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In drug addiction, environmental stimuli previously associated with cocaine use readily elicit cocaine‐associated memories, which persist long after abstinence and trigger cocaine craving and consumption. Although previous studies suggest that the medial prefrontal cortex (mPFC) is involved in the expression of cocaine‐addictive behaviors, it remains unclear whether excitatory and inhibitory neurons in the mPFC are causally related to the formation and retrieval of cocaine‐associated memories. To address this issue, we used the designer receptors exclusively activated by designer drugs (DREADD) technology combined with a cocaine‐induced conditioned place preference (CPP) paradigm. We suppressed mPFC neuronal activity in a cell‐type– and timing‐dependent manner. C57BL/6J wild‐type mice received bilateral intra‐mPFC infusion of an adeno‐associated virus (AAV) expressing inhibitory DREADD (hM4Di) under the control of CaMKII promotor to selectively suppress mPFC pyramidal neurons. GAD67‐Cre mice received bilateral intra‐mPFC infusion of a Cre‐dependent AAV expressing hM4Di to specifically silence GABAergic neurons. Chemogenetic suppression of mPFC pyramidal neurons significantly attenuated both the acquisition and expression of cocaine CPP, while suppression of mPFC GABAergic neurons affected neither the acquisition nor expression of cocaine CPP. Moreover, chemogenetic inhibition of mPFC glutamatergic neurons did not affect the acquisition and expression of lithium chloride‐induced conditioned place aversion. These results suggest that the activation of glutamatergic, but not GABAergic, neurons in the mPFC mediates both the formation and retrieval of cocaine‐associated memories.

Cocaine-associated environmental cues elicit craving and relapse to cocaine use by recalling the rewarding memory of cocaine. However, the neuronal mechanisms underlying the expression of cocaine-associated memory are not fully understood. Here, we investigated the possible contribution of γ-aminobutyrate (GABA) ergic neurons in the nucleus accumbens (NAc), a key brain region associated with the rewarding and reinforcing effects of cocaine, to the expression of cocaine-associated memory using the conditioned place preference ( Key words nucleus accumbens; cocaine; conditioned place preference; designer receptors exclusively activated by designer drugs; γ-aminobutyrate (GABA); mouse Cocaine addiction is a chronic relapsing disease characterized by compulsive drug seeking and taking. The rewarding and reinforcing properties of cocaine are readily associated with the environmental contexts where cocaine is experienced. The cocaine-associated environmental cues elicit craving and relapse to cocaine use by recalling the rewarding memory of cocaine. However, the mechanisms by which environmental cues induce the expression of cocaine-associated memory are not fully understood. To investigate these mechanisms, the conditioned place preference (CPP) test, a widely used Pavlovian conditioning paradigm is considered to be useful. 1) In the conditioning session of the CPP, animals learn to associate the rewarding effects of cocaine and a neutral environmental context that has been paired with cocaine administration by investigators. Thereafter, in the posttest session, animals exhibit a preference for the cocaine-paired environment, likely due to the expression of cocaine-associated memory. Although previous studies revealed that the mesocorticolimbic reward system consisting of the ventral tegmental area (VTA), medial prefrontal cortex (mPFC), and nucleus accumbens (NAc) is involved in the expression of cocaine-associated memory, 2-4) the precise neuronal and circuit mechanisms underlying this behavior remain unclear.The NAc plays an important role in the expression of cocaine-seeking behavior and cocaine-associated memory. [5][6][7] Recent studies have shown that activation of glutamatergic projections from the prelimbic subregion (PL) of the mPFC to the NAc core is required for cue-induced reinstatement of cocaine seeking. 8,9) In addition, intra-NAc infusion of an AMPA receptor antagonist was found to block the expression of cocaine CPP. 2) These findings suggest that excitation of the NAc is involved in the expression of cocaine-associated memory. Considering that the vast majority of NAc neurons are γ-aminobutyrate (GABA) ergic medium spiny neurons (MSNs), 10,11) these GABAergic neurons are likely to contribute to the expression of cocaine CPP. Thus, in the present study, we addressed this issue using designer receptors exclusively activated by designer drugs (DREADD) technology. 12) We selectively expressed G i/o -coupled inhibitory DREADD hM4Di in NAc GABAergic neurons of vesicular GABA transporterCre (vGAT-Cre) mic...

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