Novel role of AMPK in cocaine reinforcement via regulating CRTC1

Abstract

Repeated cocaine exposure causes compensatory neuroadaptations in neurons in the nucleus accumbens (NAc), a region that mediates reinforcing effects of drugs. Previous studies suggested a role for adenosine monophosphate-activated protein kinase (AMPK), a cellular energy sensor, in modulating neuronal morphology and membrane excitability. However, the potential involvement of AMPK in cocaine use disorder is still unclear. The present study employed a cocaine self-administration model in rats to investigate the effect of AMPK and its target cyclic adenosine monophosphate response element binding protein-regulated transcriptional co-activator 1 (CRTC1) on cocaine reinforcement and the motivation for cocaine. We found that intravenous cocaine self-administration significantly decreased AMPK activity in the NAc shell (NAcsh), which persisted for at least 7 days of withdrawal. Cocaine reinforcement, reflected by self-administration behavior, was significantly prevented or enhanced by augmenting or suppressing AMPK activity pharmacologically and genetically, respectively. No difference in sucrose self-administration behavior was found after the same manipulations. The inhibition of AMPK activity in the NAcsh also increased the motivation for cocaine in progressive-ratio schedules of reinforcement, whereas the activation of AMPK had no effect. The knockdown of CRTC1 in the NAcsh significantly impaired cocaine reinforcement, which was rescued by pharmacologically increasing AMPK activity. Altogether, these results indicate that AMPK in the NAcsh is critical for cocaine reinforcement, possibly via the regulation of CRTC1 signaling. These findings may help reveal potential therapeutic targets and have important implications for the treatment of cocaine use disorder and relapse.

Metformin Prevents Cocaine Sensitization: Involvement of Adenosine Monophosphate-Activated Protein Kinase Trafficking between Subcellular Compartments in the Corticostriatal Reward Circuit

“…Recent studies support the idea that metformin may provide a novel therapeutic strategy for the management of neuropsychiatric diseases like substance use disorders [24,34,35]. Introducing metformin to the NAc core decreased cue-induced cocaine seeking in male and female rats following self-administration and extinction [36], in line with the prior research involving direct manipulation of AMPK with viral or other pharmacological tools [27,28]. Moreover, additional preclinical literature indicates that metformin may reduce symptoms of withdrawal from another psychostimulant drug, nicotine [37].…”

“…Chronic cocaine injections producing behavioral sensitization amplified this effect [26]. In contrast, pAMPK was reduced in the NAc core following cocaine self-administration and extinction [27] and it was reduced in the NAc shell following abstinence from cocaine self-administration [28]. Moreover, manipulation of AMPK activity in the NAc core or shell reduced cue-induced cocaine seeking and diminished cocaine reinforcement, respectively [27,28].…”