A prefrontal cortex-nucleus accumbens circuit attenuates cocaine-conditioned place preference memories.

The infralimbic (IL) subregion of the prefrontal cortex (PFC), via its descending projection to the nucleus accumbens (NAc), inhibits cue-induced drug seeking and reinstatement, but the underlying mechanisms are not fully understood. Here we show that the activity of IL layer 5 pyramidal neurons projecting to the NAc shell (IL-NAcSh neurons) suppresses cocaine-associated memories. Following repeated cocaine exposures in a conditioned place preference paradigm, IL-NAcSh neurons anatomically traced by fluorescent Retrobeads undergo prolonged decrease of membrane excitability, lasting for at least 15 days after cocaine withdrawal. This persistent IL-NAcSh neuron hypoexcitability is accompanied by an increase in the rheobase, a decrease in the membrane input resistance, and an increase in the afterhyperpolarization potential. This cocaine induced maladapation in intrinsic excitability is not observed in prelimibic cortex neurons projecting to the NAc core (PL-NAcCo neurons), a separate descending circuit thought to promote cue-triggered drug seeking. Chemogenetic restoration of IL-NAcSh neuron activity reduces both the short-term and long-term retentions of cocaine conditioned place preference memories. Importantly, pharmacological activation or inhibition of the Kv7/KCNQ/M K+ channels bidirectionally regulates the rheobase and firing rate of IL-NAcSh pyramidal neurons, and local infusion of a Kv7 inhibitor in the IL attenuates cocaine place preference memories, suggesting a potential mechanism-based therapeutic. Our results provide direct support for the notion that the IL-NAcSh circuit serves to attenuate drug associated memories and restoring drug impaired IL-NAcSh neuron intrinsic excitability has the potential to mitigate drug-cue association memories and drug seeking.