The serotonin (5HT) transporter (SERT) is responsible for terminating the signal produced by 5HT. It is well established that amphetamine analogs, such as methamphetamine (METH), induce long-term changes in SERT activity. In addition, recent attention has focused on the acute effects of METH administration rapidly decreasing SERT activity. The mechanism by which METH causes this rapid decrease is not fully understood. However, it has been suggested that: 1) activation of protein kinase C (PKC) decreases 5HT uptake by internalizing the SERT; and 2) amphetamines alter calcium-dependent PKC activity. Thus, this proposal will test the hypothesis that the rapid decrease in SERT function caused by METH treatment is caused by a calcium-dependent PKC mediated phosphorylation of the transporter. This will be accomplished by completing the following specific aims: A. Identify features of the METH-induced decrease in SERT function in vitro. B. Confirm that SERT is phosphorylated after METH treatment. C. Elucidate mechanism(s) responsible for the METH-induced decrease of SERT function. The results of these studies will elucidate if METH acts via a calcium-dependent, PKC-mediated mechanism to rapidly decrease SERT activity. An understanding of this phenomenon has important implications regarding the mechanism of action of METH and other psychostimulants, as well as the physiological regulation of serotonergic systems. Such understanding could help develop better strategies for treating drug abuse, as well as serotonin-associated neurological and psychiatric disorders.
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