Elsevier

Neuroscience

Volume 172, 13 January 2011, Pages 104-109
Neuroscience

Cellular and Molecular Neuroscience
Inhibition of the mammalian target of rapamycin pathway by rapamycin blocks cocaine-induced locomotor sensitization

https://doi.org/10.1016/j.neuroscience.2010.10.041Get rights and content

Abstract

Repeated cocaine exposure induces locomotor sensitization, which is mediated by adaptive changes in synaptic transmission in the mesolimbic dopamine pathway. The molecular mechanisms underlying this adaptation remain poorly understood. One pathway that may play a role is the mammalian target of rapamycin (mTOR) which is implicated in synaptic plasticity. In the present study, we found that cocaine exposure stimulates mTOR activity in rat brain. Furthermore, inhibition of mTOR by rapamycin blocked the induction as well as the expression of cocaine-induced locomotor sensitization in rats. These data elucidate a novel mechanism by which the mTOR pathway mediates cocaine-induced behavioral changes and could suggest a new interventional strategy for drug abuse.

Research Highlights

▶ Acute cocaine exposure activates the mTOR in the cortex, VTA, and NAc. ▶ Inhibition of mTOR blocks the induction of cocaine-induced locomotor sensitization. ▶ Inhibition of mTOR blocks the expression of cocaine-induced locomotor sensitization.

Section snippets

Animals and drugs

Female Sprague–Dawley (SD) rats weighing approximately 225–250 g upon arrival were obtained from Taconic Farms (Germantown, NY, USA). Rats were individually-housed in a room maintained on a 12-h light/dark cycle (lights on 0700). Food and water were provided ad libitum. Cocaine hydrochloride was dissolved in saline, and rapamycin was dissolved in 4% ethanol and 5% Tween-20 in water at a concentration of 5 mg/ml. Both drugs were injected i.p. at a volume of 1 ml/kg. All experiments were

Cocaine activates mTOR in vivo

To determine whether mTOR is involved in mediating cocaine's effects, we examined the effect of cocaine on phosphorylation of S6, a downstream target of the mTOR, in rat brains. A single injection of cocaine (15 mg/kg) markedly stimulated S6 phosphorylation in the cortex within 1 h (Fig. 1A, B). The increased S6 phosphorylation observed was completely depleted by the mTOR inhibitor rapamycin (5 mg/kg), suggesting that the levels of phospho-S6 reflect in vivo mTOR activity (control vs. cocaine: P

Discussion

Here we report that acute cocaine exposure activates the mTOR in cortical forebrain as well as in VTA and NAc. Furthermore, inhibition of mTOR by systemically administered rapamycin blocks both the induction and expression of cocaine-induced locomotor sensitization, suggesting that the mTOR pathway may be critically involved in cocaine sensitization and perhaps play a role in the development of drug addiction.

Cocaine-induced locomotor sensitization involves two separate stages: the initial

References (29)

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