Behavioral and neurochemical consequences of repeated nicotine treatment in the serotonin-depleted rat

Rationale: Repeated exposure to addictive drugs causes neuroadaptive altera tions that are proposed to increase the incentive motivation to consume dru gs and to decrease the ability to inhibit such inappropriate motivational i mpulses and responses. Together, these behavioral consequences of drug inta ke may underlie the compulsive drug-seeking and -taking behaviors observed in drug abuse. Objective. Brain serotonin (5-HT) has been implicated in the se mechanisms and this study therefore investigated the consequences of bra in 5-HT depletion on the behavioral and neurochemical effects induced by re peated daily nicotine treatment (15 days) in male rats. Methods: The effect s of the present pharmacological manipulations were evaluated behaviorally (locomotor activity, the elevated plus-maze) and neurochemically (microdial ysis, brain biochemistry). Results: Depletion of brain 5-HT produced behavi oral disinhibition in the elevated plus-maze. In 5-HT-depleted, nicotine-in duced locomotor sensitization was on treatment days 5, 10, and 15, but only on day 15 in the sham-operated rats. Postsensitization, the locomotor stim ulatory effects of amphetamine and the dopamine receptor agonists SKF 38,39 3, apomorphine, and quinpirole were decreased in 5-HT-depleted animals, an effect that appeared to be more pronounced in nicotine-treated rats. Repeat ed nicotine treatment sensitized the nicotine-induced elevation of the extr acellular accumbal dopamine levels in sham-operated, but not in 5-HT-deplet ed rats, and was also associated with decreased D-2 autoreceptor function i n both nicotine-treated experimental groups. Conclusions: Depletion of brai n 5-HT, which produces behavioral disinhibition, may slightly facilitate th e overall expression of locomotor sensitization to nicotine and differentia lly affect the pre- and postsynaptic neuroadaptive events involved in the e xpression of these phenomena.