Noradrenaline and depression

There is substantial evidence to implicate the noradrenergic system in the pathophysiology of depression, though it is not yet clear at what point in this highly complex system the primary defect occurs. Dietary phenylalanine and tyrosine are converted intraneuronally into the catecholamines dopamin e and noradrenaline, the rate-limiting enzyme in the synthetic pathway bein g tyrosine hydroxylase. Noradrenaline released into the synaptic cleft is m ainly transported back into the neurone, a process reduced by noradrenaline reuptake inhibiting antidepressants (NARIs). The metabolism of noradrenali ne involves monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT ). MAO-inhibiting drugs (MAOIs) have antidepressant actions. The release of noradrenaline into the synaptic gap is controlled by multiple mechanisms, including the actions of presynaptic facilitatory and inhibitory adrenocept ors on the same terminal. Postsynaptic adrenoceptors are coupled by G-prote ins to effector proteins and a variety of second-messenger systems; stimula tion of these adrenoceptors leads ultimately to changes in protein phosphor ylation in the so-called third-messenger system. Activation of second- and third-messenger systems modulates receptor function, transmitter metabolism and release, protein synthesis, neuronal growth and differentiation, intra cellular messenger pathways, and learning and memory. The noradrenergic tra nsmitter system interacts with other transmitter systems via its effects on the intracellular messenger systems. There are several lines of evidence c onnecting noradrenergic mechanisms with depression, though the findings hav e not always been clear-cut. Genetic studies have not so Tar established un equivocally a link between depression and enzymes involved in noradrenaline synthesis and degradation. CSF concentrations of the main metabolite of no radrenaline, 2-methoxy-4-hydroxyphenylglycol (MHPG) are not a reliable indi cator of central noradrenergic function in depression. Studies of beta-adre noceptor densities in postmortem tissues and lymphocytes from depressed pat ients have also given equivocal results, as have studies of cw-adrenoceptor densities. Changes apparently linked to depression have been reported in i midazoline receptor density. Uncoupling of receptors from G protein may be involved in depressive mechanisms. Depression is known to be associated wit h hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, and there is evidence that the functional sensitivity of alpha(2)-adrenoceptors in t he HPA axis is reduced in depressed patients. Studies using antidepressant agents with a high degree of specificity for the noradrenergic system will help to elucidate the role of this system in depression.