Desensitization of central cholinergic mechanisms and neuroadaptation to nicotine

Abstract

This review focuses on neuroadaptation to nicotine. The first part of the paper delineates some possible general mechanisms subserving neuroadaptation to commonly abused drugs. The postulated role of the mesocorticolimbic neuroanatomical pathway and drug-receptor desensitization mechanisms in the establishment of tolerance to, dependence on, and withdrawal from psychoactive drugs are discussed. The second part of the review deals with the pharmacological effects of nicotine at both pre- and postsynaptic locations within the central nervous system, and the still-perplexing upregulation of brain nicotine-binding sites seen after chronic nicotine administration. A special emphasis has been put on desensitization of presynaptic cholinergic mechanisms, and postsynaptic neuronal nicotinic-receptor function and its modulation by endogenous substances. A comparison with the inactivation process occurring at peripheral nicotinic receptors is also included. Finally, a hypothesis on the possible connections between desensitization of central cholinergic mechanisms and neuroadaptation to nicotine is advanced. A brief comment on the necessity of fully understanding the effects of nicotine on the developing nervous system closes this work.

Cue-induced reinstatement of nicotine-seeking behavior in rats: effect of bupropion, persistence over repeated tests, and its dependence on training dose

“…Of significance is the finding that in the repeated reinstatement tests, cue-induced reinstatement of nicotine-seeking was obtained only at the two highest doses of nicotine. The explanation for the difference between higher nicotine dose groups and the lower one may reside in neuroadaptive changes that accrue after chronic high level of nicotine exposure (Ochoa et al 1990;Miyata and Yanagita 2001;Rahman et al 2004). For example, it has been found that after 25 daily 1-h nicotine (0.03 mg/kg/infusion) self-administration sessions, rats had decreased basal dopamine levels in the nucleus accumbens and a blunted dopamine increase in response to nicotine challenge (Rahman et al 2004).…”

Complex interactions between nicotine and nonpharmacological stimuli reveal multiple roles for nicotine in reinforcement

“…However, in understanding the neurobiology of nicotine reinforcement it is necessary to consider an important effect of nicotine that occurs at the nicotinic acetylcholine receptor (nAChR). A vast literature demonstrates that after initial activation, nAChRs rapidly desensitize and the duration of this inactivation varies according to the sub-unit composition of the receptor (Ochoa et al 1990;Rosecrans and Karan 1993;. In light of this effect it has remained a paradox that heavy smokers, with fairly high circulating blood-levels of nicotine (Rose et al 1999), demonstrate persistent smoking each day.…”

The functional architecture of the acetylcholine nicotinic receptor explored by affinity labelling and site-directed mutagenesis

“…Association of a-and non-a-subunits into a pentameric oligomer is considered as necessary for function (Cooper et al 1991;Anand et al 1991), with the notable exception of the a7 subunit from chick brain which forms functional homooligomers in Xenopus oocytes (Couturier et al 1990 a). Different assemblies of neuronal nicotinic receptor subunits yield, in Xenopus oocytes, functional receptors with different affinities for acetylcholine and different pharmacological specificities (for review Luetje et al 1990;Ochoa et al 1992). At this stage, the actual subunit composition of nicotinic receptors in the brain is largely unknown and the occurrence of pharmacologically non-equivalent (or equivalent) acetylcholine binding sites has not been demonstrated.…”

“…Prolonged exposure of muscle, electroplaque and brain nicotinic acetylcholine receptor to agonists causes, within seconds to minutes, a reversible decline in the ionic response to acetylcholine (Katz & Thesleff, 1957, Changeux, 1980Ochoa et al 1989Ochoa et al , 1992. Desensitization persists after purification of excitable membranes (Popot et al 1974) and after reconstitution of the purified protein (Popot et al 1981;McNamee & Ochoa, 1982;Montal et al 1986).…”

“…For example, Ca 2+ , electrical potential, reversible allosteric effectors such as some noncompetitive blockers binding to their low-affinity sites, Changeux et al 1984;Changeux, 1990;Ochoa et al 1989Ochoa et al , 1992. Also, the acetylcholine receptor is known to be phosphorylated in vitro (Teichberg & Changeux, 1976Gordon et al 1977;Vandlen et al 1979).…”