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Keywords:

  • Cocaine;
  • mTOR;
  • P70S6K;
  • rapamycin;
  • S6;
  • sensitization

ABSTRACT

The mammalian target of rapamycin (mTOR) is a serine-threonine kinase that controls global protein synthesis, in part, by modulating translation initiation, a rate-limiting step for many mRNAs. Previous studies implicate mTOR in regulating stimulant-induced sensitization and antidepressive-like behavior in rodents, as well as drug craving in abstinent heroin addicts. To determine if signaling downstream of mTOR is affected by repeated cocaine administration in reward-associated brain regions, and if inhibition of mTOR alters cocaine-induced behavioral plasticity, C57BL/6J mice received four intraperitoneal (i.p.) injections of 15 mg/kg cocaine and levels of phosphorylated P70S6 kinase and ribosomal S6 protein—two translational regulators directly downstream of mTOR—were analyzed by immunoblotting across several brain regions. Cocaine place preference and locomotor sensitization were elicited by four pairings of cocaine with a distinct environment and the effects of mTOR inhibition were assessed by pre-treating the mice with 10 mg/kg rapamycin, 1 hour prior to: (1) each saline/cocaine conditioning session; (2) a post-conditioning test; or (3) a test for locomotor sensitization conducted at 3 weeks withdrawal. While systemic pre-treatment with 10 mg/kg rapamycin during conditioning failed to alter the development of a cocaine place preference or locomotor sensitization, pre-treatment prior to the post-conditioning test attenuated the expression of the place preference. Additionally, rapamycin pre-treatment prior to a cocaine challenge 3 weeks post-conditioning blocked the expression of the sensitized locomotor response. These findings suggest a role for mTOR activity, and perhaps translational control, in the expression of cocaine-induced place preference and locomotor sensitization.