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Pharmacological Manipulations of the α2-Noradrenergic System

Effects on Cognition

  • Review Article
  • Clinical Pharmacology
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Summary

Electrophysiological and neurosurgical lesion studies with experimental animals have implicated the ascending dorsal noradrenergic bundle of the locus coeruleus system in cognitive process such as memory, learning and selective attention. However, it has also been suggested that noradrenaline (norepinephrine) is crucial in certain cognitive functions associated with the frontal lobes, particularly the prevention of distractibility by irrelevant stimuli. The α2-receptors of the prefrontal cortex appear to be of particular importance in this respect. Studies with humans and experimental primates provide substantial support for this view.

The aged primate brain is prone to degeneration of the locus coeruleus, as well as profound catecholamine depletion in the prefrontal cortex, and so is ideal for psychopharmacological investigation of the role of noradrenaline in frontal lobe function. Elderly monkeys show deficits in performance of the delayed response task, which can be reversed directly by both the mixed α1/(α2-agonist clonidine, the more specific α2-agonist guanfacine and also, indirectly, by the α2-antagonist yohimbine. It is suggested that these results can be explained by an attenuation of the distracting properties of irrelevant stimuli following stimulation of noradrenergic activity. Conversely, distractibility is magnified whenever noradrenergic activity is reduced. This is supported by similar findings in psychopharmacological studies of healthy humans. The exception to this is when the locus coeruleus is likely to be firing, e.g. in times of stress or when novel stimuli are encountered. Clonidine attenuates locus coeruleus firing on such occasions, and so counteracts any beneficial (or deleterious) effects of stress on task performance.

α2-Adrenoceptor agents have little therapeutic value in patients with dementia of the Alzheimer’s type. However, they may have some clinical use in patients who have a cognitive symptomatology similar to that of patients who have received neurosurgical excisions to the frontal lobes, e.g. deficits in working memory, executive function or focused attention, with relative sparing of episodic short term memory. Patients with Korsakoff’s disease, attention deficit disorder or schizophrenia may benefit from treatment with α2-agents. In particular, idazoxan has putative therapeutic effects in patients with a neurodegenerative disorder, namely dementia of frontal type.

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  1. Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, England

    Jennifer T. Coull

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Coull, J.T. Pharmacological Manipulations of the α2-Noradrenergic System. Drugs & Aging 5, 116–126 (1994). https://doi.org/10.2165/00002512-199405020-00005

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