Current concepts. I. Anxiety: the locus coeruleus disconnection.

For the 1643 ± 21 neurone that it contains (1) the noradrenergic nucleus locus coeruleus has received a remarkable amount of attention and research in the past five years. This blue streak at the base of the fourth ven tricle (2) has been suggested to be involved in functions as diverse as learning and memory (3,4,5), sleep (6) and blood pressure (7,8), stress (9) and extinction (10). More recently a particularly intriguing hypothesis has suggested that a function in anxiety and fear can be ascribed to this structure (11). This idea, and the evidence that has subsequently accumulated pertaining to it, are the subjects of the present discussion. A role for the locus coeruleus (LC) in anxiety was first postulated by Redmond, Huang, Snyder and Maas (11) on the basis of lesion and electrical stimulation of LC. They found that electrical stimulation of this nucleus in the awake restrained monkey (Macaca arctoides) elicited a behavioural response of scratching and grimacing which, in the wild (12), is observed most usually in fearful or threatening situations. The converse finding occurred after electrolytic lesion of LC in the primate (13). Now, threat from the human experimenter failed to elicit the usual behavioural fear response. Instead the animal remained placid and unaffected. In humans, electrical stimulation of the LC is reported to induce feelings of fear and death and, conversely, a small lesion here has a calming effect (14). Manipulations of LC firing activity using drugs also seemed to support this hypothesis. Thus, the drugs piperoxane and yohimbine, both of which have been found from microiontopho-retic studies to increase the firing of LC cells (15), elicited a corresponding increase in fear-associated behaviour patterns in the restrained monkey (16) and are reported to induce anxiety in human volunteers (17,18,19). Conversely , drugs which, among other actions, have been found from microiontopho-retic studies to reduce the firing rate of LC neurons (20,21), such as cloni-dine, desimipramine, morphine, and the barbiturates, reduce the incidence of fear behavior in the monkey and are well-known clinically for their anti-anxiety effects (22,23). Further, blocking the post-synaptic effect of nora-drenaline (NA), released as a result of LC activity, by use of the drug pro-pranolol (a beta-Mocker) also reduced fear behaviour in the experimental situation (16) and this drug has been claimed clinically to posses anti-anxiety properties (24). This seems to be strong support for the newest of the many hypotheses to …