Physiology and pathophysiology of the serotonergic system and its implications on mental and physical performance. Part I

Serotonin (5-HT), one of the evolutionary oldest central neurotransmitters, regulates the most extensive modulatory behavioral system in the brain of vertebrates. 5-HT projections are influenced by extrinsic and intrinsic imp ulses from different cortical brain areas, which reach Raphe nuclei over fe edback loops, containing external and internal body information about plann ing, evaluation, motivation or excitation. Serotonergic neurotransmission a djusts neuromodulation with consecutive adequate stimulation of the neurona l network. This depends on appropriate equilibration of presynaptic 5-HT st orage and release but also on 5-HT reuptake from synaptic cleft by 5-HT tra nsporters. The associated pre and postsynaptic 5-HT receptor cooperation, p ostsynaptic second messenger response and phosphoinositide signaling mediat ed by postsynaptic 5-HTz receptor subpopulation alter signal transduction i n which myristolated alanine rich C kinase substrate is prominently involve d in regulation of further central 5-HT areas in the brain and correspondin g functional neuronal changes. Even though the central function of 5-HT neu rotransmission is dominating in the multifold behavioral regulation, periph eral concentration of tryptophan (TRP) adjusted by hepatic and non-hepatic TRIP pyrrolase, TRP liberation from albumin especially by adrenergic stimul ation of free fatty acids, TRP passage across the blood-brain barrier and T RP hydroxylase activity are also important for appropriate 5-HT neurotransm ission as they affect central 5-HT synthesis. The high adaptability of 5-HT neurotransmission is able to compensate neuromodular dysfunctions in the b rain by mechanisms which mediate 5-HT biosynthesis, release, reuptake, pre and postsynaptic receptor stimulation with the respective second messenger response and signal transduction to various areas of the brain which are in volved in regulation of behavior, mood, memory, learning and attenuation of obsession, depending on the different vigilance states of the subject. Ade quate 5-HT system function supports regulation of intercommunicative neuron al transmission in the brain, which optimizes behavioral neuromodulation du ring and after transient disturbances of neuromodular behavior caused by st ress-induced exertions, but also in permanent disorder such as major depres sion. Serotonergic neurotransmission improves the clinical course due to co mpensatory 5-HT impulse correction. This hypothetical interpretation of the serotonergic central neuromodular regulation and interaction with the neur onal network is supported by findings both in functional disturbances and p ersistent impairments in mental disorders. A comparison of the symptomatolo gy in permanent and transient disturbance of brain neuromodulation enhances our basic knowledge on the regulative factors e.g. in endogenous depressio n and depressive behavioral changes after exhaustive exercise. This conside ration exhibits that the interaction between altered central neuromodulatio n and peripheral metabolic and hormonal dysfunctions is able to differentia te the etiology of the symptoms. It is suggested that the central neuromodu lar disturbance of stress-induced causes might initiate the manifestation o f the impairment. The theoretical background of this hypothesis is discusse d in the present review.