Abstract
σ-Receptor (σR) antagonists have been reported to block certain effects of psychostimulant drugs. The present study examined the effects of σR 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 σR 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 σR 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 σR agonists dose-dependently shifted the cocaine self-administration dose-effect curve leftward. The dopamine-uptake inhibitor, (−)-2β-carbomethoxy-3β-(4-fluorophenyl)tropane (WIN 35,428), dose-dependently shifted the DTG and PRE-084 self-administration dose-effect curves leftward. Treatment with the σR 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 σR antagonists at lower doses than those that decreased response rates maintained by food reinforcement. Although σR 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 σRs. However, the self-administration of σR agonists in cocaine-trained subjects, facilitation of cocaine self-administration by σR-agonist pretreatment, and the facilitation of σR-agonist self-administration by WIN 35,428, together suggest enhanced abuse-related effects resulting from concomitant dopaminergically mediated actions and σR-mediated actions of the drugs.
Footnotes
This work was supported by the Intramural Research Program of the National Institute on Drug Abuse; and a Japan Society for the Promotion of Science Research Fellowship for Japanese Biomedical and Behavioral Researchers at the National Institutes of Health (to T.H.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.159236
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ABBREVIATIONS:
- σR
- σ-receptor
- σ1R
- σ1-receptor
- σ2R
- σ2-receptor
- inj
- injection
- BD 1008
- N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine dihydrobromide
- BD 1047
- N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide; BD 1063, 1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine dihydrochloride
- DTG
- 1,3-di-(2-tolyl)guanidine
- PRE-084
- 2-(4-morpholinethyl)1-phenylcyclohexane-1-carboxylate hydrochloride
- SKF 10,047
- N-allylnormetazocine hydrochloride
- WIN 35,428
- (-)-2β-carbomethoxy-3β-(4-fluorophenyl)tropane tartrate
- BMY 14802
- α-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol
- NE-100
- N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine
- NPC 16377
- 6-[6-(4-hydroxypiperidinyl)hexyloxy]-3-methylflavone hydrochloride
- (+)-3-PPP
- (+)-3-(3-hydroxyphenyl-N-(1-propyl)piperidine
- ANOVA
- analysis of variance
- EXT
- extinction
- FR
- fixed ratio
- LED
- light-emitting diode.
- Received July 22, 2009.
- Accepted November 3, 2009.
- U.S. Government work not protected by U.S. copyright
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