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-HT2/1c 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-HT3/4 receptor antagonist, also failed to prevent the METH-induced decrease in TH and TPH activities at doses below 200 micrograms/kg, whereas a dose of 500 micrograms/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.
Johnson
M
M
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City.
Sonsalla
P K
PK
Letter
A A
AA
Hanson
G R
GR
Gibb
J W
JW
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D004298:Dopamine / Q000096:biosynthesis / Q000502:physiology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000502:physiology*; D016713:Ritanserin / Q000494:pharmacology; D012701:Serotonin / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013997:Time Factors; D000077526:Tropisetron; D014365:Tryptophan Hydroxylase / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D007211:Indoles; D009479:Neuropeptides; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D016713:Ritanserin; D012701:Serotonin; D008694:Methamphetamine; D000077526:Tropisetron; D014446:Tyrosine 3-Monooxygenase; D014365:Tryptophan Hydroxylase; D004298:Dopamine