Activation of Kv7.2/3 channels in the PL-NAcc circuit attenuates methamphetamine-associated contextual memory

Methamphetamine (METH), a powerful psychoactive substance, promotes the formation of the persistent drug-associated memories that have a significant contribution to relapse in drug addiction. The reward circuit of prelimbic cortical (PL) to the nucleus accumbens core (NAcc) is closely related to METH-associated contextual memory. To evaluate METH-associated contextual memory, we employed the conditioned place preference (CPP) paradigm. Inhibition of the PL-NAcc circuit by using chemogenetic strategies could significantly suppressed METH-induced CPP. The expression of Kv7.2 and Kv7.3 in the PL projecting to NAcc was reduced in METH-administered mice compared to control mice. In METH-administered mice, METH-induced CPP, neuronal excitability and synaptic plasticity in the PL-NAcc circuit could be attenuated by injecting the Kv7.2/3 agonist retigabine in PL. Furthermore, overexpression of Kv7.3 channels' in the PL-NAcc circuit attenuated METH-induced CPP. Our findings identify hat the PL-NAcc circuit could be the main reason in METH-associated contextual memory and provide evidence that Kv7.2/3′ activation in the PL may emerge as a novel therapeutic strategy for METH abuse.