Methamphetamine-induced decrease in tryptophan hydroxylase activity: role of 5-hydroxytryptaminergic transporters.
Methamphetamine-induced 5-hydroxytryptaminergic neuronal damage purportedly involves transport of newly released dopamine from extracellular spaces into 5-hydroxytryptaminergic terminals. This hypothesis is based primarily on findings that dopamine is required for, whereas 5-hydroxytryptamine (5-HT) uptake inhibitors prevent, methamphetamine-induced deficits in 5-hydroxytryptaminergic neuronal function. This hypothesis is not, however, supported by findings presented in this study that 5-hydroxytryptaminergic neuronal damage, induced by p-chloroamphetamine, does not decrease [3H]dopamine uptake into rat brain synaptosomes prepared from 5-HT-transporter-containing tissue. Moreover, despite having greater affinity for the 5-HT transporter, citalopram has an IC50 for [1H]dopamine transport into these synaptosomal preparations that is considerably greater than that of fluoxetine. These data suggest that 5-HT transporters may not effect dopamine uptake and thereby methamphetamine-induced 5-hydroxytryptaminergic neuronal damage. Other possible mechanisms related to 5-HT uptake inhibitor attenuation of methamphetamine-induced deficits were investigated. Fluoxetine pretreatment prevented the methamphetamine-induced decrease in tryptophan hydroxylase activity: this effect cannot be attributed to altered body temperatures or brain concentrations of methamphetamine which suggests that neither, per se, is sufficient to impair 5-hydroxytryptaminergic neuronal function.
Fleckenstein
A E
AE
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 84112, USA.
Beyeler
M L
ML
Jackson
J C
JC
Wilkins
D G
DG
Gibb
J W
JW
Hanson
G R
GR
D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D005473:Fluoxetine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects* / Q000378:metabolism; D026901:Membrane Transport Proteins; D008694:Methamphetamine / Q000494:pharmacology*; D009419:Nerve Tissue Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins; D014365:Tryptophan Hydroxylase / Q000187:drug effects* / Q000378:metabolism; D014793:Visual Cortex / Q000187:drug effects / Q000378:metabolism
D002352:Carrier Proteins; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D005473:Fluoxetine; D008694:Methamphetamine; D014365:Tryptophan Hydroxylase; D004298:Dopamine