Abstract
The profound alterations produced by cocaine on dopamine (DA) neurotransmission raise the possibility that dopamine transporter (DAT)-expressing neurons may modify DA transport in response to repeated cocaine exposure to maintain the appropriate efficiency of DA clearance. In this study, we determined the changes in molecular mechanisms of DAT regulation in rats with a history of repeated cocaine self-administration followed by 3 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 compared with yoked saline animals. Surface distribution, p-Ser phosphorylation, and protein phosphatase 2A catalytic subunit (PP2Ac) interaction of DAT were all altered in the CPu. Maximal velocity (Vmax) values were elevated both in the CPu and NAcc of cocaine-experienced rats compared with saline controls. Although 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.
Footnotes
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This work was supported by National Institutes of Health/National Institute on Drug Abuse Grants P50 DA-015369 (to S.R.) and DA-016753 (to L.D.J.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.130534.
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ABBREVIATIONS: SERT, serotonin transporter; NET, norepinephrine transporter; DA, dopamine; DAT, dopamine transporter; PKC, protein kinase C; PP2Ac, protein phosphatase 2A catalytic subunit; PP1, protein phosphatase 1; CPu, caudate putamen; NAcc, nucleus accumbens; ECL, enhanced chemiluminescence; PAGE, polyacrylamide gel electrophoresis; GBR 12909, 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)-piperazine; GBR12935, 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)-piperazine; sulfo-NHS-SS-biotin, sulfosuccinimidyl 2-(biotinamido)-ethyl-1,3-dithiopropionate.
- Received August 20, 2007.
- Accepted January 14, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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