Serotonergic involvement in methamphetamine-induced locomotor activity: A detailed pharmacological study

► We assessed serotonergic and dopaminergic effects on the methamphetamine-induced hyperactivity. ► Modulation was observed by 5-HT depletion, certain 5-HT receptor ligands and dopamine ligands. ► Data suggest key 5-HT involvement with potential downstream dopamine involvement. The mechanism by which the psychostimulant methamphetamine (METH) increases locomotor activity may be attributable to indirect activation of serotonin (5-HT) and dopamine (DA) receptors. In the present study, the ability of the serotonin reuptake inhibitor fluvoxamine, 5-HT 1A, 5-HT 1B, 5-HT 2A and 5-HT 2C receptor antagonists WAY100635, GR127935, M100907 and SB242084, and the 5-HT 2C receptor agonists WAY163909 and Ro 60-0175 or the 5-HT synthesis inhibitor para-chlorophenylalanine (pCPA) to alter METH-induced hyperactivity was analysed. Further, for comparative purposes, the involvement of the DA D 1 and D 2 receptor antagonists SCH23390 and haloperidol, D 2 partial agonists terguride, (−)3PPP and aripiprazole and finally clozapine were assessed. Doses of pCPA that attenuated 5-HT levels reduced METH activity. The 5-HT 1B antagonist GR127935 had no effect on METH-induced locomotor activity but blocked that induced by MDMA. The 5-HT 1A antagonist WAY100635 reduced activity but this did not reach significance. In contrast, M100907 (minimal effective dose; MED = 0.125 mg/kg), WAY163909 (MED = 3 mg/kg), Ro 60-0175 (MED = 3 mg/kg), haloperidol (MED = 0.1 mg/kg), clozapine (MED = 5 mg/kg), aripiprazole (MED = 1 mg/kg), (−)3PPP (MED = 3 mg/kg), terguride (MED = 0.2 mg/kg) and SCH23390 (MED = 0.001325 mg/kg) attenuated METH-induced locomotor activity. Administration of 20 mg/kg fluvoxamine attenuated, while SB242084 (MED = 0.25 mg/kg) potentiated METH-induced activity. These results contribute significantly to the understanding of the mechanism of action of this psychostimulant and suggest for the first time, that METH-induced locomotor stimulation is modulated by 5-HT 2A and 5-HT 2C receptors, but demonstrate that 5-HT 1B receptors are not directly involved. The involvement of the dopaminergic system was also demonstrated.