Hiranita T, Soto PL, Tanda G, Katz JL
Reinforcing Effects of {sigma}-Receptor Agonists in Rats Trained to Self-Administer Cocaine. [JOURNAL ARTICLE]
J Pharmacol Exp Ther 2009 Nov 5.
Sigma receptor (sigmaR) antagonists have been reported to block certain effects of psychostimulant drugs. The present study examined the effects of sigmaR ligands in rats trained to self-administer cocaine (0.032-1.0 mg/kg/inj, i.v.) under fixed-ratio 5-response schedules of reinforcement. Maximal rates of responding were maintained by 0.32 mg/kg/inj of cocaine, or by the sigmaR agonists, DTG (1.0 mg/kg/inj) or PRE-084 (0.32 mg/kg/inj), when substituted for cocaine. Lower response rates were maintained at higher and lower doses of the compounds. No dose of the sigmaR antagonists (BD 1008, BD 1047 and BD 1063) maintained responding appreciably above levels obtained when responding had no consequences. Pre-session treatment with sigmaR agonists dose-dependently shifted the cocaine self-administration dose-effect curve leftward. The dopamine-uptake inhibitor, WIN 35,428, dose-dependently shifted the DTG and PRE-084 self-administration dose-effect curves leftward. Treatment with the sigmaR antagonists dose-dependently decreased response rates maintained by DTG or PRE-084, but did not affect cocaine self-administration. Response rates maintained by maximally effective DTG or PRE-084 doses were decreased by sigmaR antagonists at lower doses than those that decreased response rates maintained by food reinforcement. Although sigmaR antagonists block some cocaine-induced effects, the lack of effect on cocaine self-administration suggests that the primary reinforcing effects of cocaine do not involve direct effects at sigmaRs. However, the self-administration of sigmaR agonists in cocaine-trained subjects, facilitation of cocaine self-administraton by sigmaR-agonist pretreatment, and the facilitation of sigmaR-agonist self-administration by WIN 35,428, together suggest enhanced abuserelated effects resulting from concomitant dopaminergically-mediated actions and sigmaR-mediated actions of the drugs.
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