EtOH/Ach exposure minimally affects nNOS protein levels in primary human neurons. Physiologic NO concentrations released by nNOS serve as essential neurotransmitters and an integral part of guanylate cyclase activation via NO signaling. In the nNOS knockout mice, alcohol-induced impairment and deficiency of nNOS caused microencephaly and neuronal loss [28] and neuro-cognitive deficits [29]. The present findings attempt to explain this mechanistic switch in physiologic conditions of chronic alcoholism. We hypothesize that occasional low doses of alcohol stimulate nNOS (not inducible) producing adequate levels of NO to maintain this proper physiologic function. On the contrary, high dose or chronic exposure (even at low-dose) induces iNOS in the CNS, and an excess amount of NO suppresses the proper physiological functions. The relevance of these data is supported by the findings that NOS induction was detected in cerebellar cortical neurons of alcoholics [53]. Similarly, reactive EtOH metabolites (ROS, Ach), depending on the concentrations, can have opposite effects within the active self-organizing biological system. At low concentrations, these reactive species act as activating molecules; whereas, at high concentrations, these oxidants act as transducers of oxidative stress and neurodegenerative agents.
