Metformin Prevents Cocaine Sensitization: Involvement of AMPK Trafficking between Subcellular Compartments in the Corticostriatal Reward Circuit

Abstract

Repeated cocaine produces an enhanced locomotor response (sensitization) paralleled by biological adaptations in the brain. Previous studies demonstrated region-specific responsiv-ity of adenosine monophosphate-activated protein kinase (AMPK) to repeated cocaine. AMPK maintains cellular energy homeostasis at the organismal and cellular level. Here we first quanti-fied changes in phosphorylated (active) and total AMPK in the cytosol and synaptosome of the medial prefrontal cortex, nucleus accumbens, and dorsal striatum following acute or sensitizing cocaine injections. Rats were given cocaine (15 mg/kg, IP) or saline for six days with a challenge injection on day seven resulting in four groups: saline-saline, saline-cocaine, cocaine-saline, and cocaine-cocaine. Brain region and cellular compartment selective changes in AMPK and pAMPK were found with some differences associated with acute withdrawal versus ongoing cocaine treatment. Other rats were pretreated with the indirect AMPK activator metformin. Metformin potentiated the locomotor activating effects of acute cocaine but blocked the development of sensi-tization. Sex differences largely obscured protein level treatment group effects, although pAMPK in the NAc shell cytosol was surprisingly reduced by metformin in rats receiving repeated co-caine. These data inform our understanding of AMPK activation dynamics in subcellular com-partments and provide additional support for repurposing metformin for cocaine use disorder.