Infralimbic Prefrontal Cortex Is Responsible for Inhibiting Cocaine Seeking in Extinguished Rats

The rat prelimbic prefrontal cortex and nucleus accumbens core are critical for initiating cocaine seeking. In contrast, the neural circuitry responsible for inhibiting cocaine seeking during extinction is unknown. The present findings using inhibition of selected brain nuclei with GABA agonists show that the suppression of cocaine seeking produced by previous extinction training required activity in the rat infralimbic cortex. Conversely, the reinstatement of drug seeking by a cocaine injection in extinguished animals was suppressed by increasing neuronal activity in infralimbic cortex with the glutamate agonist AMPA. The cocaine seeking induced by inactivating infralimbic cortex resembled other forms of reinstated drug seeking by depending on activity in prelimbic cortex and the basolateral amygdala. A primary efferent projection from the infralimbic cortex is to the nucleus accumbens shell. Akin to infralimbic cortex, inhibition of the accumbens shell induced cocaine seeking in extinguished rats. However, bilateral inhibition of the shell also elicited increased locomotor activity. Nonetheless, unilateral inhibition of the accumbens shell did not increase motor activity, and simultaneous unilateral inactivation of the infralimbic cortex and shell induced cocaine seeking, suggesting that an interaction between these two structures is necessary for extinction training to inhibit cocaine seeking. The infralimbic cortex and accumbens shell appear to be recruited by extinction learning because inactivation of these structures before extinction training did not alter cocaine seeking. Together, these findings suggest that a neuronal network involving the infralimbic cortex and accumbens shell is recruited by extinction training to suppress cocaine seeking.