Neurotransmitter Systems

Neurotransmitters play a central role in neuron-to-neuron information processing and in transferring information from neurons to target cells. Classical neurotransmitters include acetylcholine, the catecho-lamines (norepinephrine, epinephrine, and dopamine), and serotonine. In addition, neurotransmission may be accomplished and/or modulated by amino acids, such as glycine, glutamate, and gamma aminobutyric acid (GABA), as well as peptides (e.g., enkephalin, substance P, and cholecystokinin), gas (nitric oxide and carbon dioxide), and metals, acting as neuromodulators (zinc). Nitric oxide and carbon dioxide originally were viewed as toxic, but it has been demonstrated that they can act as biological messengers in mammals. It is important to consider that different neurotransmitters may coexist within the same neuron, and this implies a vast expansion of the potential for synaptic communication. This coexistence of multiple neurotransmitters results in a reciprocal modulation of the specific action of these substances aimed at providing the adequate response from neurons to environmental stimuli by a fine balance of the inhibitory and excitatory effect of classical neurotransmitters and their neuromodulators. Turnover, release, and binding of neurotransmitter substances constitute important steps in the mechanisms involved in signal transduction between adjacent nerve cells; therefore changes in any of them may result in functional alterations. It is well known that many synapses are identified by the neurotransmitter released, thus at terminal regions of different synapses very specific mechanisms are operating to work out these processes, and these include, in addition to the synthesis of neurotransmitters, the activity of degrading and synthesizing enzymes. Complete and reliable analysis to detect neurotransmitter changes occurring at synaptic regions should take into account studies aimed at testing proper functioning at different levels. Thus, precursor availability, synthesis of enzymes, degradation of neuro-transmitters, their storage, reuptake, and ionic regulation refer to the presynaptic area, and free neurotransmitters as well as the enzymes of their degradation pertain to transynaptic events. Receptor binding, enzyme degradation, ionic regulation, and the induction of second messengers refer to the postsynaptic zone. On the basis of this high complexity of the mechanisms of neurotransmission, the knowledge accumulated on age differences regarding this function is still fragmentary and incomplete, particularly with specific reference to human studies. In humans, the measurement of neurotransmitter substances or their metabolites is carried out in urine, blood, or cerebrospinal fluid or, recently, by using labeled probes and imaging techniques. It is clearly understandable that all these methods enable an indirect and remote analysis of the neurotransmitter substance, and any subtle alteration in the physiological condition may not be identified. Despite these difficulties, a general consensus can be envisaged among the different scientific reports; that is, during physiological aging the levels and activity of neurotransmitters and related enzymes decline in many brain regions, and the corresponding receptors may or may not respond to these changes by increasing their number and/or affinity. In details, with reference to human beings, it has been found that brain acetylcholine transferase levels as well as muscarinic binding decrease in aging (Perry, 1980). The levels of striatal dopamine uptake sites, dopamine and dopamine transporters show an age-associated decline (Kish et al., 1992) as do serotonin binding sites, a2 and adrenoceptors, and cortical GABAergic innervation (Allen et al., 1983; Kalaria et al., 1989). Alterations due to age in tissue levels of glutamate and aspartate are distributed in different brain areas (Banay-Schwartz et al., 1992). Studies in different discrete zones of the CNS of laboratory animals (rats) have shown that while the concentration of serotonine is constant throughout the lifespan, dopamine and norepinephrine progressively decease starting from adulthood. Thus, in the aging rat brain the ratio of serotonin to catecholamines progressively increases, but the functional manifestation of this imbalance may be due to the impairment of only one of these three neurotrans-mitters. It must be stressed that different neurotransmitter systems show a differential rate of aging that may be responsible for an imbalance as an early event before the appearance of changes affecting a specific neuro-transmitter. In summary, although several data have been obtained from animal studies, it may be assumed that alteration of function in aging may result from an imbalance among the many neurotransmitter substances and neuromodulators that could be due to deteriorative event(s) affecting any of them, rather than to specific focal impairments affecting a single neurotransmitter system.

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