METHAMPHETAMINE-INDUCED DECREASE IN TRYPTOPHAN-HYDROXYLASE ACTIVITY -ROLE OF 5-HYDROXYTRYPTAMINERGIC TRANSPORTERS

Methamphetamine-induced 5-hydroxytryptaminergic neuronal damage purpor tedly involves transport of newly released dopamine from extracellular spaces into 5-hydroxytlyptaminergic terminals. This hypothesis is bas ed primarily on findings that dopamine is required for, whereas 5-hydr oxytryptamine (5-HT) uptake inhibitors prevent, methamphetamine-induce d deficits in 5-hydroxytryptaminergic neuronal function. This hypothes is is not, however, supported by findings presented in this study that 5-hydroxytryptaminergic neuronal damage, induced by p-chloroamphetami ne, does not decrease [H-3]dopamine uptake into rat brain synaptosomes prepared from 5-HT-transporter-containing tissue. Moreover, despite h aving greater affinity for the 5-HT transporter, citalopram has an IC5 0 for [3H]dopamine transport into these synaptosomal preparations that is considerably greater than that of fluoxetine. These data suggest t hat 5-HT transporters may not effect dopamine uptake and thereby merha mphetamine-induced 5-hydroxytryptaminer, ic neuronal damage. Other pos sible mechanisms related to 5-HT uptake inhibitor attenuation of metha mphetamine-induced deficits were investigated. Fluoxetine pretreatment prevented the methamphetamine-induced decrease in tryptophan hydroxyl ase activity: this effect cannot be attributed to altered body tempera tures or brain concentrations of methamphetamine which suggests that n either, per se, is sufficient to impair 5-hydroxytryptaminergic neuron al function. (C) 1997 Elsevier Science B.V.