PHARMACOLOGICAL MANIPULATIONS OF THE ALPHA(2)-NORADRENERGIC SYSTEM - EFFECTS ON COGNITION

Electrophysiological and neurosurgical lesion studies with experimenta l animals have implicated the ascending dorsal noradrenergic bundle of the locus coeruleus system in cognitive process such as memory, learn ing and selective attention. However, it has also been suggested that noradrenaline (norepinephrine) is crucial in certain cognitive functio ns associated with the frontal lobes, particularly the prevention of d istractibility by irrelevant stimuli. The alpha(2)-receptors of the pr efrontal cortex appear to be of particular importance in this respect. Studies with humans and experimental primates provide substantial sup port far this view. The aged primate brain is prone to degeneration of the locus coeruleus, as well as profound catecholamine depletion in t he prefrontal cortex, and so is ideal for psychopharmacological invest igation of the role of noradrenaline in frontal lobe function. Elderly monkeys show deficits in performance of the delayed response task, wh ich can be reversed directly by both the mixed alpha(1)/alpha(2)-agoni st clonidine, the more specific alpha(2)-agonist guanfacine and also, indirectly, by the alpha(2)-antagonist yohimbine. It is suggested that these results can be explained by an attenuation of the distracting p roperties of irrelevant stimuli following stimulation of noradrenergic activity. Conversely, distractibility is magnified whenever noradrene rgic activity is reduced. This is supported by similar findings in psy chopharmacological studies of healthy humans. The exception to this is when the locus coeruleus is likely to be firing, e.g. in times of str ess 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. alpha(2)-Adren oceptor 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 patien ts 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 Ko rsakoff's disease, attention deficit disorder or schizophrenia may ben efit from treatment with alpha(2)-agents. In particular, idazoxan has putative therapeutic effects in patients with a neurodegenerative diso rder, namely dementia of frontal type.