Dopaminergic involvement in the discriminative-stimulus effects of methamphetamine in rats

Rationale: Dopamine plays a major role in the behavioral effects of methamp hetamine. Objective: In the present experiments, the effects of different d opaminergic agonists, antagonists, and uptake inhibitors were evaluated in rats discriminating methamphetamine from saline Methods: In Srague-Dawley r ats trained to discriminate 1.0 mg/kg methamphetamine, i.p., from saline un der a fixed-ratio schedule of food delivery, the ability of various dopamin ergic agonists and uptake inhibitors to substitute for methamphetamine was evaluated. Subsequently, the ability of various dopaminergic antagonists to block the discriminative-stimulus effects of the training dose of methamph etamine was tested. Results: The dopamine-uptake inhibitors cocaine (10.0 m g/kg), nomifensine (3.0 mg/kg), GBR-12909 (18.0 mg/kg), and bupropion (30.0 mg/kg) fully substituted for the 1.0 mg/kg training dose of methamphetamin e. Chloro-APB (SKF-82958), a full agonist at D1 dopamine receptors, produce d about 85% methamphetamine-appropriate responding, but the dose required ( 0.18 mg/kg) markedly decreased rates of responding. Chloro-PB (SKF-81297), another agonist at D1 receptors with a lower intrinsic activity than Chloro -APB, produced only partial generalization (maximum about 55%) at a dose of 1.0 mg/kg. Full substitution for the training dose of methamphetamine was observed with 0.03 mg/kg of the D2 agonist NPA and 0.56 mg/kg of the D3/D2 agonist 7-OH-DPAT. Both NPA and 7-OH-DPAT markedly decreased rates of respo nding at these doses. The D1 antagonist SCH-23390 (0.056 mg/kg), the D2 ant agonist spiperone (0.18 mg/kg) and the mixed D1,D2 antagonist cis-flupenthi xol (0.56 mg/kg) all completely blocked the discriminative-stimulus actions of the training dose of methamphetamine, Conclusions: The present findings in rats support previous research findings in other species indicating a m ajor role of dopamine in the discriminative-stimulus effects of methampheta mine. These findings further indicate involvement of dopamine uptake sites as well as D1 and D2 receptors.