Cocaine addiction, similar to addiction to other substances, is rooted in changes in synaptic signaling within addiction centers in the brain, primarily the nucleus accumbens (NAc). Repeated cocaine exposure leads to alterations within dopaminergic signaling pathways that underlie reward-related learning and memory processing and galvanize addiction behaviors. Specifically, cocaine blocks the dopamine transporter (DAT), which promotes dopamine (DA) accumulation in the synaptic space and increased activation of postsynaptic dopamine receptors D1R and D2R. Other studies have demonstrated that cocaine treatment leads to significant changes in protein expression, most likely through alterations to the translation machinery. In a 2015 Neuropharmacology report, Drs. Laurie Sutton and Marc Caron at Duke University explored the role of the D1R in activating mTOR (the mammalian target of rapamycin), a protein whose complexes influence protein translation and expression. The Duke investigators’ data describe a previously-unknown mechanism in which cocaine activates mTOR signaling through D1R stimulation and suggest new, potential modalities for treating cocaine addiction using mTOR inhibitors such as rapamycin.
To determine if cocaine can regulate mTOR signaling, the Duke team performed a series of biochemical assays that dissected the effects of different players in the dopamine signaling pathway on mTOR activity. Western blotting of key mTOR phosphorylation residues in NAc lysates from cocaine-treated C57BL/6J (000664) mice showed that mTOR becomes phosphorylated in response to cocaine, and that the phosphorylation is maintained when mTOR is bound to Raptor (regulatory-associated protein with mTOR) in mTOR complex 1 (mTORC1) complexes. These data suggest that activated mTOR signaling is processed through mTORC1 rather than complex 2 (mTORC2) complexes. Further, because mTORC1 has been implicated in regulating protein translation, the data support the earlier hypothesis that cocaine exposure modulates addictive behavior by modulating synaptic signaling pathways at the translational level.
The researchers next investigated the role of the dopamine receptor D1R in activating mTORC1 by breeding mice that express Cre recombinase from a D1R promoter to mice that carry either mTOR or Raptor Cre-conditional alleles (B6.129S4-Mtortm1.2Koz/J (011009) and B6.Cg-Rptortm1.1Dmsa/J (013188), respectively), to create mice that were mTOR- or Raptor-deficient in D1R-expressing neurons. Treating D1R-specific mTOR- or Raptor-knockout mice with cocaine increased the animals’ locomotor activity but to a significantly lesser degree compared to similarly treated wild-type controls, suggesting that cocaine-induced hyperactivity is mediated at least partially through mTORC1 signaling in D1R-expressing neurons. Combined with data from studies involving other addictive compounds, this study defines a new role for mTORC1 in mediating the neurological and addictive effects of cocaine, and suggests a novel therapeutic approach for treating cocaine addiction through mTOR inhibition.
Sutton LP, Caron MG. 2015. Essential role of D1R in the regulation of mTOR complex 1 signaling induced by cocaine. Neuropharmacology, 99:610-619. PMID: 26314207.