Effects of CRF1-receptor and opioid-receptor antagonists on dependence-induced increases in alcohol drinking by alcohol-preferring (P) rats

Background: Selective breeding of rats over generations and induction of alcohol dependence via chronic vapor inhalation both enhance alcohol consumption in animal models. The purpose of this study was to determine whether dependence-induced increases in alcohol consumption by P rats is sensitive to naltrexone, a general opioid receptor antagonist (but with highest affinity at the mu-opioid receptor at low doses), and the recently characterized small molecule CRF1-receptor antagonist MPZP (N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-amine). Methods: P rats (n = 20) were trained to respond for alcohol and water in a 2-lever operant situation during daily 30-minute sessions. P rats were then matched for alcohol intake and exposed to chronic intermittent alcohol vapor (n = 10) or ambient air (n = 10) for approximately 10 weeks. All rats were then administered MPZP and naltrexone in 2 separate and consecutive Latin-square designs. Results: MPZP attenuated dependence-induced increases in alcohol intake by P rats while having no effect on alcohol consumption by nondependent controls. Conversely, operant alcohol responding was reduced similarly in dependent and nondependent P rats by naltrexone. Conclusions: These results confirm a role for brain CRF1-receptor systems in dependence-induced changes in the reinforcing properties of alcohol, and CRF1-receptor blockade appears to suppress dependence-induced drinking at lower doses in P rats relative to other rat lines. Therefore, brain CRF1-receptor systems are important in the regulation of dependence-induced alcohol consumption, whereas brain opioid systems are important in the regulation of basal alcohol consumption by rats.