Conversely, the work of Bao-Ming Li has shown that infusion of the α2A-AR antagonist, yohimbine, into the dlPFC impairs working memory and impulse control and induces locomotor hyperactivity

in monkeys (reviewed in Arnsten, 2010). Thus, α2A-AR stimulation strengthens the efficacy of dlPFC microcircuit Everolimus research buy connections, enhancing mental representation and top-down regulation of behavior. Based on this research in animals, guanfacine is now being used to treat a variety of PFC disorders in human patients, including attention deficit hyperactivity disorder (extended release pediatric formulation Intuniv) (Biederman et al., 2008), Tourette’s syndrome (Scahill et al., 2001), autism spectrum illness (McCracken et al., 2010), substance abuse (S. McKee, R. Sinha, and A.F.T.A., unpublished data), and traumatic brain injury to the frontal lobe (McAllister et al., 2011). Recent research has revealed that acetylcholine (ACh)

also plays a critical, beneficial role in dlPFC function. Depletion of ACh from the primate PFC produces a marked loss of spatial working memory function, comparable to that seen with catecholamine depletion (Croxson et al., 2011). It is likely that ACh has beneficial actions through both nicotinic and muscarinic receptors, although these receptor mechanisms are just emerging. Studies of rat medial PFC have shown that nicotinic α7 receptors are localized within the postsynaptic density Bosutinib Oxalosuccinic acid in spines, likely next to NMDA receptors, as well as in their traditional locations on presynaptic axon terminals (Duffy et al., 2009). Our physiological data show that ionotophoresis of nicotinic α7 receptor agonists onto dlPFC neurons increases delay cell task-related firing and rescues firing following NMDA receptor blockade, suggesting that the arousing properties of ACh may be an important “depolarizing partner” for NMDA receptors in PFC circuits (Y. Yang, L. Jin, A.F.T.A., and M.J.W., unpublished data). Similar results are seen with the systemic administration of nicotinic α7 receptor agonists in monkeys, which improve working memory and normalize performance following NMDA antagonists (Buccafusco and Terry,

2009; Castner et al., 2011). Thus, there is converging evidence that nicotinic α7 receptors provide a vital modulatory influence in dlPFC circuits. Studies in rats indicate that acetylcholine also modulates PFC function through actions at muscarinic receptors that close KCNQ channels and increase neuronal excitability (Santini et al., 2012), and KCNQ receptors also influence neuronal excitability in the primate dlPFC during working memory (Wang et al., 2011). Thus, cholinergic stimulation may strengthen network firing through both muscarinic and nicotinic mechanisms. Little is known about the effects of other modulators (e.g., serotonin, orexin, and histamine) on the cognitive firing patterns of dlPFC neurons. This will be an important area for future work.