Abstract:
:Major antidepressant agents increase synaptic levels of monoamines. Although the monoamine hypothesis of depression remains a cornerstone of our understanding of the pathophysiology of depression, emerging data has suggested that the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subtype of glutamate receptor may also play a pivotal role in depression. Positive allosteric modulators of AMPA receptors increase brain levels of brain-derived neurotrophic factor (BDNF) that impacts the viability and generation of neurons in key brain structures. AMPA receptor potentiators are active in rodent models predictive of antidepressant efficacy. The mechanisms by which AMPA receptor potentiators produce these biological effects, however, are uncertain. Current evidence points to an antidepressant mechanism that is independent of monoaminergic facilitation that is driven by neurogenesis, a process facilitated by increased BDNF expression. However, alternative hypotheses need to be considered given uncertainties in the relationship between BDNF increases and the effects of conventional antidepressant medications. Electrophysiological and protein conformational data indicate that structural variants of AMPA receptor potentiators can differentially modulate AMPA receptor-mediated currents, although the manner in which this impacts antidepressant efficacy is yet to be understood. Conventional antidepressants such as fluoxetine positively modulate AMPA receptors. This potentiation is engendered by specific phosphorylation pathways activated through the dopamine- and cAMP-regulated phosphoprotein of Mr 32,000 (DARPP-32). Other novel compounds with antidepressant-like effects in rodents may also produce their in vivo effects through potentiation of AMPA receptors. Thus, AMPA receptor potentiation might be a general mechanism through which the clinical outcome of antidepressant efficacy is achieved.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Alt A,Nisenbaum ES,Bleakman D,Witkin JMdoi
10.1016/j.bcp.2005.12.022subject
Has Abstractpub_date
2006-04-28 00:00:00pages
1273-88issue
9eissn
0006-2952issn
1873-2968pii
S0006-2952(05)00847-6journal_volume
71pub_type
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