ABSTRACT
Alcohol use disorders (AUD) have a strong component of heritability; however, the neurobiological mechanisms mediating the propensity to consume excessive amounts of alcohol are still not well understood. Pituitary adenylate cyclase-activating polypeptide (PACAP), a highly conserved neuropeptide which exerts its effects mainly through the PAC1 receptor (PAC1R), has been suggested to be one of the mediators of the effects of drugs of abuse and alcohol. Here, we investigated the role of the PACAP/PAC1R system in excessive alcohol drinking in alcohol-preferring rats, an established animal model of AUD. Intracerebroventricular (i.c.v.) administration of the PAC1R antagonist PACAP(6-38) blocked excessive alcohol drinking and motivation to drink in Sardinian alcohol-preferring (Scr:sP) rats, without affecting water, saccharin, or sucrose intake. Notably, PACAP(6-38) did not affect ethanol responding in outbred Wistar rats. PACAP(6-38) also significantly reduced alcohol-seeking behavior under a second-order schedule of reinforcement. Using immunohistochemistry, a significant increase in the number of PAC1R positive cells was observed selectively in the nucleus accumbens (NAcc) Core of Scr:sP rats, compared to Wistar rats, following alcohol drinking. Finally, excessive drinking in Scr:sP rats was suppressed by intra-NAcc Core, but not intra-NAcc Shell, PACAP(6-38), as well as by virally-mediated PAC1R knockdown in the NAcc Core. The present study shows that hyperactivity of the PACAP/PAC1R system specifically in the NAcc Core mediates excessive drinking of alcohol-preferring rats, and indicates that this system may represent a novel target for the treatment of AUD.
Subject(s)
Alcohol Drinking , Alcoholism , Pituitary Adenylate Cyclase-Activating Polypeptide , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide , Alcohol Drinking/drug therapy , Alcohol Drinking/metabolism , Alcoholism/drug therapy , Alcoholism/metabolism , Animals , Nucleus Accumbens/metabolism , Pituitary Adenylate Cyclase-Activating Polypeptide/pharmacology , Rats , Rats, Wistar , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/antagonists & inhibitors , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/metabolismABSTRACT
BACKGROUND: Alcohol use disorder (AUD) is a complex psychiatric disease characterized by high alcohol intake as well as hyperkatifeia and hyperalgesia during withdrawal. A role for Sigma-1 receptors (Sig-1Rs) in the rewarding and reinforcing effects of alcohol has started to emerge in recent years, as rat studies have indicated that Sig-1R hyperactivity may result in excessive alcohol drinking. Sig-1R studies in mice are very scarce, and its potential role in alcohol-induced hyperalgesia is also unknown. METHODS: In this study, we investigated the role of Sig-1R in alcohol drinking and associated hyperalgesia in male mice, using an intermittent access 2-bottle choice model of heavy drinking. RESULTS: The Sig-1R antagonist BD-1063 was found dose dependently to reduce both alcohol intake and preference, without affecting either water or sucrose intake, suggesting that the effects are specific for alcohol. Notably, the ability of BD-1063 to suppress ethanol intake correlated with the individual baseline levels of alcohol drinking, suggesting that the treatment was more efficacious in heavy drinking animals. In addition, BD-1063 reversed alcohol-induced hyperalgesia during withdrawal, assessed using an automatic Hargreaves test, without affecting thermal sensitivity in alcohol-naïve animals or locomotor activity in either group. CONCLUSIONS: These data show that Sig-1R antagonism dose-dependently reduced ethanol consumption in heavy drinking mice as well as its efficacy in reducing alcohol-induced hyperalgesia. These findings provide a foundation for the development of novel treatments for AUD and associated pain states.
