Dissociation between opioid and CRF1 antagonist sensitive drinking in Sardinian Alcohol Preferring Rats

Rationale The role of positive vs negative ethanol reinforcement in ethanol intake of Sardinian alcohol-preferring (sP) rats is unclear. Objectives To test the hypothesis that spontaneous ethanol self-administration of sP rats was sensitive to the opioid receptor antagonist naltrexone, whereas withdrawal-induced, but not spontaneous, ethanol self-administration would be sensitive to corticotropin-releasing factor(1) (CRF1) antagonists, implicating differential roles for positive and negative reinforcement, respectively. Methods Male sP rats operantly (FR1, 30 min/day) self-administered ethanol (10% v/v) until responding stabilized. One group (n=11) was made ethanol dependent through intermittent ethanol vapor exposure. Both nondependent (n=10) and dependent rats received the CRF1 antagonist LWH-63 (5, 10, and 20 mg/kg, s.c.). Separate nondependent sP rats (n=10) received the opioid antagonist naltrexone (16, 50, 150, and 450 mu g/kg, s.c.). Finally, CRF1 antagonists (MJL-1-109-2, LWH-63, and R121919) were studied for their actions on home-cage ethanol drinking in nondependent sP rats (n=6-8/group) under continuous, limited-access, or stressed conditions. Results Naltrexone potently reduced ethanol self-administration in nondependent sP rats. LWH-63 reduced heightened ethanol self-administration of vapor-sensitive, dependent sP rats. CRF1 antagonists did not reduce ethanol intake in nondependent sP rats. R121919 (10 mg/kg, s.c.) retained antistress activity in sP rats, blunting novelty stress-induced suppression of ethanol intake. Conclusions Spontaneous ethanol self-administration of sP rats was opioid dependent with CRF1 receptors implicated in withdrawal-induced drinking. Opioid and CRF1 receptors play different roles in ethanol reinforcement and perhaps the ethanol addiction cycle. Such distinctions may apply to subtypes of alcoholic patients who differ in their motivation to drink and ultimately treatment response