Central blockade of muscarinic cholinergic receptors disrupts affective and attentional set-shifting.

Impairments in multiple aspects of attentional and executive function follow damage to cholinergic neurons in the central nervous system. Affective and attentional set-shifting represent two aspects of executive function controlled by different sectors of the prefrontal cortex. The involvement of cholinergic neural mechanisms in these aspects of executive function has not been specified. To determine whether central muscarinic cholinergic receptors were involved in affective and/or attentional set-shifting, we tested rats on a series of discrimination learning problems, which included affective (reversal learning) and attentional set (extradimensional shift)-shifting components, under the systemic influence of scopolamine, a muscarinic antagonist. Scopolamine impaired both reversal learning and extradimensional shifting, but was without effect on learning new discrimination problems that did not require an affective or attentional shift. Systemic administration of methylscopolamine, which does not cross the blood-brain barrier, did not impair affective or attentional set-shifting, indicating that the scopolamine effects were centrally mediated. These data implicate muscarinic receptors in the central nervous system in the control of executive function. Taken together with other recent data, they may also suggest an important role for cholinergic receptors outside of the neocortex in regulating these aspects of attention and executive function.