METHAMPHETAMINE-INDUCED ALTERATIONS IN DOPAMINE TRANSPORTER FUNCTION

Repeated methamphetamine (METH) administration has been shown to produ ce differing neurochemical as well as behavioral effects in rats. This study was designed to examine the effects of acute and chronic METH e xposure on uptake and release of [H-3]dopamine (DA) in cultured midbra in dopamine neurons to determine if persistent neuronal adaptations en sue. In addition, we have assessed DA D2 receptor function to determin e if chronic METH alters this receptor. Fetal midbrain cultures were e xposed to METH (1, 10 mu M) for 5 days and dopaminergic function exami ned 1 or 7 days after drug removal. The ability of METH to release [H- 3]DA was compared to other releasing agents as well as several potent uptake inhibitors. Chronic exposure to a release-promoting concentrati on of METH resulted in either no change or a reduction in [H-3]DA rele ase upon subsequent METH challenge. Pretreatment with METH was also fo und to cause a decrease in the B-max for [H-3]raclopride binding, sugg esting that persistently elevated DA levels cause a downregulation of DA D2 receptors. Examination of transporter kinetics utilizing initial velocity of uptake revealed that METH treatment caused a significant decrease in affinity (K-m) for the substrate (DA), while not altering the maximal velocity of uptake (V-max). Binding studies with [I-125]RT I-55 revealed that there was no alteration in either the B-max or K-d for this ligand, suggesting that the changes induced by METH treatment are due to alterations in K-m and not in the number of DA transport s ites. The results from these studies indicate that METH treatment prod uces a modification in transporter function which may be associated wi th both the altered uptake and release of [H-3]DA. These changes have broad implications for the regulation of transporter activity not only because of the relevance to pre-synaptic mechanisms controlling neuro transmission, but also to the importance of the neuronal adaptation th at occurs in response to chronic METH exposure. (C) 1998 Elsevier Scie nce B.V.