The effects of methamphetamine on serotonin transporter activity: Role of dopamine and hyperthermia

Multiple administrations of methamphetamine (METH) rapidly decreased seroto nin (5HT) transporter (SERT) function in rat striatum and hippocampus. The purpose of this study was to identify the mechanisms/factors contributing t o this METH-induced decrease in SERT function. Multiple high-dose METH inje ctions rapidly decreased 5HT uptake without altering binding of the 5HT tra nsporter ligand paroxetine. Hyperthermia contributed to this deficit in tra nsporter function in striatum and hippocampus, as prevention of METH-induce d hyper thermia attenuated this decrease. A role for dopamine (DA) was sugg ested by findings that pretreatment with the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine, the D1 antagonist SCH-23390, or the D2 antagonist eticlopride attenuated the METH-induced decrease in striatal, but not hipp ocampal, SERT activity. These effects were independent of the ability of th ese DA-antagonizing drugs to prevent METH-induced hyperthermia. These resul ts suggest that DA contributes to the decrease in SERT function caused by m ultiple METH injections in the striatum, but not hippocampus, and that hype rthermia facilitates these deficits in SERT function in both brain regions. In contrast, the response of SERT to a single administration of METH was D A and hyperthermia independent. These findings suggest that the mechanisms/ factors involved in decreasing SERT activity after a single administration of METH are distinct from that caused by multiple administrations.