Reinforcing Effects of σ-Receptor Agonists in Rats Trained to Self-Administer Cocaine

sigma-Receptor (sigma R) antagonists have been reported to block certain effects of psychostimulant drugs. The present study examined the effects of sigma R 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 cocaine, or by the sigma R agonists, 1,3-di-(2-tolyl)guanidine (DTG; 1.0 mg/kg/inj) or 2-(4-morpholinethyl) 1-phenylcyclohexane-1-carboxylate hydrochloride (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 sigma R antagonists [N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (BD 1008), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino) ethylamine (BD 1047), N-[ 2( 3,4-dichlorophenyl)ethyl]-4-methylpiperazine (BD 1063)] maintained responding appreciably above levels obtained when responding had no consequences. Presession treatment with sigma R agonists dose-dependently shifted the cocaine self-administration dose-effect curve leftward. The dopamine-uptake inhibitor, (-)-2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane (WIN 35,428), dose-dependently shifted the DTG and PRE-084 self-administration dose-effect curves leftward. Treatment with the sigma R 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 sigma R antagonists at lower doses than those that decreased response rates maintained by food reinforcement. Although sigma R 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 sigma Rs. However, the self-administration of sigma R agonists in cocaine-trained subjects, facilitation of cocaine self-administration by sigma R-agonist pretreatment, and the facilitation of sigma R-agonist self-administration by WIN 35,428, together suggest enhanced abuse-related effects resulting from concomitant dopaminergically mediated actions and sigma R-mediated actions of the drugs.