, a highly selective dopamine (DA) D3 receptor antagonist, blocks cocaine-enhanced brain stimulation reward, cocaine-seeking behaviour and reinstatement of cocaine-seeking behaviour. Here, we investigated whether SB-277011A attenuates cocaine reinforcement as assessed by cocaine self-administration under variable-cost–variable-payoff fixed-ratio (FR) and progressive-ratio (PR) reinforcement schedules. Acute i.p. administration of SB-277011A (3–24 mg/...

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

Science.gov (United States)

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

2016-02-01

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

Prenatal cocaine exposure alters alpha2 receptor expression in adolescent rats

Directory of Open Access Journals (Sweden)

Silvers Janelle M

2006-04-01

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

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.

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

Science.gov (United States)

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

2017-09-01

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

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

Science.gov (United States)

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

2017-09-01

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

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

Science.gov (United States)

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

1999-09-01

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

Impaired emotional empathy and related social network deficits in cocaine users.

Science.gov (United States)

Preller, Katrin H; Hulka, Lea M; Vonmoos, Matthias; Jenni, Daniela; Baumgartner, Markus R; Seifritz, Erich; Dziobek, Isabel; Quednow, Boris B

2014-05-01

Chronic cocaine users consistently display neurochemical and functional alterations in brain areas involved in social cognition (e.g. medial and orbitofrontal cortex). Although social functioning plays a crucial role in the development and treatment of drug dependence, studies investigating social cognition in cocaine users are lacking. Therefore, we investigated mental perspective taking ('theory of mind') and emotional and cognitive empathy in recreational (RCU) and dependent (DCU) cocaine users. Furthermore, we related these measures to real-life indicators of social functioning. One-hundred cocaine users (69 RCU, 31 DCU) and 68 stimulant-naïve healthy controls were tested with the Multifaceted Empathy Test (MET), Movie for the Assessment of Social Cognition (MASC) and Reading the Mind in the Eyes Test (RMET). The Social Network Questionnaire was conducted to assess social network size. Furthermore, participants provided information on committed criminal offenses. RCU and DCU showed less emotional empathy compared to controls (MET), whereas cognitive empathy was not impaired (MET, RMET). Additionally, DCU made more errors in mental perspective taking (MASC). Notably, cocaine users committed more criminal offenses and displayed a smaller social network and higher cocaine use was correlated with less social contacts. Diminished mental perspective taking was tentatively correlated with more intense cocaine use as well. Finally, younger age of onset of cocaine use was associated with more pronounced empathy impairment. In conclusion, social cognition impairments in cocaine users were related to real-life social functioning and should therefore be considered in therapy and prevention strategies. © 2013 Society for the Study of Addiction.

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 ...

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

Science.gov (United States)

Wells, Audrey Marie

The ability of cocaine-associated environmental contexts to promote relapse in abstinent humans and reinstatement of cocaine-seeking behavior in laboratory animals depends on the formation and maintenance of maladaptive context-response-cocaine associative memories, the latter of which can be disrupted by manipulations that interfere with memory reconsolidation. Memory reconsolidation refers to a protein synthesis-dependent phenomenon whereby memory traces are reincorporated back into long-term memory storage following their retrieval and subsequent destabilization. To elucidate the distinctive roles of the basolateral amygdala (BLA) and dorsal hippocampus (DH) in the reconsolidation of context-response-cocaine memories, Experiments 1-3 evaluated novel molecular mechanisms within each structure that control this phenomenon. Experiment 1 tested the hypothesis that activation of the extracellular signal-regulated kinase (ERK) in the BLA and nucleus accumbens core (NACc - a substrate for Pavlovian cocaine-memory reconsolidation) would critically control instrumental cocaine-memory reconsolidation. To determine this, rats were re-exposed to a context that had previously been used for cocaine self-administration (i.e., cocaine memory-reactivation) and immediately thereafter received bilateral intra-BLA or intra-NACc microinfusions of the ERK inhibitor U0126 or vehicle (VEH) and were subsequently tested for drug context-induced cocaine-seeking behavior (non-reinforced lever responding) ~72 h later. Re-exposure to the cocaine-paired context at test fully reinstated cocaine-seeking behavior, relative to responding in an alternate, extinction context, and post-reactivation U0126 treatment in the BLA, but not the NACc, impaired cocaine-seeking behavior, relative to VEH. This effect was associated with a temporary increase in ERK2, but not ERK1, phosphorylation in the BLA and required explicit reactivation of the target memory trace (i.e., did not similarly manifest when U

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

Science.gov (United States)

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

2001-01-01

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

A pilot investigation of acute inhibitory control training in cocaine users.

Science.gov (United States)

Alcorn, Joseph L; Pike, Erika; Stoops, William S; Lile, Joshua A; Rush, Craig R

2017-05-01

Disrupted response inhibition and presence of drug-cue attentional bias in cocaine-using individuals have predicted poor treatment outcomes. Inhibitory control training could help improve treatment outcomes by strengthening cognitive control. This pilot study assessed the effects of acute inhibitory control training to drug- and non-drug-related cues on response inhibition performance and cocaine-cue attentional bias in cocaine-using individuals. Participants who met criteria for a cocaine-use disorder underwent five sessions of inhibitory control training to either non-drug-related cues (i.e., rectangles) or cocaine cues (n=10/condition) in a single day. Response inhibition and attentional bias were assessed prior to and following training using the stop-signal task and visual-probe task with eye tracking, respectively. Training condition groups did not differ on demographics, inhibitory control training performance, response inhibition, or cocaine-cue attentional bias. Response inhibition performance improved as a function of inhibitory control training in both conditions. Cocaine-cue attentional bias was observed, but did not change as a function of inhibitory control training in either condition. Response inhibition in cocaine-using individuals was augmented by acute inhibitory control training, which may improve treatment outcomes through better behavioral inhibition. Future studies should investigate longer-term implementation of inhibitory control training, as well as combining inhibitory control training with other treatment modalities. Copyright © 2017 Elsevier B.V. All rights reserved.

PET imaging predicts future body weight and cocaine preference

International Nuclear Information System (INIS)

Michaelides, M.; Wang, G.; Michaelides, M.; Thanos, P.K.; Kim, R.; Cho, J.; Ananth, M.; Wang, G.-J.; Volkow N.D.

2012-01-01

Deficits in dopamine D2/D3 receptor (D2R/D3R) binding availability using PET imaging have been reported in obese humans and rodents. Similar deficits have been reported in cocaine-addicts and cocaine-exposed primates. We found that D2R/D3R binding availability negatively correlated with measures of body weight at the time of scan (ventral striatum), at 1 (ventral striatum) and 2 months (dorsal and ventral striatum) post scan in rats. Cocaine preference was negatively correlated with D2R/D3R binding availability 2 months (ventral striatum) post scan. Our findings suggest that inherent deficits in striatal D2R/D3R signaling are related to obesity and drug addiction susceptibility and that ventral and dorsal striatum serve dissociable roles in maintaining weight gain and cocaine preference. Measuring D2R/D3R binding availability provides a way for assessing susceptibility to weight gain and cocaine abuse in rodents and given the translational nature of PET imaging, potentially primates and humans.

PET imaging predicts future body weight and cocaine preference

Energy Technology Data Exchange (ETDEWEB)

Michaelides M.; Wang G.; Michaelides M.; Thanos P.K. Kim R.; Cho J.; Ananth M.; Wang G.-J.; Volkow N.D.

2011-08-28

Deficits in dopamine D2/D3 receptor (D2R/D3R) binding availability using PET imaging have been reported in obese humans and rodents. Similar deficits have been reported in cocaine-addicts and cocaine-exposed primates. We found that D2R/D3R binding availability negatively correlated with measures of body weight at the time of scan (ventral striatum), at 1 (ventral striatum) and 2 months (dorsal and ventral striatum) post scan in rats. Cocaine preference was negatively correlated with D2R/D3R binding availability 2 months (ventral striatum) post scan. Our findings suggest that inherent deficits in striatal D2R/D3R signaling are related to obesity and drug addiction susceptibility and that ventral and dorsal striatum serve dissociable roles in maintaining weight gain and cocaine preference. Measuring D2R/D3R binding availability provides a way for assessing susceptibility to weight gain and cocaine abuse in rodents and given the translational nature of PET imaging, potentially primates and humans.

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

Science.gov (United States)

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

2013-03-01

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

Screening for cocaine on Euro banknotes by a highly sensitive enzyme immunoassay.

Science.gov (United States)

Abdelshafi, Nahla A; Panne, Ulrich; Schneider, Rudolf J

2017-04-01

This study focused on quantitative detection of cocaine on Euro banknotes in Germany. A sensitive direct competitive immunoassay was developed and optimized with a limit of detection (LOD) of 5.6ng/L. Exhaustive cocaine extraction by solvent was tested using different methanol concentrations and buffered solutions. Cross-reactivity studies were performed to determine the degree of interference of cocaine metabolites with the immunoassay. Sixty-five Euro banknotes obtained from different districts in Berlin were evaluated. A 100% contamination frequency with cocaine was detected. A comparison between the amount of cocaine extracted by cotton swabbing of one square centimeter of the banknote showed a good correlation for lower contamination levels. This assay showed high sensitivity of detecting pg of cocaine per 1cm 2 of one banknote by swabbing 1cm 2 : 0, 14, and 21pg/cm 2 . Moreover, three notes of different denominations revealed high cocaine concentration; 1.1mg/note, and twice 55µg/note. Copyright © 2017 Elsevier B.V. All rights reserved.

The anatomy of a cocaine comparison case: a prosecutorial and chemistry perspective.

Science.gov (United States)

Moore, J M; Meyers, R P; Jimenez, M D

1993-11-01

Methodology used for the comparative chemical analyses of two illicit cocaine seizures, and its application in a successful criminal prosecution, is described. A description of events leading to the arrest of the defendant and an overview of the jury trial are provided. Illicit cocaine, found in the defendant's suitcase and wallet, was subjected to chemical derivatization and three distinct gas chromatographic methods for the detection and relative quantitation of cocaine manufacturing impurities/by-products. The cocaine impurities included cis- and trans-cinnamoylcocaine, the isomeric truxillines and the hydroxycocaines. Among the cocaine manufacturing byproducts detected were benzoylecgonine, ecgonine methyl ester, ecgonine, N-benzoylnorecgonine methyl ester and N-norcocaine. Chemical derivatization of the cocaine samples was accomplished using heptafluorobutyric anhydride and N,O-bis(trimethylsilyl)acetamide. The derivatized impurities/by-products were subjected to capillary gas chromatographic analysis using both flame ionization and electron-capture detectors. The comparative chemical analyses provided a positive correlation between the suitcase and wallet cocaine samples.

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.

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

Science.gov (United States)

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

2017-12-01

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

Stereochemistry and neuropharmacology of a 'bath salt' cathinone: S-enantiomer of mephedrone reduces cocaine-induced reward and withdrawal in invertebrates.

Science.gov (United States)

Vouga, Alexandre; Gregg, Ryan A; Haidery, Maryah; Ramnath, Anita; Al-Hassani, Hassan K; Tallarida, Christopher S; Grizzanti, David; Raffa, Robert B; Smith, Garry R; Reitz, Allen B; Rawls, Scott M

2015-04-01

Knowledge about the neuropharmacology of mephedrone (MEPH) applies primarily to the racemate, or street form of the drug, but not to its individual enantiomers. Here, through chemical isolation of MEPH enantiomers and subsequent behavioral characterization in established invertebrate (planarian) assays, we began separating adverse effects of MEPH from potential therapeutic actions. We first compared stereotypical and environmental place conditioning (EPC) effects of racemic MEPH, S-MEPH, and R-MEPH. Stereotypy was enhanced by acute treatment (100-1000 μM) with each compound; however, S-MEPH was less potent and efficacious than racemate and R-MEPH. Both R-MEPH (10, 100, 250 μM) and racemate (100 μM) produced EPC, but S-MEPH was ineffective at all concentrations (10-100 μM). After showing that S-MEPH lacked rewarding efficacy, we investigated its ability to alter three of cocaine's behavioral effects (EPC, withdrawal, and stereotypy). Cocaine (1 μM) produced EPC that was abolished when S-MEPH (100 μM) was administered after cocaine conditioning. Spontaneous withdrawal from chronic cocaine exposure caused a reduction in motility that was not evident during acute or continuous cocaine treatment but was attenuated by S-MEPH (100 μM) treatment during the cocaine abstinence interval. Acute stereotypy produced by 1 mM cocaine, nicotine or racemic MEPH was not affected by S-MEPH (10-250 μM). The present results obtained using planarian assays suggest that the R-enantiomer of MEPH is predominantly responsible for its stimulant and rewarding effects and the S-enantiomer is capable of antagonizing cocaine's addictive-like behaviors without producing rewarding effects of its own. Copyright © 2014 Elsevier Ltd. All rights reserved.

Influences on cocaine tolerance assessed under a multiple conjunctive schedule of reinforcement.

Science.gov (United States)

Yoon, Jin Ho; Branch, Marc N

2009-11-01

Under multiple schedules of reinforcement, previous research has generally observed tolerance to the rate-decreasing effects of cocaine that has been dependent on schedule-parameter size in the context of fixed-ratio (FR) schedules, but not under the context of fixed-interval (FI) schedules of reinforcement. The current experiment examined the effects of cocaine on key-pecking responses of White Carneau pigeons maintained under a three-component multiple conjunctive FI (10 s, 30 s, & 120 s) FR (5 responses) schedule of food presentation. Dose-effect curves representing the effects of presession cocaine on responding were assessed in the context of (1) acute administration of cocaine (2) chronic administration of cocaine and (3) daily administration of saline. Chronic administration of cocaine generally resulted in tolerance to the response-rate decreasing effects of cocaine, and that tolerance was generally independent of relative FI value, as measured by changes in ED50 values. Daily administration of saline decreased ED50 values to those observed when cocaine was administered acutely. The results show that adding a FR requirement to FI schedules is not sufficient to produce schedule-parameter-specific tolerance. Tolerance to cocaine was generally independent of FI-parameter under the present conjunctive schedules, indicating that a ratio requirement, per se, is not sufficient for tolerance to be dependent on FI parameter.

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

Science.gov (United States)

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

2016-01-06

behavior in nondrug situations. Here, rats learned about food-paired stimuli after prolonged abstinence from cocaine self-administration. Using voltammetry, we found that real-time DA signals in cocaine-experienced rats were strikingly altered relative to controls. Further, cocaine-experienced animals found reward-predictive stimuli abnormally salient and spent more time interacting with cues. Therefore, cocaine induces neuroplastic changes in the DA system that biases animals toward salient stimuli (including reward-associated cues), putting addicts at increasing risk to relapse as addiction increases in severity. Copyright © 2016 the authors 0270-6474/16/360235-16$15.00/0.

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

Science.gov (United States)

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

2016-01-01

, particularly its role in behavior in nondrug situations. Here, rats learned about food-paired stimuli after prolonged abstinence from cocaine self-administration. Using voltammetry, we found that real-time DA signals in cocaine-experienced rats were strikingly altered relative to controls. Further, cocaine-experienced animals found reward-predictive stimuli abnormally salient and spent more time interacting with cues. Therefore, cocaine induces neuroplastic changes in the DA system that biases animals toward salient stimuli (including reward-associated cues), putting addicts at increasing risk to relapse as addiction increases in severity. PMID:26740664

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.

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

Cocaine is pharmacologically active in the nonhuman primate fetal brain

DEFF Research Database (Denmark)

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

2010-01-01

Cocaine use during pregnancy is deleterious to the newborn child, in part via its disruption of placental blood flow. However, the extent to which cocaine can affect the function of the fetal primate brain is still an unresolved question. Here we used PET and MRI and show that in third-trimester ......Cocaine use during pregnancy is deleterious to the newborn child, in part via its disruption of placental blood flow. However, the extent to which cocaine can affect the function of the fetal primate brain is still an unresolved question. Here we used PET and MRI and show that in third......-trimester pregnant nonhuman primates, cocaine at doses typically used by drug abusers significantly increased brain glucose metabolism to the same extent in the mother as in the fetus (approximately 100%). Inasmuch as brain glucose metabolism is a sensitive marker of brain function, the current findings provide...

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

OpenAIRE

Felix Henrique Paim Kessler; George Woody; Luís Valmor Cruz Portela; Adriano Bretanha Lopes Tort; Raquel De Boni; Ana Carolina Wolf Baldino Peuker; Vanessa Genro; Lísia von Diemen; Diogo Onofre Gomes de Souza; Flavio Pechansky

2007-01-01

OBJECTIVE: Studies have shown signs of brain damage caused by different mechanisms in cocaine users. The serum neuron specific enolase and S100B protein are considered specific biochemical markers of neuronal and glial cell injury. This study aimed at comparing blood levels of S100B and NSE in chronic cocaine users and in volunteers who did not use cocaine or other illicit drugs. METHOD: Twenty subjects dependent on cocaine but not on alcohol or marijuana, and 20 non-substance using controls ...

Depleting adult dentate gyrus neurogenesis increases cocaine-seeking behavior.

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

2018-03-05

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

Sudden Cardiac Death of a Body Packer Due to Cocaine Cardiotoxicity

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Parthasarathi Pramanik

2016-01-01

Full Text Available This article presents a case of sudden cardiac death due to the effects of cocaine concealed in the body of a male drug smuggler in his 40s, a so-called body packer. A total of 57 body packets filled with cocaine powder were discovered in his body cavities. The detailed autopsy examination, including histopathology and toxicology findings, is discussed with the aim of describing the mechanism of cocaine intoxication in the body packer and an analysis of cocaine-induced cardiotoxicity and sudden death.

Oxytocin Reduces Cocaine Cued Fos Activation in a Regionally Specific Manner

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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

Cocaine abuse or dependency and other pyschiatric disorders. Madrid study on dual pathology.

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Arias, Francisco; Szerman, Nestor; Vega, Pablo; Mesias, Beatriz; Basurte, Ignacio; Morant, Consuelo; Ochoa, Enriqueta; Poyo, Félix; Babin, Francisco

2013-01-01

The main objective of this study was to analyse the cocaine addict subgroup from the Madrid study of prevalence of dual disorders in community mental health and substance misuse services. The sample consisted of 837 outpatients from Madrid, Spain. We compared 488 subjects who had a lifetime diagnosis of cocaine abuse or dependence, and 222 subjects who did not have a cocaine substance use disorder. We used the Mini International Neuropsychiatric Interview to evaluate axis I mental disorders, and the Personality Disorder Questionnaire to evaluate personality disorders. Almost three-quarters (73.4%) of cocaine addicts had a current dual disorder. Most prevalent were mood and anxiety disorders. Almost half (49.6%) had a personality disorder. Most of them (94.9%) had other substance use disorders. Cocaine addicts did not have higher prevalence rates of dual pathology than addicts with no cocaine abuse or dependence. Cocaine addicts were associated to a diagnosis of antisocial personality disorder, agoraphobia, and post-traumatic stress disorder, and they had an early age of onset of alcohol and cannabis use. Dual pathology is no higher in cocaine addicts in treatment than in addicts who do not use cocaine, however cocaine addicts started other drugs earlier, and were associated with specific mental disorders. Copyright © 2012 SEP y SEPB. Published by Elsevier Espana. All rights reserved.

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

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

2007-01-01

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

Optogenetically evoked gamma oscillations are disturbed by cocaine administration

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Jonathan E Dilgen

2013-11-01

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

Brain activation to cocaine cues and motivation/treatment status.

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

2014-03-01

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

The fast and furious : Cocaine, amphetamines and harm reduction

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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

Cocrystallization studies of full-length recombinant butyrylcholinesterase (BChE) with cocaine

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Asojo, Oluwatoyin Ajibola; Asojo, Oluyomi Adebola; Ngamelue, Michelle N.; Homma, Kohei; Lockridge, Oksana (Nebraska-Med)

2011-09-16

Human butyrylcholinesterase (BChE; EC 3.1.1.8) is a 340 kDa tetrameric glycoprotein that is present in human serum at about 5 mg l{sup -1} and has well documented therapeutic effects on cocaine toxicity. BChE holds promise as a therapeutic that reduces and finally eliminates the rewarding effects of cocaine, thus weaning an addict from the drug. There have been extensive computational studies of cocaine hydrolysis by BChE. Since there are no reported structures of BChE with cocaine or any of the hydrolysis products, full-length monomeric recombinant wild-type BChE was cocrystallized with cocaine. The refined 3 {angstrom} resolution structure appears to retain the hydrolysis product benzoic acid in sufficient proximity to form a hydrogen bond to the active-site Ser198.

Subchronic administration of atomoxetine causes an enduring reduction in context-induced relapse to cocaine seeking without affecting impulsive decision making

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Broos, N.; Loonstra, R.; van Mourik, Y.; Schetters, D.; Schoffelmeer, A.N.M.; Pattij, T.; de Vries, T.J.

2015-01-01

Previous work has established a robust relationship between impulsivity and addiction, and revealed that impulsive decision making predisposes the vulnerability to cocaine-seeking behavior in rats. An important next step is to assess whether elevated relapse vulnerability can be treated via the

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

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Rudoy, C A; Van Bockstaele, E J

2007-06-30

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

Quality of life, social functioning, family structure, and treatment history associated with crack cocaine use in youth from the general population.

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Narvaez, Joana C M; Pechansky, Flávio; Jansen, Karen; Pinheiro, Ricardo T; Silva, Ricardo A; Kapczinski, Flávio; Magalhães, Pedro V

2015-01-01

To assess the relationship between crack cocaine use and dimensions of quality of life and social functioning in young adults. This was a cross-sectional, population-based study involving 1,560 participants in Pelotas, Brazil. Crack cocaine use and abuse were investigated using the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) inventory. Outcomes of interest were quality of life, religiosity, and social functioning in terms of education, occupational status, family structure, and medical treatment history. Lifetime crack cocaine use was associated with poor quality of life, worse functioning, impaired academic performance, and lower religious involvement. A greater maternal presence and higher paternal absence were more also more pronounced in crack cocaine users, who were also more likely to seek psychological and psychiatric treatment than the general population. Quality of life was severely impacted by crack cocaine use, especially in terms of general and physical health. Social functioning also differed between the general population and crack users, who had lower educational attainment and religious involvement. Maternal presence, paternal absence, and mental health-seeking behaviors were also more frequent among crack cocaine users, although these individuals reported lower rates of treatment satisfaction. Crack cocaine users also had significant social impairment, so that interventions involving family management and a greater focus on general health, quality of life, and functioning may make crucial contributions to the recovery of this group.

Magnetic dispersive solid-phase extraction based on modified magnetic nanoparticles for the detection of cocaine and cocaine metabolites in human urine by high-performance liquid chromatography-mass spectrometry.

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Yang, Feiyu; Zou, Yun; Ni, Chunfang; Wang, Rong; Wu, Min; Liang, Chen; Zhang, Jiabin; Yuan, Xiaoliang; Liu, Wenbin

2017-11-01

An easy-to-handle magnetic dispersive solid-phase extraction procedure was developed for preconcentration and extraction of cocaine and cocaine metabolites in human urine. Divinyl benzene and vinyl pyrrolidone functionalized silanized Fe 3 O 4 nanoparticles were synthesized and used as adsorbents in this procedure. Scanning electron microscopy, vibrating sample magnetometry, and infrared spectroscopy were employed to characterize the modified adsorbents. A high-performance liquid chromatography with mass spectrometry method for determination of cocaine and its metabolites in human urine sample has been developed with pretreatment of the samples by magnetic dispersive solid-phase extraction. The obtained results demonstrated the higher extraction capacity of the prepared nanoparticles with recoveries between 75.1 to 105.7% and correlation coefficients higher than 0.9971. The limits of detection for the cocaine and cocaine metabolites were 0.09-1.10 ng/mL. The proposed magnetic dispersive solid-phase extraction method provided a rapid, environmentally friendly and magnetic stuff recyclable approach and it was confirmed that the prepared adsorbents material was a kind of highly effective extraction materials for the trace cocaine and cocaine metabolites analyses in human urine. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

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

2016-03-01

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

Epigenetic Modulation of Brain Gene Networks for Cocaine and Alcohol Abuse

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Sean P Farris

2015-05-01

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

On the hydration and conformation of cocaine in solution

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Gillams, Richard J.; Lorenz, Christian D.; McLain, Sylvia E.

2017-05-01

In order to develop theories relating to the mechanism through which cocaine can diffuse across the blood-brain barrier, it is important to understand the interplay between the hydration of the molecule and the adopted conformation. Here key differences in the hydration of cocaine hydrochloride (CHC) and freebase cocaine (CFB) are highlighted on the atomic scale in solution, through the use of molecular dynamics simulations. By adopting different conformations, CHC and CFB experience differing hydration environments. The interplay between these two factors may account for the vast difference in solubility of these two molecules.

Acute Toxicity from Topical Cocaine for Epistaxis: Treatment with Labetalol.

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Richards, John R; Laurin, Erik G; Tabish, Nabil; Lange, Richard A

2017-03-01

Topical cocaine is sometimes used for the treatment of epistaxis, as it has both potent anesthetic and vasoconstrictive properties. Cocaine has unpredictable cardiovascular effects, such as sudden hypertension, tachycardia, coronary arterial vasoconstriction, and dysrhythmia. We report a case of acute iatrogenic cardiovascular toxicity from the use of topical cocaine in a 56-year-old man presenting to the Emergency Department with profound epistaxis. To prepare for cauterization and nasal packing, the patient received 4% topical cocaine-soaked nasal pledgets. He became hypertensive, tachypneic, tachycardic, and dysphoric immediately after administration. To directly counter these adverse hyperadrenergic effects, the patient was given 10 mg intravenous labetalol, a mixed β- and α-blocker. This instantly normalized his vital signs and adverse subjective effects. His epistaxis was successfully treated, and he was discharged 1 h later. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: We believe that emergency physicians should be aware of the unpredictable acute cardiovascular toxicity of topical cocaine. Labetalol represents an effective first-line treatment, which, unlike benzodiazepines, directly counters the pharmacologic effects of cocaine and has no respiratory or sedative side effects. Labetalol, with its mixed β/α-blocking properties, also mitigates the potential for "unopposed α-stimulation." Copyright © 2016 Elsevier Inc. All rights reserved.

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

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

2015-09-24

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

Stereochemistry and neuropharmacology of a ‘bath salt’ cathinone: S-enantiomer of mephedrone reduces cocaine-induced reward and withdrawal in invertebrates

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Vouga, Alexandre; Gregg, Ryan A.; Haidery, Maryah; Ramnath, Anita; Al-Hassani, Hassan K.; Tallarida, Christopher S.; Grizzanti, David; Raffa, Robert B.; Smith, Garry R.; Reitz, Allen B.; Rawls, Scott M.

2015-01-01

Knowledge about the neuropharmacology of mephedrone (MEPH) applies primarily to the racemate, or street form of the drug, but not to its individual enantiomers. Here, through chemical isolation of MEPH enantiomers and subsequent behavioral characterization in established invertebrate (planarian) assays, we began separating adverse effects of MEPH from potential therapeutic actions. We first compared stereotypical and environmental place conditioning (EPC) effects of racemic MEPH, S-MEPH, and R-MEPH. Stereotypy was enhanced by acute treatment (100–1000 μM) with each compound; however, S-MEPH was less potent and efficacious than racemate and R-MEPH. Both R-MEPH (10, 100, 250 μM) and racemate (100 μM) produced EPC, but S-MEPH was ineffective at all concentrations (10–100 μM). After showing that S-MEPH lacked rewarding efficacy, we investigated its ability to alter three of cocaine's behavioral effects (EPC, withdrawal, and stereotypy). Cocaine (1 μM) produced EPC that was abolished when S-MEPH (100 μM) was administered after cocaine conditioning. Spontaneous withdrawal from chronic cocaine exposure caused a reduction in motility that was not evident during acute or continuous cocaine treatment but was attenuated by S-MEPH (100 μM) treatment during the cocaine abstinence interval. Acute stereotypy produced by 1 mM cocaine, nicotine or racemic MEPH was not affected by S-MEPH (10–250 μM). The present results obtained using planarian assays suggest that the R-enantiomer of MEPH is predominantly responsible for its stimulant and rewarding effects and the S-enantiomer is capable of antagonizing cocaine's addictive-like behaviors without producing rewarding effects of its own. PMID:25496724

Local field potentials in the ventral tegmental area during cocaine-induced locomotor activation: Measurements in freely moving rats.

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Harris Bozer, Amber L; Li, Ai-Ling; Sibi, Jiny E; Bobzean, Samara A M; Peng, Yuan B; Perrotti, Linda I

2016-03-01

The ventral tegmental area (VTA) has been established as a critical nucleus for processing behavioral changes that occur during psychostimulant use. Although it is known that cocaine induced locomotor activity is initiated in the VTA, not much is known about the electrical activity in real time. The use of our custom-designed wireless module for recording local field potential (LFP) activity provides an opportunity to confirm and identify changes in neuronal activity within the VTA of freely moving rats. The purpose of this study was to investigate the changes in VTA LFP activity in real time that underlie cocaine induced changes in locomotor behavior. Recording electrodes were implanted in the VTA of rats. Locomotor behavior and LFP activity were simultaneously recorded at baseline, and after saline and cocaine injections. Results indicate that cocaine treatment caused increases in both locomotor behavior and LFP activity in the VTA. Specifically, LFP activity was highest during the first 30 min following the cocaine injection and was most robust in Delta and Theta frequency bands; indicating the role of low frequency VTA activity in the initiation of acute stimulant-induced locomotor behavior. Our results suggest that LFP recording in freely moving animals can be used in the future to provide valuable information pertaining to drug induced changes in neural activity. Copyright © 2016 Elsevier Inc. All rights reserved.

Cocaine-induced pulmonary changes: HRCT findings

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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.

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)

Cocaine-induced pulmonary changes: HRCT findings

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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)

Impact of Sex and Gonadal Hormones on Cocaine and Food Reinforcement Paradigms

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Kerstetter, Kerry A.; Kippin, Tod E.

2011-01-01

Men and women express sexually dimorphic patterns of cocaine abuse, such that women progress faster from initially trying cocaine to becoming dependent upon the drug and display a greater incidence of relapse. Sex differences in response to cocaine are also seen in the laboratory in both humans and animal models. In this review, animal models of cocaine abuse that have reported sex differences in appetitive reinforcement are discussed. In both human and animal studies, sex differences in the ...

Factors that lead to the use of crack cocaine in combination with marijuana in Brazil: a qualitative study.

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Gonçalves, Janaina R; Nappo, Solange A

2015-07-25

In Brazil, crack cocaine use remains a healthcare challenge due to the rapid onset of its pleasurable effects, its ability to induce craving and addiction, and the fact that it is easily accessible. Delayed action on the part of the Brazilian Government in addressing the drug problem has led users to develop their own strategies for surviving the effects of crack cocaine use, particularly the drug craving and psychosis. In this context, users have sought the benefits of combining crack cocaine with marijuana. Our aim was to identify the reasons why users combine crack cocaine with marijuana and the health implications of doing so. The present study is a qualitative study, using in-depth interviews and criteria-based sampling, following 27 crack cocaine users who combined its use with marijuana. Participants were recruited using the snowball sampling technique, and the point of theoretical saturation was used to define the sample size. Data were analyzed using the content analysis technique. The interviewees reported that the combination of crack cocaine use with marijuana provided "protection" (reduced undesirable effects, improved sleep and appetite, reduced craving for crack cocaine, and allowed the patients to recover some quality of life). Combined use of cannabis as a strategy to reduce the effects of crack exhibited several significant advantages, particularly an improved quality of life, which "protected" users from the violence typical of the crack culture. Crack use is considered a serious public health problem in Brazil, and there are few solution strategies. Within that limited context, the combination of cannabis and crack deserves more thorough clinical investigation to assess its potential use as a strategy to reduce the damage associated with crack use.

Science 101: What Causes Severe Thunderstorms and Tornadoes?

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Robertson, Bill

2016-01-01

What causes severe thunderstorms and tornadoes? Tornadoes, often accompanied by severe thunderstorms and hail, form in pretty much the same way as severe thunderstorms. In the continental United States, tornadoes usually form in spring and summer, when warm, humid air from the Gulf of Mexico moves across the continent from southeast to northwest…

Changes in expression of c-Fos protein following cocaine-cue extinction learning.

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Nic Dhonnchadha, B Á; Lovascio, B F; Shrestha, N; Lin, A; Leite-Morris, K A; Man, H Y; Kaplan, G B; Kantak, K M

2012-09-01

Extinguishing abnormally strengthened learned responses to cues associated with drugs of abuse remains a key tactic for alleviating addiction. To assist in developing pharmacotherapies to augment exposure therapy for relapse prevention, investigation into neurobiological underpinnings of drug-cue extinction learning is needed. We used regional analyses of c-Fos and GluR2 protein expression to delineate neural activity and plasticity that may be associated with cocaine-cue extinction learning. Rats were trained to self-administer cocaine paired with a light cue, and later underwent a single 2h extinction session for which cocaine was withheld but response-contingent cues were presented (cocaine-cue extinction). Control groups consisted of rats yoked to animals self-administering cocaine and receiving saline non-contingently followed by an extinction session, or rats trained to self-administer cocaine followed by a no-extinction session for which levers were retracted, and cocaine and cues were withheld. Among 11 brain sites examined, extinction training increased c-Fos expression in basolateral amygdala and prelimbic prefrontal cortex of cocaine-cue extinguished rats relative to both control conditions. In dorsal subiculum and infralimbic prefrontal cortex, extinction training increased c-Fos expression in both cocaine-cue and saline-cue extinguished rats relative to the no-extinction control condition. GluR2 protein expression was not altered in any site examined after extinction or control training. Findings suggest that basolateral amygdala and prelimbic prefrontal cortex neurons are activated during acquisition of cocaine-cue extinction learning, a process that is independent of changes in GluR2 abundance. Other sites are implicated in processing the significance of cues that are present early in extinction training. Copyright © 2012 Elsevier B.V. All rights reserved.

A Methanol Extract of Brugmansia arborea Affects the Reinforcing and Motor Effects of Morphine and Cocaine in Mice

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Antonio Bracci

2013-01-01

Full Text Available Previous reports have shown that several of the effects of morphine, including the development of tolerance and physical withdrawal symptoms, are reduced by extracts of Brugmansia arborea (L. Lagerheim (Solanaceae (B. arborea. In the present study we evaluate the action of the methanol extract of B. arborea (7.5–60 mg/kg on the motor and reinforcing effects of morphine (20 and 40 mg/kg and cocaine (25 mg/kg using the conditioned place preference (CPP procedure. At the doses employed, B. arborea did not affect motor activity or induce any effect on CPP. The extract partially counteracted morphine-induced motor activity and completely blocked the CPP induced by 20 mg/kg morphine. On the other hand, B. arborea blocked cocaine-induced hyperactivity but did not block cocaine-induced CPP. Reinstatement of extinguished preference with a priming dose of morphine or cocaine was also inhibited by B. arborea. The complex mechanism of action of B. arborea, which affects the dopaminergic and the cholinergic systems, seems to provide a neurobiological substrate for the effects observed. Considered as a whole, these results point to B. arborea as a useful tool for the treatment of morphine or cocaine abuse.

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

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

2016-10-01

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

Disruption of model-based behavior and learning by cocaine self-administration in rats.

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Wied, Heather M; Jones, Joshua L; Cooch, Nisha K; Berg, Benjamin A; Schoenbaum, Geoffrey

2013-10-01

Addiction is characterized by maladaptive decision-making, in which individuals seem unable to use adverse outcomes to modify their behavior. Adverse outcomes are often infrequent, delayed, and even rare events, especially when compared to the reliable rewarding drug-associated outcomes. As a result, recognizing and using information about their occurrence put a premium on the operation of so-called model-based systems of behavioral control, which allow one to mentally simulate outcomes of different courses of action based on knowledge of the underlying associative structure of the environment. This suggests that addiction may reflect, in part, drug-induced dysfunction in these systems. Here, we tested this hypothesis. This study aimed to test whether cocaine causes deficits in model-based behavior and learning independent of requirements for response inhibition or perception of costs or punishment. We trained rats to self-administer sucrose or cocaine for 2 weeks. Four weeks later, the rats began training on a sensory preconditioning and inferred value blocking task. Like devaluation, normal performance on this task requires representations of the underlying task structure; however, unlike devaluation, it does not require either response inhibition or adapting behavior to reflect aversive outcomes. Rats trained to self-administer cocaine failed to show conditioned responding or blocking to the preconditioned cue. These deficits were not observed in sucrose-trained rats nor did they reflect any changes in responding to cues paired directly with reward. These results imply that cocaine disrupts the operation of neural circuits that mediate model-based behavioral control.

Adolescent D-amphetamine treatment in a rodent model of ADHD: Pro-cognitive effects in adolescence without an impact on cocaine cue reactivity in adulthood.

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Jordan, Chloe J; Taylor, Danielle M; Dwoskin, Linda P; Kantak, Kathleen M

2016-01-15

Attention-deficit/hyperactivity disorder (ADHD) is comorbid with cocaine abuse. Whereas initiating ADHD medication in childhood does not alter later cocaine abuse risk, initiating medication during adolescence may increase risk. Preclinical work in the Spontaneously Hypertensive Rat (SHR) model of ADHD found that adolescent methylphenidate increased cocaine self-administration in adulthood, suggesting a need to identify alternatively efficacious medications for teens with ADHD. We examined effects of adolescent d-amphetamine treatment on strategy set shifting performance during adolescence and on cocaine self-administration and reinstatement of cocaine-seeking behavior (cue reactivity) during adulthood in male SHR, Wistar-Kyoto (inbred control), and Wistar (outbred control) rats. During the set shift phase, adolescent SHR needed more trials and had a longer latency to reach criterion, made more regressive errors and trial omissions, and exhibited slower and more variable lever press reaction times. d-Amphetamine improved performance only in SHR by increasing choice accuracy and decreasing errors and latency to criterion. In adulthood, SHR self-administered more cocaine, made more cocaine-seeking responses, and took longer to extinguish lever responding than control strains. Adolescent d-amphetamine did not alter cocaine self-administration in adult rats of any strain, but reduced cocaine seeking during the first of seven reinstatement test sessions in adult SHR. These findings highlight utility of SHR in modeling cognitive dysfunction and comorbid cocaine abuse in ADHD. Unlike methylphenidate, d-amphetamine improved several aspects of flexible learning in adolescent SHR and did not increase cocaine intake or cue reactivity in adult SHR. Thus, adolescent d-amphetamine was superior to methylphenidate in this ADHD model. Copyright © 2015 Elsevier B.V. All rights reserved.

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

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

2017-07-01

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

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

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

2013-08-01

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

Mothers recovering from cocaine addiction: factors affecting parenting skills.

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Coyer, S M

2001-01-01

To identify factors that may influence parenting by mothers who are recovering from cocaine addiction. Exploratory descriptive, with in-depth unstructured interviews. Interviews were conducted in the woman's home or in a treatment center. A convenience sample of 11 women recovering from cocaine addiction who were mothers of children 3 years of age and younger. A content analysis was used to analyze the interview data. Two themes, personal/psychologic factors and environmental/contextual factors, and four subthemes emerged. They identify issues that may affect parenting by mothers being treated for cocaine addiction. Subthemes included low self-esteem, difficulty developing a maternal identity, isolation from friends and family, and chronic life stress. This study provides a better understanding of the sources contributing to vulnerability in the parenting role for mothers recovering from cocaine addiction and will assist nurses in providing care for these mothers and their children.

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

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

2016-01-01

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

Financing Cocaine Use in a Homeless Population

OpenAIRE

North, Carol S.; Pollio, David E.

2017-01-01

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: ...

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

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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.

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

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Alessandro E. Vento

2013-12-01

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

Theory of Mind Impairments in Women With Cocaine Addiction.

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Sanvicente-Vieira, Breno; Kluwe-Schiavon, Bruno; Corcoran, Rhiannon; Grassi-Oliveira, Rodrigo

2017-03-01

This study investigates the Theory of Mind performance of female cocaine-dependent users (CDUs) and possible associations between theory of mind performance and features of cocaine use. Sixty women controlled for age, education, individual income, and IQ participated in this study: 30 in the CDU group and 30 in the healthy control group. Participants were assessed for theory of mind with the Reading the Mind in the Eyes Test (RMET), a test of understanding of first-order and second-order false beliefs, and the Hinting task. Drug use parameters, clinical symptoms, and neuropsychological functioning were also assessed. Analyses of covariance indicated Theory of Mind impairments in negative mental states within the RMET and second-order false-belief understanding of Theory of Mind stories. In addition, Theory of Mind impairment was associated with drug use characteristics, including craving and number of hospitalizations. High-demand Theory of Mind is suggested to be impaired in CDU women, and the deficits appear to be related to drug addiction severity. We found associations between Theory of Mind deficits and worse clinical and social outcomes.

Coronary spasm after the topical use of cocaine in nasal surgery.

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Lenders, Guy D; Jorens, Philippe G; De Meyer, Tim; Vandendriessche, Tom; Verbrugghe, Walter; Vrints, Christiaan J

2013-01-01

Cocaine is a frequently used recreational drug which imposes important health problems with even life-threatening cardiotoxicity. The therapeutic use of cocaine is nowadays restricted to topical anesthesia in ophthalmological and nasal surgery but the possible hazards of this local anesthesia are not always fully appreciated. A 51-year old male patient with moderate cardiovascular risk profile underwent elective nasal surgery and cocaine was used as a local anesthetic. During surgery, ventricular arrhythmias and cardiogenic shock occurred, mimicking an ST-segment elevation myocardial infarction (STEMI) in sinus rhythm. Coronary angiography showed diffuse spasm of the right coronary artery (RCA) which disappeared with intracoronary nitrates. Urine analysis was positive for cocaine. The patient recovered completely with a normal echocardiography and ECG at discharge. Cocaine cardiotoxicity is not uncommon in the community but a particular situation arises when used in medicine as a topical anesthetic. This is the first case report, to our knowledge, of a cardiogenic shock mimicking a STEMI with documentation of diffuse coronary spasm after cocaine use in nasal surgery. One must be aware of the potential life-threatening complications in this low-risk surgery, moreover when safer alternatives are available.

Cocaine self-administration and reinstatement in female rats selectively bred for high and low voluntary running.

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Smethells, J R; Zlebnik, N E; Miller, D K; Will, M J; Booth, F; Carroll, M E

2016-10-01

Previous research has found that rats behaviorally screened for high (vs. low) wheel running were more vulnerable to cocaine abuse. To assess the extent to which a genetic component is involved in this drug-abuse vulnerability, rats selectively bred for high or low voluntary running (HVR or LVR, respectively) were examined for differences in cocaine seeking in the present study. Female rats were trained to lever press for food and then were assessed for differences in acquisition of cocaine (0.4mg/kg; i.v.) self-administration across 10 sessions. Once acquired, rats self-administered cocaine for a 14-day maintenance phase, followed by a 14-day extinction phase when cocaine was no longer available. Subsequently, reinstatement of cocaine seeking was examined with priming injections of cocaine (5, 10 & 15mg/kg), caffeine (30mg/kg), yohimbine (2.5mg/kg) and cocaine-paired cues. A greater percentage of LVR rats met the acquisition criteria for cocaine self-administration and in fewer sessions than HVR rats. No differences in responding for cocaine were observed between phenotypes during maintenance. However, during extinction LVR rats initially responded at higher rates and persisted in cocaine seeking for a greater number of sessions. No phenotype differences were observed following drug and cue-primed reinstatement of cocaine seeking. In general, LVR rats were more sensitive to the reinforcing effects of cocaine than HVR rats during periods of transition into and out of cocaine self-administration. Thus, LVR rats sometimes showed a greater vulnerability cocaine seeking than HVR rats. Published by Elsevier Ireland Ltd.

Effect of cocaine use on outcomes in traumatic brain injury

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Jacky T Yeung

2013-01-01

Full Text Available Context: Animal and molecular studies have shown that cocaine exerts a neuroprotective effect against cerebral ischemia. Aims: To determine if the presence of cocaine metabolites on admission following traumatic brain injury (TBI is associated with better outcomes. Settings and Design: Level-1 trauma center, retrospective cohort. Materials and Methods: After obtaining Institutional Review Board (IRB approval, the trauma registry was searched from 2006 to 2009 for all patients aged 15-55 years with blunt head trauma and non-head AIS <3. Exclusion criteria were pre-existing brain pathology and death within 30 min of admission. The primary outcome was in-hospital mortality; secondary outcomes were hospital length of stay (LOS, and Glasgow Outcome Score (GOS. Statistical Analysis: Logistic regression was used to determine the independent effect of cocaine on mortality. Hospital LOS was compared with multiple linear regression. Results: A total of 741 patients met criteria and had drug screens. The screened versus unscreened groups were similar. Cocaine positive patients were predominantly African-American (46% vs. 21%, P < 0.0001, older (40 years vs. 30 years, P < 0.0001, and had ethanol present more often (50.7% vs. 37.8%, P = 0.01. There were no differences in mortality (cocaine-positive 1.4% vs. cocaine-negative 2.7%, P = 0.6 on both univariate and multivariate analysis. Conclusions: Positive cocaine screening was not associated with mortality in TBI. An effect may not have been detected because of the low mortality rate. LOS is affected by many factors unrelated to the injury and may not be a good surrogate for recovery. Similarly, GOS may be too coarse a measure to identify a benefit.

Cocaine-Levamisole-Induced Vasculitis/Vasculopathy Syndrome.