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Cell-Type Specific Expression of p11 Controls Cocaine Reward

Published:February 27, 2014DOI:https://doi.org/10.1016/j.biopsych.2014.02.012

      Background

      The high rate of comorbidity between depression and cocaine addiction suggests shared molecular mechanisms and anatomical pathways. Limbic structures, such as the nucleus accumbens (NAc), play a crucial role in both disorders, yet how different cell types within these structures contribute to the pathogenesis remains elusive. Downregulation of p11 (S100A10), specifically in the NAc, elicits depressive-like behaviors in mice, but its role in drug addiction is unknown.

      Methods

      We combined mouse genetics and viral strategies to determine how the titration of p11 levels within the entire NAc affects the rewarding actions of cocaine on behavior (six to eight mice per group) and molecular correlates (three experiments, five to eight mice per group). Finally, the manipulation of p11 expression in distinct NAc dopaminoceptive neuronal subsets distinguished cell-type specific effects of p11 on cocaine reward (five to eight mice per group).

      Results

      We demonstrated that p11 knockout mice have enhanced cocaine conditioned place preference, which is reproduced by the focal downregulation of p11 in the NAc of wild-type mice. In wild-type mice, cocaine reduced p11 expression in the NAc, while p11 overexpression exclusively in the NAc reduced cocaine conditioned place preference. Finally, we identified dopamine receptor-1 expressing medium spiny neurons as key mediators of the effects of p11 on cocaine reward.

      Conclusions

      Our data provide evidence that disruption of p11 homeostasis in the NAc, particularly in dopamine receptor-1 expressing medium spiny neurons, may underlie pathophysiological mechanisms of cocaine rewarding action. Treatments to counter maladaptation of p11 levels may provide novel therapeutic opportunities for cocaine addiction.

      Key Words

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      Linked Article

      • Reductions of p11 and 5-HT1B Receptor Availability in Limbic Brain Regions in Cocaine Dependence
        Biological PsychiatryVol. 76Issue 10
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          Results from the 2012 National Survey on Drug Use and Health reported that approximately 1.6 million individuals aged 12 or over are cocaine abusers in the United States (1). In addition, cocaine abusers often have comorbid disorders, and it has been estimated that 30% to 40% of individuals suffering from drug abuse have a mood or anxiety disorder (2). The high rate of comorbidity between mood disorders and cocaine dependence suggests shared anatomical pathways and molecular mechanisms. Accordingly, it has been reported that both depression and cocaine dependence are associated with alterations in the reward circuitry of the brain, particularly in the nucleus accumbens.
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