Antidepressant mechanisms: functional and molecular correlates of excitatory amino acid neurotransmission.
Specific targeting of the serotonergic and noradrenergic systems for the development of antidepressant compounds has resulted in drugs with more favourable side-effect profiles but essentially no greater efficacy than those compounds discovered more than 40 years ago. Alternative targets are now being considered in the hope that they will have a faster onset of action and be useful for those patients currently unresponsive to conventional treatments. Excitatory amino acid neurotransmission has been attributed various roles in both normal and abnormal brain function. The N-methyl-D-aspartate receptor in particular has long been postulated to play a role in the formation of memories. Major depressive disorder is characterised by alterations in cognitive function, as well as affect. Although there is evidence that early adverse events and stress can have a causal influence on depression, the underlying neurobiology of the disorder is poorly understood. This review will document current evidence for the involvement of excitatory amino acid neurotransmission in the pathophysiology of the affective disorders. The preclinical literature suggests that both electroconvulsive stimulation and antidepressant drugs can affect hippocampal long-term potentiation and the expression of excitatory amino acid receptor subtypes. Exposing animals to stress, including the kind that produces learned helplessness, can also affect synaptic plasticity in the hippocampus. There is clinical evidence that patients with chronic depression have structural brain abnormalities, including hippocampal atrophy, and a preliminary study has shown that an N-methyl-D-aspartate receptor antagonist may have antidepressant efficacy.
Stewart
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University of Dundee, Department of Psychiatry, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK. c.a.stewart@dundee.ac.uk
Reid
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D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D018846:Excitatory Amino Acids / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009473:Neuronal Plasticity / Q000187:drug effects; D013315:Stress, Psychological / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
D000928:Antidepressive Agents; D018846:Excitatory Amino Acids