Pavlovian Cue-Driven Alcohol-Seeking: The Role of Dopamine and Impact of Vendor Differences in Long Evans Rats

摘要

Rationale Drug-associated environmental stimuli can acquire incentive and motivational properties through Pavlovian conditioning, and come to function as conditioned cues that elicit drug-seeking behavior. Objectives The current experiments tested the hypothesis that dopamine mediates alcohol-seeking driven by Pavlovian alcohol-predictive cues. Studies were conducted in Long-Evans rats obtained from two different sources, based on published reports that oral alcohol consumption can differ within-strain. Method Male, Long-Evans rats (220-240 g on arrival) from Charles River (St-Constant, Canada) and Harlan Laboratories (Indianapolis, USA) received intermittent, 24-h access to ethanol (15%; v/v) and water via 2 bottles on the home cage (21 sessions). Next, rats were trained to discriminate between 2 auditory stimuli (10-sec each; white noise or clicker); one stimulus (CS+) was paired with ethanol (0.2 ml per CS+; 3.2 ml per session; oral consumption) and the second stimulus (CS-) was not paired with ethanol. During 17 daily, 60-min Pavlovian discrimination training (PDT) sessions rats received 16 random presentations each of the CS+ and CS- delivered according to a variable-time 67-sec schedule. Entries made into a fluid port to consume ethanol were recorded before, during and after each CS. Following PDT, rats were habituated (5 sessions; 60-min) to a different, non-alcohol context where the cues and ethanol were withheld. At test, responding to the non-extinguished CS+ and CS- was measured in the second, non-alcohol context in the absence of ethanol. Rats received injections of a dopamine D1-like receptor antagonist (SCH 23390; 0, 3.33 and 10 µg/kg; 1 ml/kg; s.c.) or a dopamine D2-like receptor antagonist (eticlopride; 0, 5, 10 µg/kg; 1 ml/kg; s.c.) 15-min before the test. In addition, we examined the impact of SCH 23390 (10 µg/kg; 1 ml/kg; s.c.); and eticlopride (10 µg/kg; 1 ml/kg; s.c.) on responding to the CS+ and CS- during PDT sessions when the CS+ was paired with ethanol. Results Rats from Charles River gained weight more rapidly and attained significantly higher overall weights than rats from Harlan. Across pre-exposure, ethanol consumption and preference were higher in Harlan rats. Across PDT sessions, rats from both vendors responded more to the alcohol-paired CS+ than the CS-. Total port-entry responses decreased across habituation in the second context. At test in a non-alcohol context, saline infused rats responded more to the CS+ than the CS-, indicating that discrimination between the two cues remained intact despite the absence of ethanol at test. Pre-treatment with SCH 23390 dose-dependently attenuated CS+ responding in rats from both vendors. However, eticlopride dose-dependently reduced CS+ responding in Harlan rats, but not in rats from Charles River. An infusion of SCH 23390, but not eticlopride reduced CS+ responding when cue presentations were paired with ethanol. Conclusion These results indicate novel differences in Long Evans rats obtained from different breeders. They also suggest that dopamine neurotransmission is required for responding to Pavlovian alcohol-predictive cues that are experienced in a non-alcohol context.ududKeywords: Alcohol, Pavlovian conditioning, cues, context, dopamine, SCH 23390, eticlopride, vendor differences, Long-Evansud