Working Memory Impairing Actions of Corticotropin-Releasing Factor (CRF) Neurotransmission in the Prefrontal Cortex

The prefrontal cortex (PFC) regulates cognitive processes critical for goal-directed behavior. PFC cognitive dysfunction is implicated in multiple psychopathologies, including attention deficit hyperactivity disorder (ADHD). Although it has long been known that corticotropin-releasing factor (CRF) and CRF receptors are prominent in the PFC, the cognitive effects of CRF action within the PFC are poorly understood. The current studies examined whether CRF receptor activation in the PFC modulates cognitive function in rats as measured in a delayed response task of spatial working memory. CRF dose-dependently impaired working memory performance when administered either intracerebroventricularly (ICV) or directly into the PFC. The working memory actions of CRF in the PFC were topographically organized, with impairment observed only following CRF infusions into the caudal dorsomedial PFC (dmPFC). Additional studies examined whether endogenous CRF modulates working memory. Both ICV and intra-dmPFC administration of the nonselective CRF antagonist, D-Phe-CRF, dose-dependently improved working memory performance. To better assess the translational potential of CRF antagonists, we examined the cognitive effects of systemic administration of the CRF1 receptor selective antagonist, NBI 35965. Similar procognitive actions were observed in these studies. These results are the first to demonstrate that CRF acts in the PFC to regulate PFC-dependent cognition. Importantly, the ability of CRF antagonists to improve working memory is identical to that seen with all approved treatments for ADHD. These observations suggest that CRF antagonists may represent a novel approach for the treatment of ADHD and other disorders associated with dysregulated prefrontal cognitive function.