Received for publication August 20, 2007.
Revised January 11, 2008.
Accepted for publication January 14, 2008.

Dysregulation of Dopamine Transporter Trafficking and Function Following Abstinence from Cocaine Self-administration in Rats: Evidence for Differential Regulation in Caudate-Putamen and Nucleus Accumbens

Abstract

The profound alterations produced by cocaine on dopamine (DA) neurotransmission raises the possibility that DAT-expressing neurons may modify DA transport in response to repeated cocaine exposure in order to maintain the appropriate efficiency of DA clearance. Here we determined the changes in molecular mechanisms of DAT regulation in rats with a history of repeated cocaine self-administration followed by three weeks of abstinence. Using Ex vivo caudate-putamen (CPu) and nucleus accumbens (NAcc) synaptosomal preparations, we found that DA uptake was significantly higher in the CPu and NAcc of cocaine-experienced animals as compared to yoked-saline animals. Surface distribution, p-Ser-phosphorylation, and protein phosphatase 2A catalytic subunit (PP2Ac) interaction of DAT were all altered in the CPu. Maximum velocity (Vmax) values were elevated both in the CPu and NAcc of cocaine-experienced rats compared to saline controls. While there was no change in the apparent affinity for DA in the CPu, increased DA affinity was evident in the NAcc. Consistent with elevated DAT activity in cocaine-experienced animals, a higher level of surface DAT, DAT-PP2Ac association, and decreased serine phosphorylation of DAT were observed in the CPu, but not in the NAcc. These results, for the first time, suggest that chronic cocaine self-administration followed by abstinence leads to persisting alterations in normal DAT-trafficking and catalytic regulatory cascades in the CPu and NAcc in a brain-region specific manner.

Key words: Cocaine, Dopamine, Phosphorylation, Regulation, Trafficking, Transporter