Abstract
Repeated exposure to cocaine results in neuroadaptations that can alter the way the brain responds to subsequent stimuli. Earlier studies demonstrated that acute administration of cocaine up-regulates the immediate-early gene fos-related antigen 2 (fra-2) followed by a later up-regulation of σ1 receptor gene and protein levels in brain regions involved in addiction and reward. To test whether such alterations could have long-term consequences on behavior, the present study was undertaken. Using a cocaine-induced behavioral sensitization model coupled with gene and protein expression studies in mice, the results show that cocaine induces the expression of fra-2, which leads to a progressive increase in σ1 receptor gene and protein expression over a period of days. This progressive increase in σ1 expression corresponds to the steady increase in the locomotor response to repeated cocaine administration in mice. The cocaine-induced changes in fra-2 and σ1 receptor gene and protein expression occur in brain regions that subserve drug abuse, such as the cortex, striatum, and hippocampus, but not the cerebellum. Moreover, the prototypic σ1 receptor antagonist 1-[2-(3,4-dichloropheny)ethyl]-4-methylpiperazine (BD1063) significantly attenuates both the molecular adaptations and behavioral sensitization induced by cocaine. These data suggest that repeated exposure to cocaine elicits alterations in fra-2 and σ1 receptor-mediated mechanisms, which ultimately manifest as altered behavioral responses to cocaine.
Footnotes
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This study was supported by the National Institute on Drug Abuse (Grant DA017756).
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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.108.141051.
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ABBREVIATIONS: Coc, cocaine; PCR, polymerase chain reaction; fra-2, fos-related antigen 2; IEG, immediate-early gene; BD1063, 1-[2-(3,4-dichloropheny)ethyl]-4-methylpiperazine; AP-1, activator protein 1; 5-HT, 5-hydroxytryptamine; Ct, threshold cycle; BD, BD1063; CREB, cAMP response-element binding protein.
- Received May 10, 2008.
- Accepted June 27, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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