Antidepressant activity and calcium signaling cascades

Although antidepressant treatments produce clear effects on monoaminergic n euronal function, the link between these effects and therapeutic response t o treatment is controversial. Previous studies have demonstrated that antag onists of the NMDA receptor-gated calcium ionophore result in antidepressan t-like responses in rodents and humans. Likewise, antidepressant treatments produce regionally selective adaptation of the NMDA receptor suggestive of diminished capacity to gate calcium into receptive neurons. Similarly, vol tage-dependent calcium channel antagonists have been reported to produce an tidepressant-like effects in rodents. A major target of increases in subcel lular calcium concentration is nitric oxide synthase (NOS) which liberates NO in response to stimulation. Recently, we have demonstrated that nitric o xide synthase antagonists produced antidepressant-like response in both in vivo preclinical screening procedures and in post-mortem in vitro studies o f beta -adrenoceptor density. We propose: 1) that interruption of the Ca2+- calmodulin-NOS-guanylyl cyclase subcellular signaling pathway at any point will produce antidepressant-like effects; 2) that the acute actions of anti depressants in preclinical screening procedures are a consequence of their ability to disrupt Ca2+-calmodulin-NOS-guanylyl cyclase signaling; 3) that chronic but, not acute treatment with antidepressants results in adaptation of the Ca2+-calmodulin-NOS-guanylyl cyclase signaling pathway; 4) that thi s adaptation is necessary for the achievement of the therapeutic actions of antidepressants and; 5) that major depression is accompanied by an alterat ion (hyperactivity?) of subcellular Ca2+ signaling. Copyright (C) 2001 John Wiley & Sons, Ltd.