Abstract for presentation at 6th World Congress on Stress

The mechanism of action of antidepressants remains poorly understood while the nexus between the elevation of monoamine neurotransmitter concentrations and the relief of the symptoms of depression remains problematic. Pre-clinical investigations over the past decade have suggested that while interactions with mono-aminergic receptors remain an essential element of the mode of action of antidepressants, intra-cellular cascades and the regulation of genes instigated by this interaction are more salient features for the relief of depression. These investigations have lead to the formulation of a so called neurogenesis hypothesis of the mechanism of action of antidepressants. By implication the hypothesis suggests that depression arises due to neurodegenerative changes within the brain and in particular the role of the hippocampus would appear to be pivotal. This presentation will review evidence for a hippocampal neurodegeneration in depressive illness and its potential aetiology. The crucial role played by elevated cortisol and the consequent effect on hippocampal structure will be canvassed. Data from pre-clinical models suggests that neurodegeneration may not be a critical factor in the development of "depression like" behavioural syndromes in rodents, such as learned helplessness. On the other hand several independent pre-clinical studies have shown that antidepressants act by increasing concentrations of neurotrophic factors within the hippocampus and inducing cell proliferation. A crucial question is whether such cell proliferation is associated with the growth of mature neurons and the replenishment of hippocampal volume. The neurogenesis hypothesis has provided a new paradigm with which to investigate novel molecules as antidepressants. It suggests that presynaptic blockade of reuptake of monoamines and interactions at cell surface receptors may not be a necessary condition for antidepressant activity. The prospect for the treatment of depression into the future is a generation of agents designed specifically to target appropriate intracellular messengers.