Effect of SCH 23390 on (+/-)-3,4-methylenedioxymethamphetamine hyperactivity and self-administration in rats.

Recently, we demonstrated that (+/-)-3,4-methylenedioxymethamphetamine (MDMA; ecstasy) was reliably and dose-dependently self-administered by previously drug-naïve laboratory rats. The neurochemical basis of MDMA self-administration has not, however, been extensively studied. The present study investigated the role of dopamine in MDMA self-administration and hyperactivity. Pretreatment with the D1-like antagonist, SCH 23390 (0.01-0.08 mg/kg) produced a dose-dependent attenuation of MDMA (20.0 mg/kg)-produced hyperactivity. In self-administration tests, the baseline rate of responding maintained by intravenous infusions varied inversely with MDMA dose; as the dose available was changed, responding also changed so that about 10.0 mg/kg MDMA was self-administered during each daily 2-h session. Pretreatment with SCH 23390 (0.02 mg/kg) produced a rightward shift in the MDMA dose-response curve. These findings suggest that MDMA self-administration, like self-administration of other drugs of abuse, is dependent on the activation of dopaminergic substrates.

Effects of SCH 23390 and eticlopride on cocaine-seeking produced by cocaine and WIN 35,428 in rats.

RATIONALE: Exposure to a small amount of cocaine can trigger relapse, and so an understanding of the mechanisms underlying cocaine-seeking are important for the development of effective anti-relapse treatments. OBJECTIVES: The present study sought to compare the contributions of dopamine D(1)- and D(2)-like receptors in drug-seeking produced by cocaine and WIN 35,428. METHODS: Reinstatement of extinguished cocaine self-administration was measured for rats that received injections of cocaine (5.0-20.0 mg/kg) or WIN 35,428 (0.1-1.0 mg/kg) following extinction. Prior to the injection of cocaine or WIN 35,428, rats received an injection of the D(1)-like antagonist, SCH 23390 (0.001-0.010 mg/kg) or the D(2)-like antagonist, eticlopride (0.01-0.30 mg/kg). Effects of SCH 23390 (0.01 mg/kg) on cocaine-produced locomotor activation were also measured in separate groups of rats. RESULTS: The ability of both cocaine and WIN 35,428 to produce cocaine-seeking was dose-dependent. Within the range of doses tested, SCH 23390 failed significantly to attenuate the ability of either cocaine or WIN 35,428 to reinstate extinguished cocaine self-administration, although cocaine-produced locomotor activation was significantly attenuated by pretreatment with the highest dose of SCH 23390. Eticlopride attenuated both cocaine and WIN 35,428 produced cocaine-seeking but lower doses were required to decrease WIN 35,428-produced cocaine-seeking. CONCLUSIONS: These results suggest that dopamine D(2) mechanisms are involved in cocaine-seeking produced by both cocaine and WIN 35,428. The lower potency of eticlopride in attenuating cocaine-produced cocaine-seeking suggest that cocaine's effects at sites other than the dopamine transporter contribute to its ability to elicit drug-seeking.