• Energy Research

AbstractAs the contribution of cannabinoid (CB1) receptors in the neuroadaptations following chronic alcohol exposure is unknown, we investigated the neuroadaptations induced by chronic alcohol exposure on both NMDA and GABAA receptors in CB1−/− mice. Our results show that basal levels of hippocampal [3H]MK‐801 ((1)‐5‐methyl‐10,11‐dihydro‐5Hdibenzo[a,d]cyclohepten‐5,10‐imine) binding sites were decreased in CB1−/− mice and that these mice were also less sensitive to the locomotor effects of MK‐801. Basal level of both hippocampal and cerebellar [3H]muscimol binding was lower and sensitivity to the hypothermic effects of diazepam and pentobarbital was increased in CB1−/− mice. GABAAα1, β2, and γ2 and NMDA receptor (NR) 1 and 2B subunit mRNA levels were altered in striatum of CB1−/− mice. Our results also showed that [3H]MK‐801 binding sites were increased in cerebral cortex and hippocampus after chronic ethanol ingestion only in wild‐type mice. Chronic ethanol ingestion did not modify the sensitivity to the locomotor effects of MK‐801 in both genotypes. Similarly, chronic ethanol ingestion reduced the number of [3H]muscimol binding sites in cerebral cortex, but not in cerebellum, only in CB1+/+ mice. We conclude that lifelong deletion of CB1 receptors impairs neuroadaptations of both NMDA and GABAA receptors after chronic ethanol exposure and that the endocannabinoid/CB1 receptor system is involved in alcohol dependence.

AbstractConverging evidence indicates that epigenetic mechanisms are involved in drug addiction, and that enzymes involved in chromatin remodeling may represent interesting targets in addiction treatment. No study has addressed whether histone deacetylase (HDAC) inhibitors (HDACi) can reduce excessive ethanol intake or prevent relapse in alcohol‐dependent animals. Here, we assessed the effects of two HDACi, sodium butyrate (NaB) and MS‐275, in the operant ethanol self‐administration paradigm in dependent and non‐dependent rats. To characterize some of the epigenetic mechanisms associated with alcohol dependence and NaB treatment, we measured the levels of histone H3 acetylation in different brain areas of dependent and non‐dependent rats, submitted or not to NaB treatment. Our results demonstrated that (1) NaB and MS‐275 strongly decreased excessive alcohol intake of dependent rats in the operant ethanol self‐administration paradigm but not of non‐dependent rats; (2) NaB reduced excessive drinking and prevented the escalation of ethanol intake in the intermittent access to 20% ethanol paradigm; and (3) NaB completely blocked the increase of ethanol consumption induced by an alcohol deprivation, thus demonstrating a preventive effect of NaB on relapse. The mapping of cerebral histone H3 acetylation revealed a hyperacetylation in the amygdala and cortical areas in dependent rats. Interestingly, NaB did not exacerbate the hyperacetylation observed in these regions, but instead restored it, specifically in cortical areas. Altogether, our results clearly demonstrated the efficacy of NaB in preventing excessive ethanol intake and relapse and support the hypothesis that HDACi may have a potential use in alcohol addiction treatment.

Background: Ethanol addiction has been conceptualized as a progression from occasional, impulsive use to compulsive behavior. Ethanol‐dependence is a chronic pathology with repeated cycles of withdrawal, craving, and relapse. Specific molecular and cellular mechanisms underlie these transition stages.Methods: This review aimed at elucidating whether there are also adaptations in the pattern of brain regions responding to ethanol. This paper reviews the evidence in rodents for activation of specific brain regions, assessed by induction of IEG expression, following acute and chronic ethanol exposure.Results: The review sheds light on the specific patterns of response in regions of the brain to different types of ethanol exposure and shows that activation of specific brain regions may occur in particular phases of the development of ethanol addiction. Some brain regions respond consistently following acute or chronic treatments or withdrawal: the prefrontal cortex; nucleus accumbens; lateral septum; hippocampus; perioculomotor urocortin‐containing cells population (pIIIu), also known as Edinger‐Westphal nucleus; central nucleus of the amygdale; and the paraventricular nucleus of hypothalamus. The two last brain areas are particularly activated by relapse‐inducing stressors. It is of interest that the amygdala, hippocampus, and prefrontal cortex, which belong to the reward system, are activated by cue‐induced relapse to ethanol self‐administration in rodents and humans, while activation of these regions is reversed with anticraving compounds. Following chronic exposure, IEG induction desensitizes while withdrawal reactivates these regions.Discussion: Some responding regions are implicated in reward related processes (VTA, extended amygdala, hypothalamus, hippocampus, prelimbic cortex, ventral part of lateral septum) and some others in aversive‐related processes (area postrema, nucleus of solitary tract).Conclusion: A better understanding of the neural circuits affected by ethanol and their adaptations during the development of ethanol addiction will provide new opportunities for developing appropriate therapies.

Adolescent alcohol binge drinking constitutes a major vulnerability factor to develop alcoholism. However, mechanisms underlying this susceptibility remain unknown. We evaluated the effect of adolescent binge-like ethanol intoxication on vulnerability to alcohol abuse in Sprague-Dawley rats. To model binge-like ethanol intoxication, every 2 days, rats received an ethanol injection (3.0 g/kg) for 2 consecutive days across 14 days either from postnatal day 30 (PND30) to 43 (early adolescence) or from PND 45 to PND 58 (late adolescence). In young adult animals, we measured free ethanol consumption in the two-bottle choice paradigm, motivation for ethanol in the operant self-administration task and both ethanol's rewarding and aversive properties in the conditioned place preference (CPP) and taste aversion (CTA) paradigms. While intermittent ethanol intoxications (IEI) during late adolescence had no effect on free-choice 10% ethanol consumption, we found that IEI during early adolescence promoted free-choice 10% ethanol consumption, enhanced motivation for ethanol in the self-administration paradigm and induced a loss of both ethanol-induced CPP and CTA in young adults. No modification in either sucrose self-administration or amphetamine-induced CPP was observed. As the nucleus accumbens (Nac) is particularly involved in addictive behavior, we analyzed IEI-induced long-term neuroadaptations in the Nac using c-Fos immunohistochemistry and an array of neurotransmission-related genes. This vulnerability to ethanol abuse was associated with a lower c-Fos immunoreactivity in the Nac and enduring alterations of the expression of Penk and Slc6a4, 2 neurotransmission-related genes that have been shown to play critical roles in the behavioral effects of ethanol and alcoholism.

Growth factors, long studied for their involvement in neuronal development and plasticity, also regulate responses to drugs of abuse, including alcohol. This review details the intricate interaction between the Brain-Derived Neurotrophic Factor (BDNF) and alcohol, and provides evidence to suggest that corticostriatal BDNF signaling acts to keep alcohol drinking in moderation. Specifically, we describe studies in rodent models suggesting that moderate consumption of alcohol increases BDNF levels in the dorsal striatum, which in turn act to suppress alcohol intake by activating a Mitogen-Activated Protein Kinase (MAPK)-dependent genomic mechanism. We further provide data to suggest that alcohol intake levels escalate when the endogenous corticostriatal BDNF pathway becomes dysregulated. Finally, we summarize recent studies suggesting that specific microRNAs targeting BDNF mRNA in the medial prefrontal cortex (mPFC) regulate the breakdown of the protective corticostriatal BDNF pathway.

We have shown previously that mice lacking the adenosine A2A receptor (A2AR) generated on a CD1 background self‐administer more ethanol and exhibit hyposensitivity to acute ethanol. We aimed to investigate if the increased propensity of A2A−/− mice to consume ethanol is associated with an altered sensitivity in the motivational properties of ethanol in the conditioned place preference (CPP) and conditioned taste aversion (CTA) paradigms and with an altered development of sensitization to the locomotor effects of ethanol. We also tested their sensitivity to the anxiolytic effects of ethanol. Our results show that A2A−/− mice produced on a CD1 background displayed a reduced ethanol‐induced CPP and an increased sensitivity to the anxiolytic and locomotor‐stimulant effects of ethanol, but they did not show alteration in ethanol‐induced CTA and locomotor sensitization. Ethanol‐induced CPP, ethanol consumption and the locomotor effects of ethanol were also tested in A2A−/− mice produced on a C57BL/6J background. Our results emphasized the importance of the genetic background because alteration in ethanol consumption and preference, ethanol‐induced CPP and locomotor‐stimulant effects were not found in knockout mice produced on the alcohol‐preferring C57BL/6J genetic background. Finally, the A2AR agonist, 2‐p‐(2‐carboxyethyl)‐phenylethylamino‐5′‐N‐ethylcarboxamidoadenosine hydrochloride (CGS 21680), reduced ethanol consumption and preference in C57BL/6J mice. In conclusion, A2AR deficiency in mice generated on a CD1 background leads to high ethanol consumption that is associated with an increased sensitivity to the locomotor‐stimulant/anxiolytic effects of ethanol and a decrease in ethanol‐induced CPP.

An important factor that may influence addiction liability is exposure during the early life period. Exposure to ethanol, early in life, can have long-lasting implications on brain function and drugs of abuse response later in life. In the present study we investigated the behavioral responses to ethanol and to psychostimulants in Long Evans rats that have been exposed to pre- and postnatal ethanol. Since a relationship between heightened drug intake and susceptibility to drug-induced locomotor activity/sensitization has been demonstrated, we tested these behavioral responses, in control and early life ethanol-exposed animals. The young adult male and female progeny were tested for locomotor response to alcohol, cocaine and d-amphetamine. Sedative, rewarding effects of alcohol and alcohol consumption were measured. Our results show that early life ethanol exposure behaviorally sensitized animals to subsequent ethanol and psychostimulants exposure. Ethanol-exposed animals were also more sensitive to the hyperlocomotor effects of all drugs of abuse tested and to those of the dopamine receptor agonist apomorphine. Locomotor sensitization to repeated injections of cocaine was facilitated in ethanol-exposed animals. Ethanol-induced conditioned place preference was also facilitated in ethanol-exposed animals. Ethanol consumption and preference were increased after early life ethanol exposure and this was associated with decreased sensitivity to the sedative effects of ethanol. The altered behavioral responses to drugs of abuse were associated with decreased striatal dopamine transporter and hippocampal NMDAR binding. Our results outline an increased vulnerability to rewarding and stimulant effects of ethanol and psychostimulants and support the epidemiological and clinical data that suggested that early chronic exposure to ethanol may increase the propensity for later self-administration of ethanol or other substances.