title: Reinforcing effects of sigma-receptor agonists in rats trained to self-administer cocaine.
abstract: 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 cocaine, or by the sigmaR 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 sigmaR 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 sigmaR agonists dose-dependently shifted the cocaine self-administration dose-effect curve leftward. The dopamine-uptake inhibitor, (-)-2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane (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-administration by sigmaR-agonist pretreatment, and the facilitation of sigmaR-agonist self-administration by WIN 35,428, together suggest enhanced abuse-related effects resulting from concomitant dopaminergically mediated actions and sigmaR-mediated actions of the drugs.
authors.affiliation: Psychobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Takato
authors.initials: T
authors.lastname: Hiranita
authors.forename: Paul L
authors.initials: PL
authors.lastname: Soto
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Tanda
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Katz
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005021:Ethylamines / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000819:agonists* / Q000037:antagonists & inhibitors*; D012055:Reinforcement Schedule; D012201:Reward; D012646:Self Administration
chemical_list: C093337:1-(2-(3,4-dichlorophenyl)ethyl)-4-methylpiperazine; D018765:Dopamine Uptake Inhibitors; D005021:Ethylamines; D006146:Guanidines; D009025:Morpholines; D010879:Piperazines; D017480:Receptors, sigma; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine; C050232:1,3-ditolylguanidine