AMPA receptor activation in dorsal medial prefrontal cortex-to-nucleus accumbens neurons regulates the expression of conditioned approach.

The medial prefrontal cortex (mPFC) is crucial for motivated behavior, but the distinct roles of its dorsal (dmPFC) and ventral (vmPFC) regions, and specific contributions of NMDA and AMPA receptor activation in the acquisition and expression of conditioned approach (CA), remain unclear. Long-Evans male rats underwent associative conditioning on three alternating days (acquisition) or seven consecutive days (expression), in which each of 30 presentations of a light stimulus (conditioned stimulus: CS) was paired with a food pellet (unconditioned stimulus: US). In acquisition of CA, NMDA receptors were blocked with AP5 prior to each conditioning session. In expression of CA, AMPA receptors were blocked with CNQX prior to the CS-only test session. Rats treated with AP5 in either region of mPFC showed substantially greater CA in comparison to the vehicle group. However, rats treated with CNQX in the dmPFC showed significant dose-dependent reduction in CA compared to vehicle-treated rats. Those treated with CNQX in the vmPFC showed significantly greater CA scores than their corresponding controls. Moreover, the CS resulted in significantly higher numbers of glutamatergic neuron activation than a light stimulus not explicitly paired with food (i.e., a neutral stimulus). Finally, chemogenetic inhibition of glutamatergic projections from dmPFC to nucleus accumbens (nAc) significantly reduced expression of CA. These results show that AMPA receptor stimulation in the dmPFC is essential for the expression of CA. They also demonstrate that a CS activates glutamatergic neurons in the dmPFC and that these neurons in the dmPFC-nAc pathway are critical for the expression of CA.