Alpha-1 noradrenergic receptor stimulation impairs prefrontal cortical cognitive function

Biol Psychiatry. 1999 Jan 1;45(1):26-31. doi: 10.1016/s0006-3223(98)00296-0.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenergic alpha-1 Receptor Agonists*
  • Adrenergic alpha-Agonists / administration & dosage
  • Adrenergic alpha-Agonists / pharmacology
  • Adrenergic alpha-Antagonists / administration & dosage
  • Adrenergic alpha-Antagonists / pharmacology
  • Animals
  • Cognition / drug effects
  • Cognition / physiology*
  • Lithium Chloride / administration & dosage
  • Lithium Chloride / pharmacology
  • Male
  • Norepinephrine / metabolism*
  • Phenylephrine / administration & dosage
  • Phenylephrine / pharmacology
  • Phosphatidylinositols / antagonists & inhibitors
  • Piperazines / administration & dosage
  • Piperazines / pharmacology
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / physiology*
  • Psychomotor Performance / drug effects
  • Rats
  • Rats, Sprague-Dawley


  • Adrenergic alpha-1 Receptor Agonists
  • Adrenergic alpha-Agonists
  • Adrenergic alpha-Antagonists
  • Phosphatidylinositols
  • Piperazines
  • Phenylephrine
  • urapidil
  • Lithium Chloride
  • Norepinephrine