Cocaine

Availability of N-Methyl-d-Aspartate Receptor Coagonists Affects Cocaine-Induced Conditioned Place Preference and Locomotor Sensitization: Implications for Comorbid Schizophrenia and Substance Abuse.[Pubmed:25788713]

J Pharmacol Exp Ther. 2015 Jun;353(3):465-70.

Schizophrenia is associated with high prevalence of substance abuse. Recent research suggests that dysregulation of N-methyl-d-aspartate receptor (NMDAR) function may play a role in the pathophysiology of both schizophrenia and drug addiction, and thus, may account for this high comorbidity. Our laboratory has developed two transgenic mouse lines that exhibit contrasting NMDAR activity based on the availability of the glycine modulatory site (GMS) agonists d-serine and glycine. Glycine transporter 1 knockdowns (GlyT1(+/-)) exhibit NMDAR hyperfunction, whereas serine racemase knockouts (SR(-/-)) exhibit NMDAR hypofunction. We characterized the behavior of these lines in a Cocaine-induced (20 mg/kg) conditioned place preference (CPP) and locomotor sensitization paradigm. Compared with wild-type mice, GlyT1(+/-) mice displayed hastened extinction of CPP and robust Cocaine-induced reinstatement. SR(-/-) mice appeared to immediately "forget" the learned preference, because they did not exhibit Cocaine-induced reinstatement and also displayed attenuated locomotor sensitization. Treatment of GlyT1(+/-) mice with gavestinel (10 mg/kg on day 1; 5 mg/kg on days 2-17), a GMS antagonist, attenuated Cocaine-induced CPP and caused them to immediately "forget" the learned preference. Treatment of SR(-/-) mice with d-serine (300 mg/kg on day 1; 150 mg/kg on days 2-17) to normalize brain levels caused them to avoid the Cocaine-paired side of the chamber during extinction. These results highlight NMDAR dysfunction as a possible neural mechanism underlying comorbid schizophrenia and substance abuse. Also, these findings suggest drugs that directly or indirectly activate the NMDAR GMS could be an effective treatment of Cocaine abuse.

Orexin-corticotropin-releasing factor receptor heteromers in the ventral tegmental area as targets for cocaine.[Pubmed:25926444]

J Neurosci. 2015 Apr 29;35(17):6639-53.

Release of the neuropeptides corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced Cocaine-seeking behavior. We provide evidence for pharmacologically significant interactions between CRF and orexin-A that depend on oligomerization of CRF1 receptor (CRF1R) and orexin OX1 receptors (OX1R). CRF1R-OX1R heteromers are the conduits of a negative crosstalk between orexin-A and CRF as demonstrated in transfected cells and rat VTA, in which they significantly modulate dendritic dopamine release. The Cocaine target sigma1 receptor (sigma1R) also associates with the CRF1R-OX1R heteromer. Cocaine binding to the sigma1R-CRF1R-OX1R complex promotes a long-term disruption of the orexin-A-CRF negative crosstalk. Through this mechanism, Cocaine sensitizes VTA cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces Cocaine seeking.

Cocaine modulates HIV-1 integration in primary CD4+ T cells: implications in HIV-1 pathogenesis in drug-abusing patients.[Pubmed:25691383]

J Leukoc Biol. 2015 Apr;97(4):779-90.

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 microM-100 microM). Proviral DNA integration in the host genome was measured by nested qPCR. Our results illustrated that Cocaine from 1 microM through 50 microM 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.

Changes in brain-derived neurotrophic factor (BDNF) during abstinence could be associated with relapse in cocaine-dependent patients.[Pubmed:25592977]

Psychiatry Res. 2015 Feb 28;225(3):309-14.

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

Effects of cocaine-positive urine screens on serum thyrotropin levels in patients admitted to an inpatient mental health unit.[Pubmed:25688900]

South Med J. 2015 Feb;108(2):130-1.

OBJECTIVE: To assess the effect of a positive urine screen for Cocaine on thyrotropin (TSH, also thyroid-stimulating hormone) concentrations. METHODS: In this retrospective cohort study, patients admitted to the mental health unit at an academic inpatient setting with a diagnosis of Cocaine dependence or Cocaine intoxication were routinely screened with urine drug toxicology tests and TSH concentrations. TSH concentrations from patients who tested positive for Cocaine on urine toxicology were compared with patients having negative Cocaine screenings. RESULTS: A total of 192 patients were included: 122 with a positive Cocaine screen and 70 with a negative Cocaine screen. All patients were screened using a highly sensitive TSH assay. A positive Cocaine screen was not associated with a statistically significant difference in TSH concentrations compared with a negative Cocaine screen. The percentage of patients with hypothyroidism (TSH >4.50 muIU/mL) or hyperthyroidism (TSH <0.40 muIU/mL) were similar in both study groups. CONCLUSIONS: The study failed to show that a positive urine screen for Cocaine was associated with a significant effect on serum TSH levels in patients admitted to a mental health unit with a diagnosis of Cocaine dependence or Cocaine intoxication. Our findings support those of a prior study that Cocaine use does not affect routine thyroid function tests. The present study does not support the clinical practice of ordering a serum TSH screening test on patients admitted to inpatient psychiatry units soley because the urine screen is positive for Cocaine.