• Energy Research

In the present study, we aimed to assess the impact of early life stress, in the form of early maternal deprivation (MD, 24 h on postnatal day, pnd, 9), on voluntary alcohol intake in adolescent male and femaleWistarrats. During adolescence, from pnd 28 to pnd 50, voluntary ethanol intake (20%, v/v) was investigated using the two-bottle free choice paradigm. To better understand the relationship between stress and alcohol consumption, voluntary alcohol intake was also evaluated following additional stressful events later in life, that is, a week of alcohol cessation and a week of alcohol cessation combined with exposure to restraint stress. Female animals consumed more alcohol than males only after a second episode of alcohol cessation combined with restraint stress. MD did not affect baseline voluntary alcohol intake but increased voluntary alcohol intake after stress exposure, indicating that MD may render animals more vulnerable to the effects of stress on alcohol intake. During adolescence, when animals had free access to alcohol, MD animals showed lower body weight gain but a higher growth rate than control animals. Moreover, the higher growth rate was accompanied by a decrease in food intake, suggesting an altered metabolic regulation in MD animals that may interact with alcohol intake.

Tobacco and alcohol are highly co-abused by humans. Most experimental studies have evaluated ethanol consumption in animals exposed concomitantly to nicotine. However, little is known regarding the effects of nicotine administered during periods of alcohol deprivation. In the present study, adult male Wistar rats with an extended background of operant self-administration of ethanol were alcohol-deprived and treated with nicotine (0.1, 0.2, 0.4 and 0.8 mg/kg) or saline during five consecutive days in one chamber of a place conditioning apparatus. Nicotine-induced changes in locomotion were monitored daily, whereas the expression of place conditioning was studied the day after the last nicotine injection. Forty-eight hours after testing for conditioning, the animals resumed operant self-administration of ethanol and their alcohol intake was evaluated during the next 14 days. We observed that alcohol consumption was increased in animals treated with nicotine at doses of 0.2, 0.4 and 0.8 mg/kg but not in animals treated with the dose of 0.1 mg/kg or saline. Additionally, the dose of 0.8 mg/kg of nicotine not only induced persistent changes in alcohol self-administration but also produced conditioned place aversion and depressed locomotor activity. These results indicate that nicotine administration during the ethanol deprivation period can exacerbate the maintenance of alcohol consumption.

Recreational use of (±)-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is often associated with other drugs, among which ethanol (EtOH) is one of the most common. However, little is known about how neurochemical sensitization produced by MDMA can modulate EtOH abuse. In this study we used EtOH operant self-administration tasks to investigate the effect of several low doses (0.33, 1.0 and 3.0 mg/kg) of MDMA in Dark Agouti rats. Motor activity was recorded after each MDMA administration. Changes in extracellular dopamine in the nucleus accumbens following a single EtOH injection (1.5 g/kg i.p.) were measured using intracerebral microdialysis in vivo after 1 wk of abstinence from EtOH, in order to mimic the dopaminergic response associated with reinstatement into EtOH consumption. Animals exposed to higher doses of MDMA (1.0 and 3.0 mg/kg) showed significantly enhanced EtOH self-administration during reinstatement and an increased EtOH-induced dopamine efflux. MDMA treatment acutely elevated motor activity after each administration in a dose-dependent manner. These findings suggest that repeated administration of MDMA, a relatively common drug of abuse, even at low doses, can alter subsequent vulnerability to EtOH consumption.

Alcoholism is characterized by successive periods of abstinence and relapse, resulting from long-lasting changes in various circuits of the central nervous system. Accumulating evidence points to the endocannabinoid system as one of the most relevant biochemical systems mediating alcohol addiction. The endocannabinoid system regulates adult neurogenesis, a form of long-lasting adult plasticity that occurs in a few areas of the brain, including the dentate gyrus. Because exposure to psychotropic drugs regulates adult neurogenesis, it is possible that neurogenesis might be implicated in the pathophysiology, and hence treatment, of neurobiological illnesses related to drugs of abuse. Here, we investigated the sensitivity of adult hippocampal neurogenesis to alcohol and the cannabinoid receptor agonist WIN 55,212-2 (WIN). Specifically, we analysed the potential link between alcohol relapse, cannabinoid receptor activation, and adult neurogenesis. Adult rats were exposed to subchronic alcohol binge intoxication and received the cannabinoid receptor agonist WIN. Another group of rats were subjected to an alcohol operant self-administration task. Half of these latter animals had continuous access to alcohol, while the other half were subjected to alcohol deprivation, with or without WIN administration. WIN treatment, when administered during alcohol deprivation, resulted in the greatest increase in alcohol consumption during relapse. Together, forced alcohol binge intoxication and WIN administration dramatically reduced hippocampal neurogenesis. Furthermore, adult neurogenesis inversely correlated with voluntary consumption of alcohol. These findings suggest that adult hippocampal neurogenesis is a key factor involved in drug abuse and that it may provide a new strategy for the treatment of alcohol addiction and dependence.

Background and PurposeRecent and ongoing clinical studies have indicated that topiramate (Topamax®) could be effective in treating ethanol or cocaine abuse. However, the effects of topiramate on the co‐administration of ethanol and cocaine remain largely unknown.Experimental ApproachWe studied the effects of topiramate, inWistar rats, on operant ethanol self‐administration with the co‐administration of cocaine (i.p.). The psychomotor effects of topiramate were examined before ethanol self‐administration and cocaine exposure. Blood samples were collected to analyse ethanol and cocaine metabolism (blood ethanol levels and benzoylecgonine). Quantitative real‐timePCRwas used to characterize the gene expression in the prefrontal cortex.Key ResultsTopiramate prevented the cocaine‐induced increased response to ethanol in a dose‐dependent manner without causing any motor impairment by itself. This effect was observed when topiramate was administered before ethanol access, but not when topiramate was administered before the cocaine injection. Topiramate did not block cocaine‐induced psychomotor stimulation. Topiramate reduced blood ethanol levels but did not affect cocaine metabolism. Ethanol increased the gene expression ofDNAmethyltransferases (Dnmt1andDnmt3a), the corepressorDnmt1‐associated protein 1 (Dmap1), and theRNAmethyltransferaseTrdmt1. These effects were prevented by topiramate or cocaine. Gene expression of histone deacetylase‐2 and glutamate receptor kainate‐1 were only increased by cocaine treatment. Topiramate and cocaine co‐administration caused an up‐regulation of dopamine (Drd1,Th) and opioid (Oprm1) receptor genes. Topiramate showed a tendency to alter episodic‐like memory.Conclusions and ImplicationsTopiramate is an effective inhibitor of the cocaine‐induced increase in operant ethanol self‐administration.

Alcoholism is characterized by successive relapses. Recent data have shown a cross-talk between the cannabinoid system and ethanol. In this study, male Wistar rats with a limited (30 min sessions), intermittent, and extended background of alcohol operant self-administration were used. The relapse to alcohol after 1 week of alcohol deprivation was evaluated. Two weeks later, the animals were treated with the cannabinoid agonist WIN 55,212-2 (R-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate) (0, 0.4, 2.0, and 10.0 mg/kg, s.c.) during a similar alcohol deprivation period, and alcohol relapse during 2 weeks was assessed. A conditioned place preference (CPP) paradigm was used to study the rewarding properties of the cannabinoid agonist. Locomotor activity was also recorded. All doses of WIN 55,212-2 produced aversion in the CPP paradigm. The doses of 2.0 and 10.0 mg/kg resulted in an important suppression of spontaneous locomotor activity and a progressive weight loss during the next 2 weeks. The single alcohol deprivation was followed by a transient increase in their responding for alcohol from a range of 20-24 lever presses at baseline to a range of 38-48 responses in the first and second days (alcohol deprivation effect). However, the administration of WIN 55,212-2 during ethanol deprivation produced similar increased responses for alcohol but in a long-term way (at least over 2 weeks). These findings suggest that noncontingent chronic exposure to cannabinoids during alcohol deprivation can potentiate the relapse into alcohol use, indicating that functional changes in the cannabinoid brain receptor may play a key role in ethanol relapse.

ABSTRACTα‐Synuclein (α‐syn) protein and endocannabinoid CB1 receptors are primarily located in presynaptic terminals. An association between α‐syn and CB1 receptors has recently been established in Parkinson's disease, but it is completely unknown whether there is an association between these two proteins in alcohol addiction. Therefore, we aimed to examine the α‐syn mRNA transcript and protein expression levels in the prefrontal cortex, striatum, amygdala and hippocampus. These brain regions are the most frequently implicated in alcohol and other drug addiction. In these studies, we used C57BL/6 mice carrying a spontaneous deletion of the α‐syn gene (C57BL/6Snca‐/‐) and their respective controls (C57BL/6Snca+/+). These animals were monitored for spontaneous alcohol consumption (3–10%) and their response to a hypnotic‐sedative dose of alcohol (3 g kg−1) was also assessed. Compared with the C57BL/6Snca+/+ mice, we found that the C57BL/6Snca‐/‐ mice exhibited a higher expression level of the CB1 mRNA transcript and CB1 receptor in the hippocampus and amygdala. Furthermore, C57BL/6Snca‐/‐ mice showed an increase in alcohol consumption when offered a 10% alcohol solution. There was no significant difference in sleep time after the injection of 3 g/kg alcohol. These results are the first to reveal an association between α‐syn and the CB1 receptor in the brain regions that are most frequently implicated in alcohol and other drug addictions. Synapse 00:000–000, 2013. © 2013 Wiley Periodicals, Inc.