Effect of flunarizine and nimodipine on the decrease in tryptophan hydroxylase activity induced by methamphetamine and 3,4-methylenedioxymethamphetamine.
The effect of calcium channel blockers on the decrease in central tryptophan hydroxylase (TPH) activity and serotonin (5-HT) concentration induced by repeated large doses of methamphetamine (METH) or 3,4-methylenedioxymethamphetamine (MDMA) was evaluated. Rats received four or five injections of METH (10 or 15 mg/kg) or MDMA (10 mg/kg) at 6-h intervals, and were sacrificed 18 to 20 h or 1 week after the last administration. Flunarizine (30 mg/kg) prevented the decline in cortical and neostriatal TPH activity induced by MDMA, but failed to alter the effect of METH. The effect of flunarizine on the METH- and MDMA-induced changes in cortical 5-HT and 5-hydroxyindoleacetic acid concentrations paralleled the changes in enzyme activity. Nimodipine, diltiazem or TA-3090 failed to prevent the MDMA- and the METH-induced decline in TPH activity or in 5-HT and 5-hydroxyindoleacetic acid content. Because haloperidol failed to mimic the protective action of flunarizine, it is unlikely that flunarizine exerts its action by blocking the dopamine D-2 receptors. This study suggests that calcium influx may participate in the MDMA-induced decline in central TPH activity, and that the mechanism by which MDMA and METH decreases TPH activity differs.
Johnson
M
M
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City.
Mitros
K
K
Stone
D M
DM
Zobrist
R
R
Hanson
G R
GR
Gibb
J W
JW
D015104:3,4-Methylenedioxyamphetamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002851:Chromatography, High Pressure Liquid; D004110:Diltiazem / Q000494:pharmacology; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D005444:Flunarizine / Q000494:pharmacology*; D006897:Hydroxyindoleacetic Acid / Q000737:chemistry; D007279:Injections, Subcutaneous; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D009553:Nimodipine / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2; D012701:Serotonin / Q000737:chemistry; D014365:Tryptophan Hydroxylase / Q000096:biosynthesis* / Q000378:metabolism
D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D012701:Serotonin; D008694:Methamphetamine; D015104:3,4-Methylenedioxyamphetamine; D006897:Hydroxyindoleacetic Acid; D009553:Nimodipine; D014365:Tryptophan Hydroxylase; D004110:Diltiazem; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D005444:Flunarizine