Alpha-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 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.


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.
Arnsten
A F
AF
Section of Neurobiology, Yale Medical School, New Haven, Connecticut 06520-8001, USA.
Mathew
R
R
Ubriani
R
R
Taylor
J R
JR
Li
B M
BM
D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D018021:Lithium Chloride / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D010656:Phenylephrine / Q000008:administration & dosage / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000037:antagonists & inhibitors; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D010716:Phosphatidylinositols; D010879:Piperazines; D010656:Phenylephrine; C015568:urapidil; D018021:Lithium Chloride; D009638:Norepinephrine