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.