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

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) is necessary for synaptic plasticity, as it is critically involved in the translation of synaptic transmission-related proteins, such as Ca 2 þ /Calmodulin-dependent kinase II alpha (CAMKIIa) and AMPA receptor subunits (GluAs). Although recent studies have implicated mTORC1 signaling in drug-motivated behavior, the ineffectiveness of rapamycin, an mTORC1 inhibitor, in suppressing cocaine self-administration has raised questions regarding the specific role of mTORC1 in drug-related behaviors. Here, we examined mTORC1's role in three drug-related behaviors: cocaine taking, withdrawal, and reinstatement of cocaine seeking, by measuring indices of mTORC1 activity and assessing the effect of intra-cerebroventricular rapamycin on these behaviors in rats. We found that withdrawal from cocaine self-administration increased indices of mTORC1 activity in the nucleus accumbens (NAC). Intra-cerebroventricular rapamycin attenuated progressive ratio (PR) break points and reduced phospho-p70 ribosomal S6 kinase, GluA1 AMPAR, and CAMKIIa levels in the NAC shell (NACsh) and core (NACc). In a subsequent study, we treated rats with intra-NACsh infusions of rapamycin (2.5 mg/side/day for 5 days) during cocaine self-administration and then tracked the expression of addiction-relevant behaviors through to withdrawal and extinction. Rapamycin reduced drug seeking in signaled non-drug-available periods, PR responding, and cue-induced reinstatement, with these effects linked to reduced mTORC1 activity, total CAMKIIa, and GluA1 AMPAR levels in the NACsh. Together, these data highlight a role for mTORC1 in the neural processes that control the expression and maintenance of drug reward, including protracted relapse vulnerability. These effects appear to involve a role for mTORC1 in the regulation of GluA1 AMPARs and CAMKIIa in the NACsh.

mTOR in Brain Physiology and Pathologies

“…Moreover, peripheral administration or local infusion of rapamycin in the amygdala, during cue-alcohol exposure, disrupts alcohol-associated memories, leading to a long-lasting suppression of relapse (19). Similarly, mTORC1 has been involved in memory processes participating in cocaine-conditioned place preference, drug seeking, and cue-induced reinstatement (15,117,296). In contrast, CB 1 receptor activation by delta9-tetrahydrocannabinol (THC) decreases hippocampal long-term memory via the inhibition of GABA release, the activation of NMDA receptors, and the stimulation of mTORC1.…”

Temporally specific miRNA expression patterns in the dorsal and ventral striatum of addiction‐prone rats

“…To test whether the BMA model was over‐fitting the data, we performed out‐of‐sample validation with an additional sample of rats ( n = 6) that served as vehicle controls in a previously published experiment (James et al ) but otherwise experienced the same protocol as described earlier. The BMA model predicted the out‐of‐sample data well, explaining 55 percent of the variance in out‐of‐sample relapse scores.…”

“…However, information flow from NAcC to NAcSh has also been predicted based on studies using protein synthesis inhibitors in the core, which prevent increased spine density formation in the NAcSh (Marie et al ). Further, there is strong evidence that extended drug self‐administration is associated with molecular and cellular changes that promote increased synaptic strength in NAcSh (Anderson et al ; Mameli et al ; Wolf & Ferrario ; James et al ). This may reflect the strengthening of associations between the hedonic properties of the drug and the environmental context, as NAcSh is important for the expression of context‐driven drug seeking (Bossert et al ; James et al ).…”

“…Further, there is strong evidence that extended drug self‐administration is associated with molecular and cellular changes that promote increased synaptic strength in NAcSh (Anderson et al ; Mameli et al ; Wolf & Ferrario ; James et al ). This may reflect the strengthening of associations between the hedonic properties of the drug and the environmental context, as NAcSh is important for the expression of context‐driven drug seeking (Bossert et al ; James et al ). Furthermore, with extended training, NAcSh versus core neurons appear to respond to changes in reward outcome and modulate behaviour accordingly (Saddoris, Stamatakis, & Carelli ).…”

“…Finally, we were interested in the expression of miR‐101b, as this miRNA is a known regulator of mTOR , a plasticity‐associated kinase that regulates drug motivated behaviour (Neasta et al ; James et al ; Quinn et al ; James et al ). Our observation that self‐administration of cocaine decreased miR‐101b in the NAcC aligns closely with previous findings from our laboratory and others' that cocaine and alcohol increase mTOR levels in the NAc (Neasta et al ; James et al ). Similarly, increased levels of miR‐101b in the NAcSh in addiction‐prone rats following relapse supports our previous observation that these rats show deficits in mTOR in this ventral striatum (Brown et al ).…”