Dopamine and noradrenaline efflux in the medial prefrontal cortex during serial reversals and extinction of instrumental goal-directed behavior.

The prefrontal cortex (PFC) of the rat supports cognitive flexibility, the ability to spontaneously adapt goal-directed behavior in response to radically changing situational demands. We have shown previously that transient inactivation of the rat medial PFC (mPFC) impairs initial reversal learning in a spatial 2-lever discrimination task. Given the importance of dopamine (DA) for PFC function, we studied DA (and noradrenaline [NA]) efflux in the mPFC during reversal learning. We observed a higher and more extended increase in DA efflux in rats performing the first reversal compared with controls performing the previously acquired discrimination. The results of an additional experiment suggest that such a difference between the reversal- and control-induced DA increases was absent during a third reversal. During the extinction session, DA efflux did not increase from basal levels. Increases in NA efflux were less than in DA and did not differ between control and any condition. We conclude that prefrontal DA activity is increased during execution of instrumental discrimination tasks and that this increase is amplified during the acquisition of a first, but not of later reversals. These data corroborate our previous findings and indicate that DA is critically involved in this form of cognitive flexibility.

The NMDA-receptor antagonist MK-801 selectively disrupts reversal learning in rats.

We tested the hypothesis that inhibition of NMDA-receptors in rats would lead to a selective impairment of reversal learning in a serial reversal task in the Skinner box. Low doses of MK-801 (0.025 and 0.05 mg/kg) did not affect acquisition of the two-lever discrimination, but impaired performance during the first reversal more than during the third reversal. Similar effects were observed during the series of extinction sessions. The high dose (0.1 mg/kg) completely inhibited reversal and extinction learning, as the rats perseverated in pressing the previously rewarded lever(s). We conclude that NMDA receptor blockade leads to a selective impairment in cognitive flexibility, and shows some similarity to transient inactivation of the medial prefrontal cortex in this respect.