Modulatory role of presynaptic nicotinic receptors in synaptic and non-synaptic chemical communication in the central nervous system.

Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a family of ligand-gated channels closely related to but distinct from the muscle nAChRs. Recent progress in neurochemical and pharmacological methods supports the hypothesis of presynaptically located nAChRs on axon terminals and indicates that the major effect of nAChR is the modulation rather than processing of fast synaptic transmission. Strong neurochemical evidence indicate that the most important function of presynaptic nAChRs in either synaptic or non-synaptic localization is to increase transmitter release initiated by axonal firing, or directly induce Na(+) and Ca(2+) influx followed by a depolarization sufficient to activate local voltage-sensitive Ca(2+) channels, as a result transmitter of vesicular origin will be released. Therefore, it is somewhat expected that nicotine-induced transmitter release of different monoamines including norepinephrine (NE), dopamine (DA), serotonin (5-HT) can be tetrodotoxin (TTX)- and [Ca(2+)](o)-sensitive. However, some of the nAChR agonists at higher concentrations (1, 1-dimethyl-4-phenylpiperazinium (DMPP) and lobeline), besides their effects on presynaptic nAChRs, are able to inhibit the uptake of NE and 5-HT into nerve terminals, thereby their transmitter releasing effects are extended in time and space. The effect on the uptake process is different from classical nicotinic actions, not being sensitive to nAChR antagonism, but can be prevented by selective uptake blockers or reduced temperature. Considering neurochemical, pharmacological and electrophysiological evidence it seems likely that presynaptic nAChRs on monoaminergic fibers are composed of alpha3 or alpha4 subunits in combination with the beta2 subunit. This is supported by the observation that nicotinic agonists have no presynaptic effect on transmitter release in knockout mice lacking the beta2 nAChR subunit gene. The essential brain function lies not only in impulse transmission within a hard-wired neuronal circuitry but also within synaptic and non-synaptic communication subjected to presynaptic modulation. Since the varicose noradrenergic, dopaminergic, serotonergic, glutamatergic and cholinergic axon terminals mainly do not make synaptic contact, but their varicosities are equipped with nAChRs and these non-synaptically localized receptors are of high affinity, it is suggested that nicotine inhaled during smoking might exert its behavioral, psychological, neurological and neuroendocrinological effects via these receptors.