PubMed1997
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.