Depression in an animal model: focus on the locus ceruleus

When rats are exposed to highly stressful events over which they have no control, they subsequently show many of the symptoms seen in depression in humans. In the attempt to discover neurochemical factors underlying depression, the neurochemical basis of stress-induced behavioural depression in rats has been studied extensively. Initial research (1968-1976) indicated that behavioural depression in this model was produced by alteration of noradrenaline (NA) concentrations in the brain. More recent research has indicated that the critical change may be a large depletion of NA in the locus ceruleus (LC). Behavioural depression may result when such NA depletion is sufficient to reduce NA release in the LC region, leading to a 'functional blockade' of inhibitory alpha 2-receptors in that brain region. Studies have now shown that behavioural depression after uncontrollable shock can be mimicked by pharmacological blockade of alpha 2-receptors in the LC region. Conversely, behavioural depression can be eliminated by either infusion of clonidine into the LC to replace at the alpha 2-receptors the NA depleted after uncontrollable shock, or infusion of pargyline into the LC to prevent the depletion of NA that otherwise follows uncontrollable shock. If alpha 2-receptors are functionally blocked in depression, then release of NA in regions innervated by the LC should be increased and stimulation of postsynaptic adrenoceptors outside the LC should be higher than normal. Thus, higher-than-normal stimulation of postsynaptic NA receptors should also produce behavioural depression; this has been demonstrated.