Nucleus Accumbens Core Mammalian Target of Rapamycin Signaling Pathway Is Critical for Cue-Induced Reinstatement of Cocaine Seeking in Rats

Abstract

Relapse to drug seeking was studied using a rodent model of reinstatement induced by exposure to drug-related cues. The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase that regulates cell growth and survival by controlling translation in response to nutrients and growth factors, has been demonstrated to be involved in neuronal adaptations that underlie drug addiction and learning and memory. We investigated the potential role of the mTOR signaling pathway in relapse to cocaine seeking by using the cue-induced reinstatement model in self-administering rats. We found that exposure to a cocaine-related cue induced reinstatement to cocaine seeking and increased phosphorylation of p70s6 kinase (p70s6k) and ribosomal protein s6 (rps6), measures of mTOR activity, in the nucleus accumbens (NAc) core but not shell. Furthermore, inhibition of NAc core but not shell p70s6k and rps6 phosphorylation by rapamycin decreased cue-induced reinstatement of cocaine seeking. Finally, stimulation of NAc core p70s6k and rps6 phosphorylation by NMDA enhanced cue-induced reinstatement, an effect reversed by rapamycin pretreatment. Additionally, rapamycin infusion into the NAc core or shell did not alter ongoing cocaine self-administration or cue-induced reinstatement of sucrose seeking. These findings indicate that cue-induced reinstatement of cocaine seeking is mediated by activation of the mTOR signaling pathway in the NAc core.

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

“…In accordance with findings of Lu and colleagues (Wang et al, 2010b), we found that cocaine self-administration (FR5) was unaffected by intra-NAC rapamycin injections (Experiment 3). However, i.c.v.…”

“…Notably, rapamycin treatment did not affect locomotor activity or produce other non-specific effects on baseline motivational performance (ie, FR5 cocaine responding), findings that support recent demonstrations that rapamycin does not affect responding for a natural rewards (Neasta et al, 2010;Wang et al, 2010b). Thus, reductions in baseline mTORC1 in drug naive rats may be insufficient to alter general motivation status.…”

“…These findings indicate that mTORC1 may have a role in controlling the processes responsible for the strengthening of drug/cue associations. NAC mTORC1 inhibition also attenuated cue-induced reinstatement of cocaine seeking but, interestingly, had no effect on cocaine self-administration under a fixed-ratio 1 (FR1) schedule of reinforcement (Wang et al, 2010b).…”

Delayed Noradrenergic Activation in the Dorsal Hippocampus Promotes the Long-Term Persistence of Extinguished Fear

“…The western blot method was based on our previous studies (Ren et al, 2013;Wang et al, 2010;Xue et al, 2012). All rats were decapitated without anesthesia 1 h after the end of extinction.…”

Glycine site N-methyl-D-aspartate receptor antagonist 7-CTKA produces rapid antidepressant-like effects in male rats

“…6,22 Rapamycin (50 µg/0.5 µl) was also purchased from Sigma and dissolved in saline containing 5% DMSO, as described in a previous report. 23 We purchased D-serine (50 µg/0.5 µL) from Beijing Redwood Fine Chemical Co. Ltd. and dissolved it in saline containing 2% DMSO, as described in a previous report. 24 All drugs and vehicles were bilaterally infused into the mPFC at a volume of 0.5 µl per side.…”