TRPM3 on Glutamatergic Neurons in Anterior Cingulate Cortex Modulates Retrieval of Methamphetamine Reward-Associated Context Memory

Abstract

Exposure to drug of abuse produces strong drug reward-associated environmental contextual memories, which contribute to driving compulsive drug-seeking behaviors or even relapse upon cue exposure. The anterior cingulate cortex (ACC), a pivotal brain region involved in regulating decision-making and motivation, has recently been found to be activated in methamphetamine (METH) users when exposed to drug cues; however, its underlying mechanisms remain elusive. Here, we utilized a METH-induced conditioned place preference (CPP) model in mice to investigate the role of the ACC and to explore the potential molecules in the retrieval of METH-associated memories. We found that the glutamatergic neurons in the ACC were significantly activated during the METH CPP test. Further, chemogenetic suppression of ACC glutamatergic neurons effectively blocked METH-induced CPP. By RNA sequencing analysis, we found that transient receptor potential melastatin 3 (TRPM3), a non-selective cation channel, was upregulated in ACC glutamatergic neurons following METH CPP, with a concomitant increase in the phosphorylation levels of its downstream molecules-extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB). Most importantly, either local pharmacological inhibition of ACC TRPM3 activity with isosakuranetin (ISO) or selective knockdown of TRPM3 levels in ACC glutamatergic neurons significantly attenuated the METH-induced CPP. Collectively, our findings demonstrate that TRPM3 in ACC glutamatergic neurons plays a critical role in modulating METH reward-associated memory, highlighting TRPM3 as a potential therapeutic target for METH-induced abnormal neuro-behaviors.