Affective disorders and nitric oxide: A role in pathways to relapse and refractoriness?

Glutamatergic mechanisms are powerful activators of the L-arginine-nitric oxide (NO) pathway in the central nervous system (CNS). While these mechanisms have been implicated in a variety of neurodegenerative disorders, as well as psychiatric disorders such as schizophrenia and anxiety, a possible role in affective disorders has not been defined. Low gamma-hydroxy butyric acid (GABA)/high glutamate ratios appear to be aetiological factors in the syndrome of depression. In addition to effects on biogenic amines, typical antidepressants exhibit both glutamate-modulating actions and GABA enhancing properties, while N-methyl-D-aspartate (NMDA)-receptor antagonists, similarly, display antidepressant efficacy. Excessive activation of glutamatergic/nitrergic mechanisms, leading to limbic and subcortical kindling and the synthesis of specific immediate early genes (IEG) and retrograde messengers such as NO, allow the formation of memory traces which can either predict remission of dysphoric mood or, alternatively, the development of relapse and treatment refractoriness. In parallel to its ability to induce refractoriness, lithium can augment glutamate responses, is proconvulsant, regulates gene expression and has distinct effects on NO and cGMP. These effects, including refractoriness, may be overcome with anticonvulsant/GABA-agonists or an NMDA antagonist. Not only are anti-glutamatergic or GABA-enhancing mechanisms thus vital for successful remission of depression, they may also regulate homeostatic mechanisms preventing dysphoric mood recurrence. The diverse effects of NO and cGMP on subcellular events, the unique physico-chemical properties of NO and its involvement in cellular memory processes and synaptic plasticity makes it an ideal regulator of short- and long-term adaptive changes associated with mood regulation.