The role of cholecystokinin (CCK), CCK-A or CCK-B receptor antagonists in the spontaneous preference for drugs of abuse (alcohol or cocaine) in naiverats

A "free choice" two-bottle drinking lest paradigm was implemented in naive adult male Wistar rats, resulting in a clear identification of rats drinkin g,mainly water (water-preferring, WP rats) and mrs spontaneously drinking a lso a consistent amount of a solution of cocaine (0.5 mg/ml water; cocaine- drinking CD rats) or ethanol 10% v/v (ethanol-drinking, ED rats). Low, sele ctive doses (5 mu g/kg) of the the specific cholecystokinin (CCK)-A recepto r antagonist L-364,718 largely reduced the intake of ethanol 10% of ED rats only. rn contrast, ion: selective doses of GV-150013 (5 mu g/kg) reduced s ignificantly the consumption of cocaine of Co rats only These results indic ate that the CCK-A or B receptors are selectively involved in the modulatio n of alcohol or cocaine intake, respectively, and suggest an involvement of the CCKergic system in fire drug-seeking behavior: WP rats and CD rats wer e then prepared for ex vivo electro-neurochemical analysis by means of diff erential pulse voltammetry (DPV) with micro-biosensors to monitor catechol, 5-hydroxyindole and peptidergic oxidation signals in the nucleus accumbens (nAcc). In this area, the peptidergic signal appeared to be related to the oxidation of endogenous CCK, which basal levels resulted higher in ED and CD rats than WP rats. Thus, the hypothesis that the endogenous tone of the CCK system is higher in the ED and CD rats than in the CD rats is proposed, and is supported by the observation that treatment with CCK-5 (CCK recepto r agonist) selectively induced the WP rats to drink alcohol or cocaine. The selective effect of the CCK-antagonists on reducing the drug intake of ED or CD rats further supports this view, as it suggests that CCK antagonists may modify the individual sensitivity towards drugs of abuse set by the sti mulating effect of high endogenous CCKergic tone over CCK-B or CCK-A recept ors ill spontaneous ED or CD rats, respectively Therefore, the present data indicate that: i) Free-choice models mall reveal the presence of individua l sensitivity to alcohol or cocaine in naive rats; ii) the dopaminergic sys tem is involved within the reward state, while peptidergic (CCKergic) activ ities modulate the drug-seeking state (craving state); iii) the CCK system could be a new target in the study of the drug dependency phenomenon. In pa rticular the data imply a CCK-A receptor mechanism in the regulation of ind ividual sensitivity ton;ards ethanol and a CCK-B receptor mechanism in the regulation of individual sensitivity towards cocaine. Thus, a potential the rapeutic role for CCK-A antagonists in the treatment of ethanol abuse and f or CCK-B antagonists DI the treatment of cocaine abuse is proposed. (C) 199 8 Prous Science. All Fights reserved.