Cocaine-seeking behavior in response to drug-associated stimuli in rats: Involvement of D3 and D2 dopamine receptors

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 28; no. 6; pp. 1150 - 1159
• Main Authors: CERVO, L, CARNOVALI, F, STARK, J. A, MENNINI, T
• Format: Journal Article
• Language: English
• Published: New York, NY Nature Publishing 01.06.2003; Nature Publishing Group
• Subjects: Animals; Behavior, Addictive - psychology; Biological and medical sciences; Cocaine; Cocaine - administration & dosage; Cues; Dopamine; Drug addictions; Drug dosages; Extinction; Extinction, Psychological - drug effects; Extinction, Psychological - physiology; Laboratory animals; Male; Medical sciences; Nervous system; Piperazines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2 - agonists; Receptors, Dopamine D2 - physiology; Receptors, Dopamine D3; Self Administration - methods; Self Administration - psychology; Tetrahydronaphthalenes - pharmacology; Toxicology; Italy; Agonist; Relapse; Intravenous administration; Rat; Psychotropic; Self administration; WAY 100,635; D3 Dopamine receptor; BP897; Learning; raclopride; Ester; 7-OH-DPAT; Acquisition process; reinstatement; Dependence; Reinforcement; Drug of abuse; Chemical stimulus; CNS stimulant; Rodentia; Instrumental conditioning; Vertebrata; Mammalia; D2 Dopamine receptor; Animal; Cocaine; Stimulus discrimination; dopamine
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/sj.npp.1300169

Previous studies employed a second-order schedule paradigm maintained by cocaine reinforcement to show that BP897, a dopamine D(3) 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 (S(D)) with the availability of intravenous (i.v.) 0.25 mg/0.1 ml/infusion cocaine (S(D+)) or no-reward (S(D-)) 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 S(D)s were withheld. Every other 3 days on which rats met the extinction criterion, reinstatement tests were conducted, presenting the S(D+) or S(D-) 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 D(3) receptors, raclopride, a preferential antagonist to D(2) receptors, and WAY 100,635, an antagonist at 5-HT(1A) 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 D(3) receptors, BP897, might be a useful medication, also suggest a role of D(2) receptors in cue-induced cocaine-seeking behavior.