Neural circuit competition in cocaine-seeking: roles of the infralimbic cortex and nucleus accumbens shell

Following cocaine self-administration and extinction training, activity in the infralimbic cortex (IL) suppresses cocaine-seeking behavior. IL inactivation induces cocaine-seeking whereas activation suppresses cocaine-reinstated drug-seeking. We asked how the suppression of cocaine-seeking induced by IL activation integrates with the circuitry promoting reinstated cocaine-seeking. Following cocaine self-administration and extinction training, rats underwent cue-induced reinstatement. In order to activate IL projections, microinjections of PEPA, a positive allosteric modulator of AMPA receptors, were made into the IL in combination with microinjections into a variety of nuclei known to regulate cocaine-seeking. Intra-IL PEPA administration suppressed cue-induced reinstatement without affecting locomotor activity. The suppression of cocaine-seeking was reversed by activating dopamine neurons in the ventral tegmental area with microinjections of the mu-opioid receptor agonist DAMGO, and was partially reversed by dopamine microinjections into the prelimbic cortex or basolateral amygdala. Previous evidence suggests that the nucleus accumbens shell both promotes and suppresses cocaine-seeking. The suppression of cue-induced cocaine seeking by PEPA in the IL was reversed by intra-shell microinjections of either dopamine or the AMPA receptor antagonist CNQX, suggesting that the accumbens shell bidirectionally regulates cocaine-seeking depending on whether dopamine input is mimicked or glutamate input is inhibited. Together, these findings indicate that the IL acts upstream from structures promoting cocaine-seeking, including from the mesolimbic dopamine projections to the prelimbic cortex and basolateral amygdala, and that the accumbens shell may be a crucial point of integration between the circuits that promote (ventral tegmental area) and inhibit (IL) reinstated cocaine-seeking.