Abstract
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.
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Acknowledgements
Fruitful discussions with Dr Friedbert Weiss, Department of Neuropharmacology, Scripps Insitute, La Jolla, CA, USA, and Professor Vincenzo Crunelli, School of Bioscience, Cardiff University, Cardiff, Wales, UK, are gratefully acknowledged.
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This manuscript is dedicated to the memory of Dr Rosario Samanin.
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Cervo, L., Carnovali, F., Stark, J. et al. Cocaine-Seeking Behavior in Response to Drug-Associated Stimuli in Rats: Involvement of D3 and D2 Dopamine Receptors. Neuropsychopharmacol 28, 1150–1159 (2003). https://doi.org/10.1038/sj.npp.1300169
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DOI: https://doi.org/10.1038/sj.npp.1300169
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