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.