Gonzalez C.R.,Maimónides University |
Gonzalez B.,CONICET |
Matzkin M.E.,CONICET |
Muniz J.A.,CONICET |
And 5 more authors.
PLoS ONE | Year: 2015
Several organ systems can be affected by psychostimulant toxicity. However, there is not sufficient evidence about the impact of psychostimulant intake on testicular physiology and catecholaminergic systems. The aim of the present study was to further explore potential toxic consequences of chronic exposure to cocaine, caffeine, and their combination on testicular physiology. Mice were injected with a 13-day chronic binge regimen of caffeine (3x5mg/kg), cocaine (3×10mg/kg), or combined administration. Mice treated with cocaine alone or combined with caffeine showed reduced volume of the seminiferous tubule associated to a reduction in the number of spermatogonia. Cocaine-only and combined treatments induced increased lipid peroxidation evaluated by TBARS assay and decreased glutathione peroxidase mRNA expression. Importantly, caffeine-cocaine combination potentiated the cocaine-induced germ cell loss, and induced pro-apoptotic BAX protein expression and diminished adenosine receptor A1 mRNA levels. We analyzed markers of dopaminergic function in the testis and detected the presence of tyrosine hydroxylase (TH) in the cytoplasm of androgen-producing Leydig cells, but also in meiotic germs cells within seminiferous tubules. Moreover, using transgenic BAC-Drd1a-tdTomato and D2R-eGFP mice, we report for the first time the presence of dopamine receptors (DRs) D1 and D2 in testicular mouse Leydig cells. Interestingly, the presence of DRD1 was also detected in the spermatogonia nearest the basal lamina of the seminiferous tubules, which did not show TH staining. We observed that psychostimulants induced downregulation of DRs mRNA expression and upregulation of TH protein expression in the testis. These findings suggest a potential role of the local dopaminergic system in psychostimulant-induced testicular pathology.
Krasnova I.N.,Molecular Neuropsychiatry Research Branch |
Marchant N.J.,Behavioral Neuroscience Research Branch |
Marchant N.J.,University of Melbourne |
Ladenheim B.,Molecular Neuropsychiatry Research Branch |
And 5 more authors.
Neuropsychopharmacology | Year: 2014
In a rat model of drug craving and relapse, cue-induced drug seeking progressively increases after withdrawal from methamphetamine and other drugs, a phenomenon termed 'incubation of drug craving'. However, current experimental procedures used to study incubation of drug craving do not incorporate negative consequences of drug use, which is a common factor promoting abstinence in humans. Here, we studied whether incubation of methamphetamine craving is observed after suppression of drug seeking by adverse consequences (punishment). We trained rats to self-administer methamphetamine or palatable food for 9 h per day for 14 days; reward delivery was paired with a tone-light cue. Subsequently, for one group within each reward type, 50% of the lever-presses were punished by mild footshock for 9-10 days, whereas for the other group lever-presses were not punished. Shock intensity was gradually increased over time. Next, we assessed cue-induced reward seeking in 1-h extinction sessions on withdrawal days 2 and 21. Response-contingent punishment suppressed extended-access methamphetamine or food self-administration; surprisingly, food-trained rats showed greater resistance to punishment than methamphetamine-trained rats. During the relapse tests, both punished and unpunished methamphetamine- and food-trained rats showed significantly higher cue-induced reward seeking on withdrawal day 21 than on day 2. These results demonstrate that incubation of both methamphetamine and food craving occur after punishment-induced suppression of methamphetamine or palatable food self-administration. Our procedure can be used to investigate mechanisms of relapse to drug and palatable food seeking under conditions that more closely approximate the human condition. © 2014 American College of Neuropsychopharmacology. All rights reserved.
PubMed | Molecular Neuropsychiatry Research Branch and Stevenson University
Type: | Journal: Scientific reports | Year: 2015
Methamphetamine (METH) produces increases in the expression of immediate early genes (IEGs) and of histone deacetylase 2 (HDAC2) in the rat nucleus accumbens (NAc). Here, we tested whether HDAC2 deletion influenced the effects of METH on IEG expression in the NAc. Microarray analyses showed no baseline differences in IEG expression between wild-type (WT) and HDAC2 knockout (KO) mice. Quantitative-PCR analysis shows that an acute METH injection produced time-dependent increases in mRNA levels of several IEGs in both genotypes. Interestingly, HDAC2KO mice displayed greater METH-induced increases in Egr1 and Egr2 mRNA levels measured at one hour post-injection. The levels of Fosb, Fra2, Egr1, and Egr3 mRNAs stayed elevated in the HDAC2KO mice 2 hours after the METH injection whereas these mRNAs had normalized in the WT mice. In WT mice, METH caused increased HDAC2 recruitment to the promoters some IEGs at 2 hours post injection. METH-induced prolonged increases in Fosb, Fra2, Egr1, and Egr3 mRNA levels in HDAC2KO mice were associated with increased enrichment of phosphorylated CREB (pCREB) on the promoters of these genes. Based on our observations, we hypothesize that HDAC2 may regulate the expression of these genes, in part, by prolonging the actions of pCREB in the mouse NAc.
Omonijo O.,Molecular Neuropsychiatry Research Branch |
Wongprayoon P.,Mahidol University |
Ladenheim B.,Molecular Neuropsychiatry Research Branch |
McCoy M.T.,Molecular Neuropsychiatry Research Branch |
And 3 more authors.
NeuroToxicology | Year: 2014
Methamphetamine use disorder is characterized by recurrent binge episodes. Humans addicted to methamphetamine experience various degrees of cognitive deficits and show evidence of neurodegenerative processes in the brain. Binge injections of METH to rodents also cause significant toxic changes in the brain. In addition, this pattern of METH injections can alter gene expression in the dorsal striatum. Gene expression is regulated, in part, by histone deacetylation. We thus tested the possibility that METH toxic doses might cause changes in the mRNA levels of histone deacetylases (HDACs). We found that METH did produce significant decreases in the mRNA expression of HDAC8, which is a class I HDAC. METH also decreased expression of HDAC6, HDAC9, and HDAC10 that are class II HDACs. The expression of the class IV HDAC, HDAC11, was also suppressed by METH. The expression of Sirt2, Sirt5, and Sirt6 that are members of class III HDACs was also downregulated by METH injections. Our findings implicate changes in HDAC expression may be an early indicator of impending METH-induced neurotoxicity in the striatum. This idea is consistent with the accumulated evidence that some HDACs are involved in neurodegenerative processes in the brain. © 2014 2014 Published by Elsevier Inc.
Cadet J.L.,Molecular Neuropsychiatry Research Branch
Molecular Psychiatry | Year: 2016
Epigenetic consequences of exposure to psychostimulants are substantial but the relationship of these changes to compulsive drug taking and abstinence is not clear. Here, we used a paradigm that helped to segregate rats that reduce or stop their methamphetamine (METH) intake (nonaddicted) from those that continue to take the drug compulsively (addicted) in the presence of footshocks. We used that model to investigate potential alterations in global DNA hydroxymethylation in the nucleus accumbens (NAc) because neuroplastic changes in the NAc may participate in the development and maintenance of drug-taking behaviors. We found that METH-addicted rats did indeed show differential DNA hydroxymethylation in comparison with both control and nonaddicted rats. Nonaddicted rats also showed differences from control rats. Differential DNA hydroxymethylation observed in addicted rats occurred mostly at intergenic sites located on long and short interspersed elements. Interestingly, differentially hydroxymethylated regions in genes encoding voltage (Kv1.1, Kv1.2, Kvb1 and Kv2.2)- and calcium (Kcnma1, Kcnn1 and Kcnn2)-gated potassium channels observed in the NAc of nonaddicted rats were accompanied by increased mRNA levels of these potassium channels when compared with mRNA expression in METH-addicted rats. These observations indicate that changes in differentially hydroxymethylated regions and increased expression of specific potassium channels in the NAc may promote abstinence from drug-taking behaviors. Thus, activation of specific subclasses of voltage- and/or calcium-gated potassium channels may provide an important approach to the beneficial treatment for METH addiction.Molecular Psychiatry advance online publication, 5 April 2016; doi:10.1038/mp.2016.48. © 2016 Macmillan Publishers Limited
Cadet J.L.,Molecular Neuropsychiatry Research Branch
Current Neuropharmacology | Year: 2016
Substance use disorders are neuropsychiatric illnesses that have substantial negative biopsychosocial impact. These diseases are defined as compulsive abuse of licit or illicit substances despite adverse medicolegal consequences. Although much research has been conducted to elucidate the pathobiological bases of these disorders, much remains to be done to develop an overarching neurobiological understanding that might be translatable to beneficial pharmacological therapies. Recent advances in epigenetics promise to lead to such an elucidation. Here I provide a brief overview of observations obtained using some models of psychostimulant administration in rodents. The review identifies CREB binding protein (CBP), HDAC1, HDAC2, HADC3, HDAC4, and HDAC5 as important players in the acetylation and deacetylation processes that occur after contingent or non-contingent administration of psychostimulants. These observations are discussed within a framework that suggests a need for better animal models of addiction in order to bring these epigenetic advances to bear on the pharmacological treatment of human addicts. © 2016 Bentham Science Publishers.
PubMed | Molecular Neuropsychiatry Research Branch
Type: Journal Article | Journal: Current neuropharmacology | Year: 2016
Substance use disorders are neuropsychiatric illnesses that have substantial negative biopsychosocial impact. These diseases are defined as compulsive abuse of licit or illicit substances despite adverse medicolegal consequences. Although much research has been conducted to elucidate the pathobiological bases of these disorders, much remains to be done to develop an overarching neurobiological understanding that might be translatable to beneficial pharmacological therapies. Recent advances in epigenetics promise to lead to such an elucidation. Here I provide a brief overview of observations obtained using some models of psychostimulant administration in rodents. The review identifies CREB binding protein (CBP), HDAC1, HDAC2, HADC3, HDAC4, and HDAC5 as important players in the acetylation and deacetylation processes that occur after contingent or non-contingent administration of psychostimulants. These observations are discussed within a framework that suggests a need for better animal models of addiction in order to bring these epigenetic advances to bear on the pharmacological treatment of human addicts.
PubMed | Molecular Neuropsychiatry Research Branch and Florida International University
Type: | Journal: Behavioral and brain functions : BBF | Year: 2015
HIV-infected individuals continue to experience neurocognitive deterioration despite virologically successful treatments. The causes of neurocognitive impairment are still unclear. However, several factors have been suggested including the role of genetics. There is evidence suggesting that neurocognitive impairment is heritable and individual differences in cognition are strongly driven by genetic variations. The contribution of genetic variants affecting the metabolism and activity of dopamine may influence these individual differences.The present study explored the relationship between two candidate genes (DRD4 and DRD2) and neurocognitive performance in HIV-infected adults. A total of 267 HIV-infected adults were genotyped for polymorphisms, DRD4 48 bp-variable number tandem repeat (VNTR), DRD2 rs6277 and ANKK1 rs1800497. The Short Category (SCT), Color Trail (CTT) and Rey-Osterrieth Complex Figure Tests (ROCT) were used to measure executive function and memory.Results showed significant associations with the SNP rs6277 and impaired executive function (odds ratio = 3.3, 95% CI 1.2-2.6; p = 0.004) and cognitive flexibility (odds ratio = 1.6, 95% CI 2.0-5.7; p = 0.001). The results were further stratified by race and sex and significant results were seen in males (odds ratio = 3.5, 95% CI 1.5-5.5; p = 0.008) and in African Americans (odds ratio = 3.1, 95% CI 2.3-3.5; p = 0.01). Also, DRD4 VNTR 7-allele was significantly associated with executive dysfunction.The study shows that genetically determined differences in the SNP rs6277 DRD2 gene and DRD4 48 bp VNTR may be risk factors for deficits in executive function and cognitive flexibility.