A "free choice" two-bottle drinking lest paradigm was implemented in naive adult male Wistar rats, resulting in a clear identification of rats drinking mainly water (water-preferring, WP rats) and mrs spontaneously drinking also 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, selective doses (5 mu g/kg) of the the specific cholecystokinin (CCK)-A receptor antagonist L-364,718 largely reduced the intake of ethanol 10% of ED rats only. In contrast, low selective doses of GV-150013 (5 mu g/kg) reduced significantly the consumption of cocaine of Co rats only These results indicate that the CCK-A or B receptors are selectively involved in the modulation of alcohol or cocaine intake, respectively, and suggest an involvement of the CCKergic system in fire drug-seeking behavior: WP rats and CD rats were then prepared for ex vivo electro-neurochemical analysis by means of differential 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 receptor 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 stimulating effect of high endogenous CCKergic tone over CCK-B or CCK-A receptors in spontaneous ED or CD rats, respectively Therefore, the present data indicate that: i) Free-choice models mall reveal the presence of individual sensitivity to alcohol or cocaine in naive rats; ii) the dopaminergic system is involved within the reward state, while peptidergic (CCKergic) activities 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 particular the data imply a CCK-A receptor mechanism in the regulation of individual sensitivity towards ethanol and a CCK-B receptor mechanism in the regulation of individual sensitivity towards cocaine. Thus, a potential therapeutic role for CCK-A antagonists in the treatment of ethanol abuse and for CCK-B antagonists in the treatment of cocaine abuse is proposed. (C) 1998 Prous Science. All Fights reserved.
