Reinforcing effects of sigma-receptor agonists in rats trained to self-administer cocaine - PubMed (original) (raw)

Reinforcing effects of sigma-receptor agonists in rats trained to self-administer cocaine

Takato Hiranita et al. J Pharmacol Exp Ther. 2010 Feb.

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.

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Figures

Fig. 1.

Fig. 1.

Representative cumulative records of self-administration maintained by intravenous cocaine injection under the fixed-ratio five-response schedule and those obtained when σR agonists or saline were substituted for cocaine. Ordinates, cumulative responses. Abscissae, time. Each experimental session started with a 2-min time-out period during which all LEDs over the levers were off, and responses had no scheduled consequences (lower event line up). After the time-out (lower event line down), lights above the levers were illuminated, although responses had no scheduled consequences (extinction, EXT) for 20 min, followed by another 2-min time-out. When the LEDs were again illuminated, each fifth response turned off the LEDs and activated the infusion pump (diagonal marks on the cumulative record). Vertical marks on the line below the cumulative curve indicate responses on the left (inactive) lever. A 20-s time-out period during which lights were off and responding had no scheduled consequences followed each injection, after which the LEDs were again illuminated, and each fifth response produced an injection. During each 20-min period of drug availability, the injection volumes were adjusted to deliver doses (in mg/kg/inj as indicated on the figure) in an ascending order. The cumulative curve reset to the baseline at the end of the 20-min component.

Fig. 2.

Fig. 2.

Substitution of σR ligands in rats trained to self-administer cocaine. Ordinates, responses per second. Abscissae, injection dose in mg/kg. Each point represents the mean ± S.E.M. (n = 6). A, cocaine (●), DTG (□), and PRE-084 (Δ). B, cocaine (●), BD 1008 (□), BD 1047 (Δ), and BD 1063 (○).

Fig. 3.

Fig. 3.

Effects of presession treatments with σR antagonists on cocaine self-administration. Ordinates, responses per second. Abscissae, injection dose in mg/kg. Each point represents the mean ± S.E.M. (n = 6). BD 1008, BD 1047, and BD 1063 were administered intraperitoneally at 5, 15, and 5 min before sessions, respectively. A, effects of BD 1008 (3.2, 10, and 32 mg/kg) on cocaine self-administration. B, effects of BD 1047 (3.2, 10, and 32 mg/kg) on cocaine self-administration. C, effects of BD 1063 (3.2, 10, and 32 mg/kg) on cocaine self-administration.

Fig. 4.

Fig. 4.

Effects of presession treatments with σR antagonists on self-administration of DTG in rats trained to self-administer cocaine. Ordinates, responses per second. Abscissae, injection dose in mg/kg. Each point represents the mean ± S.E.M. (n = 6). BD 1008, BD 1047, and BD 1063 were administered intraperitoneally at 5, 15, and 5 min before sessions, respectively. A, effects of BD 1008 (1.0, 3.2, and 10 mg/kg) on DTG self-administration. B, effects of BD 1047 (1.0, 3.2, and 10 mg/kg) on DTG self-administration. C, effects of BD 1063 (1.0, 3.2, and 10 mg/kg) on DTG self-administration.

Fig. 5.

Fig. 5.

Effects of presession treatments with σR antagonists on self-administration of PRE-084 in rats trained to self-administer cocaine. Ordinates, responses per second. Abscissae, injection dose in mg/kg. Each point represents the mean ± S.E.M. (n = 6). BD 1008, BD 1047, and BD 1063 were administered intraperitoneally at 5, 15, and 5 min before sessions, respectively. A, effects of BD 1008 (1.0, 3.2, and 10 mg/kg) on PRE-084 self-administration. B, effects of BD 1047 or BD 1063 (each at 10 mg/kg) on PRE-084 self-administration.

Fig. 6.

Fig. 6.

Effects of presession treatments with σR agonists on cocaine self-administration. Ordinates, responses per second. Abscissae, injection dose in mg/kg. Each point represents the mean ± S.E.M. (n = 6). Both σR agonists were administered intraperitoneally at 30 min before sessions. A, effects of DTG (3.2, 10, and 32 mg/kg) on cocaine self-administration. B, effects of PRE-084 (1.0, 3.2, and 10 mg/kg) on cocaine self-administration.

Fig. 7.

Fig. 7.

Effects of presession treatments with WIN 35,428 on self-administration of σR agonists in rats trained to self-administer cocaine. Ordinates, responses per second. Abscissae, injection dose in mg/kg. Each point represents the mean ± S.E.M. (n = 6). WIN 35,428 was administered intraperitoneally at 5 min before sessions. A, effects of WIN 35,428 (0.1, 0.32, and 1.0 mg/kg) on DTG self-administration. B, effects of WIN 35,428 (0.1, 0.32, and 1.0 mg/kg) on PRE-084 self-administration.

Fig. 8.

Fig. 8.

Effects of presession treatments with σR antagonists on responding maintained by cocaine, PRE-084, or DTG injection or food presentation. Ordinates, response rates as percentage of control response rates (sessions before drug tests). Abscissae, mg/kg test compounds administered intraperitoneally, log scale. BD 1008, BD 1047, and BD 1063 were administered intraperitoneally at 5, 15, and 5 min before sessions, respectively. Responding was from the fourth 20-min component of the session (see Materials and Methods). Each point represents the mean ± S.E.M. (n = 6). Rates of responding maintained by food reinforcement averaged 0.58 ± 0.11 responses/s, whereas those maintained by cocaine, DTG, and PRE-084 averaged 0.39 ± 0.10, 0.39 ± 0.12, and 0.43 ± 0.12 responses/s, respectively. None of these control response rates were significantly different (p = 0.255, one-way ANOVA).

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