Nicotine is an addictive drug that activates a diverse subset of ionotropic acetyl-choline receptors. Most cholinergic actions in brain, both by ionotropic and metabotropic receptors, are modulatory, and very few fast synapses exist that utilize acetylcholine as a transmitter. Interestingly, although some ionotropic acetylcholine receptors are postsynaptic, a relatively large proportion, much larger than observed for other neurotransmitters, appears to be presynaptic. A possible pathway accounting for the addictive actions of nicotine was discovered in the observation that presynaptic nicotinic acetylcholine receptors, when activated, mediate the influx of Ca2+ into presynaptic terminals, and thereby stimulate the release of neurotransmitters (Wannacott, 1997). Interestingly, this effect appears to operate via a class of nico-tinic acetylcholine receptors containing a6 subunits that are relatively enriched in the nigrostriatal pathway, suggesting that nicotine may be addictive by increasing dopamine release (Quik and McIntosh, 2006). Thus the presynaptic facilitation of neurotransmitter release by cholinergic nicotinic receptors is one of the best and physiologically most important systems illustrating how presynaptically acting receptors can regulate release.
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