Molecular and Cellular Aspects of Nicotine Abuse

Abstract

conducting cations, and are in desensitized or inactive states while unresponsive to agonist. The likelihood of *Division of Neuroscience Baylor College of Medicine being in a particular state depends on many factors, including the nAChR subtype, the agonist concentra-Houston, Texas 77030-3498 † Molecular Neurobiology Laboratory tion, and the rate of agonist application. A rapid pulse of agonist causes synchronized activation of nAChRs, The Salk Institute San Diego, California 92186-5800 but long-term exposure to an agonist causes desensitization. A slow application of a low agonist concentration Tobacco use in developed countries has been estimated can cause some desensitization without activation because the desensitized receptor has a higher affinity for to cause nearly 20% of all deaths, making it the largest single cause of premature death (Peto et al., 1992). The agonist than the resting or open receptor. In addition, there is evidence that neuronal nAChRs can exist on drive for tobacco by humans is clear. The majority of smokers have tried repeatedly to quit and failed. In about the cell surface as nonfunctional receptors (Margiotta et al., 1987) or can enter long-lived inactivated states 80% of the attempts to quit, smokers return to tobacco in less than 2 years (Schelling, 1992). Although the un- (Lester and Dani, 1994). The higher affinity of the desensitized receptor for derlying mechanisms that cause tobacco abuse are not well understood, the accumulation of evidence indicates agonist and the changing distribution of nAChRs among the various functional states must be considered to un-that nicotine is the primary component of tobacco that motivates continued use despite harmful effects (Schel-derstand what takes place during sustained nicotine use. A knowledge of long-term forms of inactivation may ling, 1992; Stolerman and Shoaib, 1991).Nicotine alone, free of smoke or associated factors, be especially important for understanding the phases of withdrawal symptoms and the development of toler-can elicit drug-seeking behavior in animal studies as demonstrated by self-administration and place prefer-ance to nicotine. Aspects of tolerance and withdrawal could be explained by nicotinic receptors slowly recov-ence experiments (Stolerman and Shoaib, 1991;Corrigall and Coen, 1989). Intravenous self-administration of ering to functional states from various levels of desensitization and inactivation. nicotine is best demonstrated under conditions of limited availability; rats have higher lever-pressing rates Pathways of Reward in Nicotine AbuseA multiplicity of psychopharmacological effects contrib-when nicotine is delivered intermittently rather than continuously (Goldberg and Henningfield, 1988). The re-ute to the reinforcing actions of drugs. A widely accepted hypothesis is that drugs of abuse commandeer sponding rate to nicotine is dose dependent, falling off at both lower and higher concentrations. Responding existing reward pathways that are normally essential for survival. The mesolimbic dopaminergic sys...

Desensitization of neuronal nicotinic receptors

“…Occupancy of these deep desensitized states by nicotine could serve as the trigger for up-regulation in receptor number (Dani and Heinemann, 1996;Fenster et al, 1999b), shown to occur in vivo for ␣4␤2 nAChRs during chronic nicotine exposure (Marks et al, 1983;Schwartz and Kellar, 1985;Flores et al, 1992;Balfour, 1994); this again could potentially involve biochemical steps, because chronic nicotine promotes enhanced ␣4 subunit phosphorylation (Hsu et al, 1997). While controversy exists over whether prolonged agonist exposure results in up-or down-regulation of receptor function (Buisson and Bertrand, 2002), recovery from this "state," whether it requires purely time (slow transition rates) or de novo receptor synthesis (Boyd, 1987;Hsu et al, 1996), likely influences synaptic transmission for prolonged periods.…”

Cellular and synaptic mechanisms of nicotine addiction

“…A common feature of many addictive drugs, including nicotine, is that they increase dopamine (DA) levels in the nucleus accumbens (NAcc) at the same concentrations that are achieved in serum during selfadministration (Stolerman and Jarvis, 1995;Dani and Heinemann, 1996;Picciotto et al, 1998;Dani and De Biasi, 2001). The principal dopaminergic projections to the NAcc arise from neurons in the VTA (Fig.…”

Regulatory mechanisms that govern nicotinic synapse formation in neurons

“…In the PNS, nAChRs mediate fast excitatory synaptic transmission. In the CNS, their functions also include modulating neurotransmitter release from presynaptic terminals, reinforcing nicotine addiction, and increasing attention, arousal and memory formation (Dani and Heinemann, 1996;Jones et al, 1999;Perry et al, 1999). Abnormalities in nAChR number and function have been implicated in neurologic disorders such as Alzheimer's disease, Parkinson's disease, familial frontal lobe epilepsy, and auditory-gating schizophrenia (Lena and Changeux, 1997;Court et al, 2000).…”