Alpha-1 noradrenergic receptor stimulation impairs prefrontal cortical cognitive function.

Many neuropsychiatric disorders are associated with high levels of noradrenergic turnover, and most antipsychotic medications have alpha-1 adrenoceptor blocking properties, yet little is known about alpha-1 influences on higher cortical function. The alpha-1 adrenergic agonist, phenylephrine, was infused into the prefrontal cortex (PFC) of rats (0.1 microgram/0.5 microL) performing a spatial working memory task, delayed alternation. The phenylephrine response was challenged with coinfusion of the alpha-1 adrenergic antagonist, uripidil (0.01 microgram), or with a dose of lithium chloride (4 mEq/kg, i.p., 18 hours) known to suppress phosphotidylinositol (PI) turnover, the second messenger pathway coupled to alpha-1 adrenoceptors. Phenylephrine infusions in PFC markedly impaired delayed alternation performance. The phenylephrine response was reversed by coinfusion of uripidil, or by pretreatment with lithium, consistent with actions at alpha-1 adrenoceptors coupled to a PI pathway. These findings demonstrate that alpha-1 adrenoceptor stimulation in the PFC impairs cognitive function. Excessive stimulation of alpha-1 adrenoceptors may contribute to PFC deficits (e.g., distractibility, impulsivity) in disorders such as mania, dementia, and anxiety associated with high noradrenergic turnover.