Role of the 5-HT₂ receptor in the methamphetamine-induced neurochemical alterations

The possibility that serotonin (5-HT) modulates dopamine (DA) synthesis by acting at 5-HT₂ receptor sites during methamphetamine (METH) treatment was investigated. The neostriatal accumulation of 3,4-dihydroxyphenylalanine was not altered by ritanserin (1 mg/kg i.p.), a 5-HT(2/1c) receptor antagonist, or by METH (15 or 25 mg/kg s.c.), which indicates that METH-induced DA and 5- HT release did not invoke increased DA synthesis. Interestingly, the combined treatment of METH with ritanserin reduced 3,4-dihydroxyphenylalanine formation. We also examined the possibility that 5-HT₂ receptors participate in the mechanism by which METH alters central tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities as well as the concentration of neurotensin-like and substance P-like immunoreactivity. Five administrations of METH given at 6-hr intervals reduced neostriatal TH and TPH activity to 27 and 13% of control, respectively, 18 to 20 hr after the last drug administration; ritanserin failed to alter these decreases significantly. Ritanserin also failed to alter the METH-induced increase in neostriatal neurotensin-like immunoreactivity or in nigral neurotensin-like immunoreactivity and substance P-like immunoreactivity. Finally, the administration of ICS 205-930, a 5-HT(3/4) receptor antagonist, also failed to prevent the METH-induced decrease in TH and TPH activities at doses below 200 μg/kg, whereas a dose of 500 μg/kg potentiated the effect of METH. These results suggest that 5-HT₂ does not modulate DA synthesis nor does it mediate the changes in central TH and TPH activity, or neurotensin-like immunoreactivity and substance P-like immunoreactivity content induced by METH. Because 3,4-methylenedioxymethamphetamine is reported to stimulate DA synthesis by a 5-HT₂ receptor-dependent mechanism, these observations suggest that METH and 3,4-methylenedioxymethamphetamine regulate the central dopaminergic system in a different manner.