α-1 noradrenergic receptor stimulation impairs prefrontal cortical cognitive function

Background: 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. Methods: The alpha-1 adrenergic agonist, phenylephrine, was infused into the prefrontal cortex (PFC) of rats (0.1 mu g/0.5 mu L) performing a spatial working memory task, delayed alternation, The phenylephrine response was challenged with coinfusion of the alpha-1 adrenergic antagonist, uripidil (0.01 mu g), or with a dose of lithium chloride (4 mEq/kg, IP, 18 hours) known to suppress phosphotidylinositol (PI) turnover the second messenger pathway coupled to alpha-1 adrenoceptors. Results: 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 Conclusions: 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 Biol Psychiatry 1999;45:26-31 (C) 1999 Society of Biological Psychiatry.