Cellular and Molecular NeuroscienceInhibition of the mammalian target of rapamycin pathway by rapamycin blocks cocaine-induced locomotor sensitization
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
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2018, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Activated mTORC1 initiates translational machinery, including activation/phosphorylation of p70 ribosomal S6 kinase (S6K) and consequent phosphorylation of the down-stream substrates, the S6 protein and the eIF4E-binding proteins (4E-BPs) (Zoncu et al., 2011). Previous studies have found co-administration of the mTOR inhibitor, rapamycin, suppressed cocaine sensitization (Wu et al., 2011), cocaine-evoked drug reinstatement (Wang et al., 2010) or morphine-induced conditioned place preference (CPP) (Cui et al., 2010) and altered mTOR and/or S6K/S6 phosphorylation. These results imply that mTOR-dependent signaling participates in drug addiction/reward in various aspects.
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