Role for mammalian target of rapamycin complex 1 signaling in neuroadaptations underlying alcohol-related disorders

Abstract

Alcohol addiction is a chronically relapsing disorder that includes certain maladaptive learning and memory. The serine and threonine kinase complex, mammalian target of rapamycin complex 1 (mTORC1), has been implicated in synaptic plasticity, learning, and memory by controlling protein translation. Here we show that administration of alcohol and excessive voluntary consumption of alcohol induce the activation of the mTORC1-mediated signaling pathway in the nucleus accumbens (NAc) of rodents. We further show that the protein expression levels of GluR1 and Homer, two synaptic proteins whose translation has been shown to be modulated by mTORC1, are up-regulated in the NAc of rodents with a history of excessive alcohol consumption. In addition, our results document that the Food and Drug Administration-approved inhibitor of mTORC1, rapamycin, decreases expression of alcohol-induced locomotor sensitization and place preference, as well as excessive alcohol intake and seeking in preclinical rodent models of alcohol abuse. Together, our results suggest that mTORC1 within the NAc is a contributor to molecular mechanisms underlying alcohol-drinking behaviors. Furthermore, despite its massive health and socioeconomic impact worldwide, pharmacotherapies for alcohol abuse and addiction remain limited. Our data therefore put forward the possibility that targeting the mTORC1 signaling cascade is an innovative and valuable strategy for the treatment of alcohol use and abuse disorders.addiction | mTOR | ethanol | reward | nucleus accumbens

mTORC1 Inhibition in the Nucleus Accumbens ‘Protects’ Against the Expression of Drug Seeking and ‘Relapse’ and Is Associated with Reductions in GluA1 AMPAR and CAMKIIα Levels

“…These findings are highly consistent with the report of Neasta et al (2010), who showed that markers of mTORC1 activity were increased after withdrawal from alcohol. It is possible that changes in mTORC1 activity manifest on a different time scale in the NACsh versus NACc.…”

“…rapamycin, we found significant reductions in indices of mTORC1 activity and GluA1 AMPARs and CAMKIIa within the NAC. The magnitude of these effects was similar to previous studies (Barak et al, 2013;Neasta et al, 2010). These findings are interesting given that dopamine D1-like agonists increase AMPAR insertion into NAC MSNs through a process involving CAMKIIa (Anderson et al, 2008;Sun et al, 2008) and that both dopamine and CAMKIIa have been shown to be important for the expression of psychostimulant sensitization and drugseeking behavior (Licata and Pierce, 2003;Loweth et al, 2008;Pierce et al, 1998).…”

“…To date, data supporting the role for mTORC1 in psychostimulant reinforcement has been limited to CPP and sensitization studies (Bailey et al, 2012;Narita et al, 2005). However, mTORC1 inhibition has been reported to reduce low-effort alcohol drinking in mice and FR1 alcohol self-administration in rats (Neasta et al, 2010). With respect to biochemical changes induced by i.c.v.…”

“…On days 4-6, rats received an infusion of rapamycin (12.5 mg/ml, i.c.v., 1 ml/min for 2 min; n ¼ 10) or vehicle (n ¼ 9) 3 h before PR testing through an injector (28 gauge; Plastics One, VA, USA), which protruded 1 mm below the guide cannulae. The timing and dose of rapamycin was based on previous studies (Cota et al, 2008;Neasta et al, 2010). The injector remained in place for 60 seconds to ensure diffusion of the injectate.…”

“…More recently, experiments using rapamycin have implicated mTORC1 signaling in addiction-relevant behaviors and in alcohol-related memory consolidation (Barak et al, 2013). Both acute systemic and intra-NAC injections of rapamycin attenuated alcohol-drinking behaviors and conditioned place preference (CPP) for alcohol (Neasta et al, 2010). Acute systemic rapamycin treatment also suppressed the expression of cocaine CPP, behavioral sensitization to cocaine (Bailey et al, 2012), and the sensitization of meth-amphetamine CPP (Narita et al, 2005).…”