Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2.

Epigenetic processes have been implicated in the pathophysiology of alcohol dependence, but the specific molecular mechanisms mediating dependence-induced neuroadaptations remain largely unknown. Here, we found that a history of alcohol dependence persistently decreased the expression of Prdm2, a histone methyltransferase that monomethylates histone 3 at the lysine 9 residue (H3K9me1), in the rat dorsomedial prefrontal cortex (dmPFC). Downregulation of Prdm2 was associated with decreased H3K9me1, supporting that changes in Prdm2 mRNA levels affected its activity. Chromatin immunoprecipitation followed by massively parallel DNA sequencing showed that genes involved in synaptic communication are epigenetically regulated by H3K9me1 in dependent rats. In non-dependent rats, viral-vector-mediated knockdown of Prdm2 in the dmPFC resulted in expression changes similar to those observed following a history of alcohol dependence. Prdm2 knockdown resulted in increased alcohol self-administration, increased aversion-resistant alcohol intake and enhanced stress-induced relapse to alcohol seeking, a phenocopy of postdependent rats. Collectively, these results identify a novel epigenetic mechanism that contributes to the development of alcohol-seeking behavior following a history of dependence.

Preclinical evaluation of the kappa-opioid receptor antagonist CERC-501 as a candidate therapeutic for alcohol use disorders.

Prior work suggests a role of kappa-opioid signaling in the control of alcohol drinking, in particular when drinking is escalated due to alcohol-induced long-term neuroadaptations. Here, we examined the small molecule selective kappa antagonist CERC-501 in rat models of alcohol-related behaviors, with the objective to evaluate its potential as a candidate therapeutic for alcohol use disorders. We first tested the effect of CERC-501 on acute alcohol withdrawal-induced anxiety-like behavior. CERC-501 was then tested on basal as well as escalated alcohol self-administration induced by 20% alcohol intermittent access. Finally, we determined the effects of CERC-501 on relapse to alcohol seeking triggered by both stress and alcohol-associated cues. Control experiments were performed to confirm the specificity of CERC-501 effects on alcohol-related behaviors. CERC-501 reversed anxiety-like behavior induced by alcohol withdrawal. It did not affect basal alcohol self-administration but did dose-dependently suppress self-administration that had escalated following long-term intermittent access to alcohol. CERC-501 blocked relapse to alcohol seeking induced by stress, but not when relapse-like behavior was triggered by alcohol-associated cues. The effects of CERC-501 were observed in the absence of sedative side effects and were not due to effects on alcohol metabolism. Thus, in a broad battery of preclinical alcohol models, CERC-501 has an activity profile characteristic of anti-stress compounds. Combined with its demonstrated preclinical and clinical safety profile, these data support clinical development of CERC-501 for alcohol use disorders, in particular for patients with negatively reinforced, stress-driven alcohol seeking and use.

Wistar rats acquire and maintain self-administration of 20 % ethanol without water deprivation, saccharin/sucrose fading, or extended access training.

RATIONALE: Operant self-administration (SA) is an important model of motivation to consume ethanol (EtOH), but low rates of voluntary consumption in rats are thought to necessitate water deprivation and saccharin/sucrose fading for acquisition of responding. OBJECTIVES: Here, we sought to devise an effective model of SA that does not use water deprivation or saccharin/sucrose fading. METHODS: First, we tested if Wistar rats would acquire and maintain SA behavior of 20 % EtOH under two conditions, water deprivation (WD) and non-water deprivation (NWD). Second, we tested the efficacy of our SA procedure by confirming a prior study which found that the NK1 antagonist L822429 specifically blocked stress-induced reinstatement of EtOH seeking but not SA. Finally, we assessed the effect of naltrexone, an FDA-approved medication for alcohol dependence that has been shown to suppress EtOH SA in rodents. RESULTS: Lever presses (LPs) and rewards were consistent with previous reports that utilized WD and saccharin/sucrose fading. Similar to previous findings, we found that L822429 blocked stress-induced reinstatement but not baseline SA of 20 % EtOH. Moreover, naltrexone dose-dependently decreased alcohol intake and motivation to consume alcohol for rats that are self-administering 20 % EtOH. CONCLUSIONS: Our findings provide a method for voluntary oral EtOH SA in rats that is convenient for experimenters and eliminates the potential confound of sweeteners in EtOH-operant SA studies. Unlike models that use intermittent access to 20 % EtOH, this method does not induce escalation, and based on pharmacological experiments, it appears to be driven by the positive reinforcing effects of EtOH.