Cocaine-Seeking Behavior in Response to Drug-Associated Stimuli in Rats: Involvement of D3 and D2 Dopamine Receptors.

Previous studies employed a second-order schedule paradigm maintained by cocaine reinforcement to show that BP897, a dopamine D3 partial agonist, selectively modulated drug-seeking behavior. We investigated its effect on drug-seeking behavior induced by presentation of stimuli associated with and predictive of cocaine availability after a period of extinction and in the absence of any further cocaine. Male rats were trained to associate discriminative stimuli (SD) with the availability of intravenous (i.v.) 0.25 mg/0.1 ml/infusion cocaine (SD+) or no-reward (SD-) saline solution. Each infusion of cocaine or saline was followed by a response-cue signaling 20-s time-out (TO). After meeting the self-administration training criterion rats were placed on extinction conditions during which i.v. solutions and SDs were withheld. Every other 3 days on which rats met the extinction criterion, reinstatement tests were conducted, presenting the SD+ or SD- noncontingently together with a contingent presentation of cocaine- or saline-cues signaling 20-s TO. Regardless of the order of presentation or the nature of the stimuli (auditory or visual), cocaine-associated but not saline-associated stimuli reinstated responding on the previously active lever. Presentation of cocaine-associated stimuli induced lasting drug-seeking behavior for at least eight test sessions. BP897 (1.0 mg/kg i.p.) significantly attenuated this behavior. Since it has been reported that BP897 can interact with a panel of different receptors with high affinity, we evaluated the effects of 7-OH-DPAT, an agonist to D3 receptors, raclopride, a preferential antagonist to D2 receptors, and WAY 100,635, an antagonist at 5-HT1A receptors, on drug-seeking behavior. 7-OH-DPAT (0.1-3.0 mg/kg i.p.) had biphasic effects on reinstatement induced by the cocaine-associated cues, low dosages reducing and high dosages increasing the impact of cocaine-associated stimuli on rats' behavior. Raclopride (0.1, 0.3 mg/kg s.c.) completely prevented drug-seeking behavior induced by the reintroduction of cocaine-associated stimuli. WAY 100,635 (0.1-1.0 mg/kg s.c.) had no effect on this behavior. These results, while confirming that the partial agonist at the D3 receptors, BP897, might be a useful medication, also suggest a role of D2 receptors in cue-induced cocaine-seeking behavior. [ABSTRACT FROM AUTHOR]