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 influe
nces on higher cortical function.
Methods: The alpha-1 adrenergic agonist, phenylephrine, was infused into th
e 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 ch
allenged 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 pathwa
y coupled to alpha-1 adrenoceptors.
Results: Phenylephrine infusions in PFC markedly impaired delayed alternati
on performance. The phenylephrine response was reversed by coinfusion of ur
ipidil, 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 stimulati
on in the PFC impairs cognitive function. Excessive stimulation of alpha-1
adrenoceptors may contribute to PFC deficits (e.g., distractibility, impuls
ivity) in disorders such as mania, dementia, and anxiety associated with hi
gh noradrenergic turnover Biol Psychiatry 1999;45:26-31 (C) 1999 Society of
Biological Psychiatry.