Portal de Periódicos da CAPES

Molecular and Cellular Aspects of Nicotine Abuse

1996; Cell Press; Volume: 16; Issue: 5 Linguagem: Inglês

10.1016/s0896-6273(00)80112-9

1097-4199

John A. Dani, Steve Heinemann,

Receptor Mechanisms and Signaling

Tobacco use in developed countries has been estimated to cause nearly 20% of all deaths, making it the largest single cause of premature death (19Peto R Lopez A.D Boreham J Thun M Heath C Lancet. 1992; 339: 1268-1278Abstract PubMed Scopus (1094) Google Scholar). The drive for tobacco by humans is clear. The majority of smokers have tried repeatedly to quit and failed. In about 80% of the attempts to quit, smokers return to tobacco in less than 2 years (21Schelling T.C Science. 1992; 255: 430-433Crossref PubMed Scopus (53) Google Scholar). Although the underlying mechanisms that cause tobacco abuse are not well understood, the accumulation of evidence indicates that nicotine is the primary component of tobacco that motivates continued use despite harmful effects (21Schelling T.C Science. 1992; 255: 430-433Crossref PubMed Scopus (53) Google Scholar, 23Stolerman I.P Shoaib M Trends Pharmacol. Sci. 1991; 12: 466-473Abstract Full Text PDF Scopus (174) Google Scholar). Nicotine alone, free of smoke or associated factors, can elicit drug-seeking behavior in animal studies as demonstrated by self-administration and place preference experiments (23Stolerman I.P Shoaib M Trends Pharmacol. Sci. 1991; 12: 466-473Abstract Full Text PDF Scopus (174) Google Scholar, 5Corrigall W.A Coen K.M Psychopharmacology. 1989; 99: 473-478Crossref PubMed Scopus (506) Google Scholar). Intravenous self-administration of nicotine is best demonstrated under conditions of limited availability; rats have higher lever-pressing rates when nicotine is delivered intermittently rather than continuously (9Goldberg S.R Henningfield J.E Pharmacol. Biochem. Behav. 1988; 30: 227-234Crossref PubMed Scopus (74) Google Scholar). The responding rate to nicotine is dose dependent, falling off at both lower and higher concentrations. Responding rates sometimes continue until rats experience toxic effects. At these and higher concentrations, nicotine causes vomiting, tremors, convulsions, and death at extreme doses. The onset of aversive effects can complicate the reinforcing effectiveness of nicotine when compared with other drugs, which serve as reinforcers over a wider range of test situations. The evidence is clear, however, that like other addictive drugs, nicotine reinforces self-administration, increases locomotor activity, enhances reward from brain stimulation, and reinforces place preference (4Clarke, P.B.S. (1991). In Effects of Nicotine on Biological Systems, F. Adlkofer and K. Thurau, eds. (Basel, Switzerland: Birkhäuser Verlag), pp. 285–294.Google Scholar, 9Goldberg S.R Henningfield J.E Pharmacol. Biochem. Behav. 1988; 30: 227-234Crossref PubMed Scopus (74) Google Scholar, 23Stolerman I.P Shoaib M Trends Pharmacol. Sci. 1991; 12: 466-473Abstract Full Text PDF Scopus (174) Google Scholar). It is likely that nicotinic acetylcholine receptors (nAChRs) are the initial sites of action for nicotine obtained from tobacco. Understanding nicotine abuse will require some knowledge of how these receptors function within the neuronal pathways that are relevant to addiction. A nAChR normally binds acetylcholine (ACh) and undergoes a conformational change that opens a cation-selective channel for several milliseconds. Subsequently, the ion channel closes, and the receptor may be refractory to agonist for many milliseconds or more. Evidence from a variety of sources indicates that nicotinic receptors can exist in many different functional states (Figure 1; 3Changeux J.-P Devillers-Thiery A Chemouilli P Science. 1984; 225: 1335-1345Crossref PubMed Scopus (441) Google Scholar). Nicotinic receptors are largely in a closed (resting) state before agonist arrives, are briefly in an open state while the channel is conducting cations, and are in desensitized or inactive states while unresponsive to agonist. The likelihood of being in a particular state depends on many factors, including the nAChR subtype, the agonist concentration, and the rate of agonist application. A rapid pulse of agonist causes synchronized activation of nAChRs, but long-term exposure to an agonist causes desensitization. A slow application of a low agonist concentration can cause some desensitization without activation because the desensitized receptor has a higher affinity for agonist than the resting or open receptor. In addition, there is evidence that neuronal nAChRs can exist on the cell surface as nonfunctional receptors (14Margiotta J.F Berg D.K Dionne V.E Proc. Natl. Acad. Sci. USA. 1987; 84: 8155-8159Crossref PubMed Scopus (94) Google Scholar) or can enter long-lived inactivated states (13Lester R.A.J Dani J.A Neuropharmacology. 1994; 33: 27-34Crossref PubMed Scopus (37) Google Scholar). The higher affinity of the desensitized receptor for agonist and the changing distribution of nAChRs among the various functional states must be considered to understand what takes place during sustained nicotine use. A knowledge of long-term forms of inactivation may be especially important for understanding the phases of withdrawal symptoms and the development of tolerance to nicotine. Aspects of tolerance and withdrawal could be explained by nicotinic receptors slowly recovering to functional states from various levels of desensitization and inactivation. A multiplicity of psychopharmacological effects contribute to the reinforcing actions of drugs. A widely accepted hypothesis is that drugs of abuse commandeer existing reward pathways that are normally essential for survival. The mesolimbic dopaminergic system is known to have an important role in mediating reward and contributes to the rewarding effects of cocaine and d-amphetamine (12Koob G.F Trends Pharmacol. Sci. 1992; 13: 177-184Abstract Full Text PDF PubMed Scopus (1916) Google Scholar). Cocaine, for instance, is thought to act by inhibiting the DA transporter; knockout mice lacking the DA transporter are unaffected by the administration of cocaine (8Giros B Jaber M Jones S.R Wightman R.M Caron M.G Nature. 1996; 379: 606-612Crossref PubMed Scopus (2065) Google Scholar). The most important dopamine (DA) pathway originates in the ventral tegmental area (VTA) of the midbrain and projects to forebrain structures including the prefrontal cortex and to limbic areas such as the olfactory tubercle, the amygdala, the septal region, and the nucleus accumbens. A range of studies using DA agonists and antagonists and behavioral studies on the self-administration of drugs after destruction of mesolimbic neurons have led to the conclusion that DA release in the nucleus accumbens is "rewarding" or represents an encounter with reward from the environment. There is direct evidence that nicotine acts upon the mesolimbic pathways. Autoradiography and in situ hybridization indicate that multiple nAChR α and β subunits are present throughout these areas (16Marks M.J Pauly J.R Gross S.D Deneris E.S Hermans-Borgmeyer I Heinemann S.F Collins A.C J. Neurosci. 1992; 12: 2765-2784Crossref PubMed Google Scholar, 17McGehee D.S Role L.W Annu. Rev. Physiol. 1995; 57: 521-546Crossref PubMed Scopus (897) Google Scholar, 24Wada E Waka K Boulter J Deneris E Heinemann S Patrick J Swanson L.W J. Comp. Neurol. 1989; 284: 314-335Crossref PubMed Scopus (928) Google Scholar). VTA neurons have nAChRs located on their cell bodies and on their terminals in the nucleus accumbens. Intermittently administered nicotinic receptor agonists directly excite VTA neurons, but during long exposure, the influence of the nicotinic agonists decreases (2Calabresi P Lacey M.G North R.A Br. J. Pharmacol. 1989; 98: 135-140Crossref PubMed Scopus (241) Google Scholar). Nicotine stimulates the release of DA in the nucleus accumbens of freely moving rats and stimulates release from synaptosomes isolated from various areas including the nucleus accumbens (4Clarke, P.B.S. (1991). In Effects of Nicotine on Biological Systems, F. Adlkofer and K. Thurau, eds. (Basel, Switzerland: Birkhäuser Verlag), pp. 285–294.Google Scholar). Finally, the role of the mesolimbic system in nicotine abuse is supported by the findings that DA antagonists or lesions of the nucleus accumbens reduce nicotine self-administration in rats (6Corrigall W.A Franklin K.B Coen K.M Clarke P.B Psychopharmacology. 1992; 107: 285-289Crossref PubMed Scopus (726) Google Scholar, 23Stolerman I.P Shoaib M Trends Pharmacol. Sci. 1991; 12: 466-473Abstract Full Text PDF Scopus (174) Google Scholar). It must be kept in mind, however, that there are other reward pathways and that other compounds in tobacco may affect the reward. For instance, monoamine oxidase B (MAOB), which participates in the degradation of DA, is partially inhibited in the brains of smokers (7Fowler J.S Volkow N.D Wang G.-J Pappas N Logan J MacGregor R Alexoff D Shea C Schlyer D Wolf A.P Warner D Zezulkova I Cilento R Nature. 1996; 379: 733-736Crossref PubMed Scopus (594) Google Scholar). Although inhibitors of MAOB do not seem to have addictive potency, the increased availability of DA to chronic smokers arising from MAOB inhibition could enhance the addictive power of nicotine. Furthermore, other pathways involved in reward, in addition to the mesolimbic pathway, could be affected directly and indirectly by nicotine, possibly contributing to a myriad of reinforcing effects and learned behaviors. In addition to the possibility of an immediate effect on the functional states of nAChRs, long-term nicotine exposure causes an increase in the actual number of nAChRs in humans, mice, and rats (16Marks M.J Pauly J.R Gross S.D Deneris E.S Hermans-Borgmeyer I Heinemann S.F Collins A.C J. Neurosci. 1992; 12: 2765-2784Crossref PubMed Google Scholar, 25Wonnacott S Trends Pharmacol. Sci. 1990; 11: 216-218Abstract Full Text PDF PubMed Scopus (330) Google Scholar). This increase is specific to nicotinic AChRs. Muscarinic ACh receptors, for instance, do not increase. An increased number of nAChRs is not a response that might at first be expected because chronic exposure to an agonist usually produces excessive receptor activation; homeostasis is then achieved by down-regulation of the receptors. Likewise, chronic exposure to an antagonist produces receptor up-regulation in many systems. These forms of self-regulation are presumably mechanisms to maintain relatively normal synaptic transmission and brain function in the presence of abnormal receptor activity induced by endogenous or exogenous agonists or antagonists. A reasonable explanation for the unexpected increase in nAChRs is that low levels of nicotine cause significant receptor desensitization, and over the long term, nAChRs enter long-lasting inactive states (13Lester R.A.J Dani J.A Neuropharmacology. 1994; 33: 27-34Crossref PubMed Scopus (37) Google Scholar, 18Peng X Gerzanich V Anand R Whiting P.J Lindstrom J Mol. Pharmacol. 1994; 46: 523-530PubMed Google Scholar, 25Wonnacott S Trends Pharmacol. Sci. 1990; 11: 216-218Abstract Full Text PDF PubMed Scopus (330) Google Scholar). These changes would enable some cholinergic systems to move toward their initial levels of excitability even as the number of nAChRs increases due to chronic nicotine exposure. Direct support for this idea is provided by the finding that high doses of the nAChR antagonist mecamylamine also cause an increased number of nAChRs. There is evidence that the number of surface receptors increases when nAChRs enter particular unresponsive states. Interestingly, the number of nicotinic receptors seems to be regulated by a posttranscriptional mechanism that decreases nicotinic receptor turnover (18Peng X Gerzanich V Anand R Whiting P.J Lindstrom J Mol. Pharmacol. 1994; 46: 523-530PubMed Google Scholar); the level of nAChR mRNA does not seem to change (16Marks M.J Pauly J.R Gross S.D Deneris E.S Hermans-Borgmeyer I Heinemann S.F Collins A.C J. Neurosci. 1992; 12: 2765-2784Crossref PubMed Google Scholar). In summary, there is support for the following model: chronic exposure to low levels of nicotine induces inactivation of some nAChRs, which then turn over more slowly (18Peng X Gerzanich V Anand R Whiting P.J Lindstrom J Mol. Pharmacol. 1994; 46: 523-530PubMed Google Scholar). Consequently, the number of nicotinic receptors on the surface of the membrane increases. Depending on cholinergic activity and changes in nicotine concentration in the brain, these nAChRs will distribute among the various functional states: resting, open, short-term desensitized, and long-term inactivated. Different nAChR subtypes and particular cholinergic systems would be expected to recover from inactivation to responsive states at different rates. Although nAChR desensitization and inactivation may underlie the increase in nAChRs, the cholinergic systems are probably not relaxing back to the initial condition present before nicotine exposure. In some cases, cholinergic sensitivity has been shown to increase after the number of nicotinic sites increases. For example, in rats after chronic treatment, nicotine induces greater magnitudes of conditioned placed preference and evokes greater DA release from striatal synaptosomes (22Shoaib M Stolerman I.P Kumar R.C Psychopharmacology. 1994; 113: 445-452Crossref PubMed Scopus (131) Google Scholar, 25Wonnacott S Trends Pharmacol. Sci. 1990; 11: 216-218Abstract Full Text PDF PubMed Scopus (330) Google Scholar). In other cases, however, cholinergic efficacy decreases. After chronic nicotine, a single pulse of nicotine induces less prolactin release (Hulihan-Gublin et al., 1990), evokes a smaller behavioral response in mice, and evokes less DA release from mouse striatal synaptosomes (15Marks M.J Grady S.R Collins A.C J. Pharmacol. Exp. Ther. 1993; 266: 1268-1276PubMed Google Scholar). These differences could arise from various factors. One factor might be multiphasic recovery from inactivation by distinct nAChR subtypes in separate areas of the brain. There are many subtypes of nAChRs that respond differently to agonists (17McGehee D.S Role L.W Annu. Rev. Physiol. 1995; 57: 521-546Crossref PubMed Scopus (897) Google Scholar). Theoretically, there could be a range of relaxation times as the various nAChR subtypes distribute among functional states in response to the changing concentration of nicotine. A basic question in the study of nicotine abuse is how much nAChR activation and inactivation is caused by a smoker's level of nicotine (4Clarke, P.B.S. (1991). In Effects of Nicotine on Biological Systems, F. Adlkofer and K. Thurau, eds. (Basel, Switzerland: Birkhäuser Verlag), pp. 285–294.Google Scholar, 25Wonnacott S Trends Pharmacol. Sci. 1990; 11: 216-218Abstract Full Text PDF PubMed Scopus (330) Google Scholar). A smoker can deliver small pulses of nicotine into the arterial blood in the range of about 0.5 μM (10Henningfield J.E Stapleton J.M Benowitz N.L Grayson R.F London E.D Drug Alcohol Depend. 1993; 33: 23-29Abstract Full Text PDF PubMed Scopus (311) Google Scholar). It is appealing to speculate that nicotine may be abused because the small peaks of nicotine associated with each cigarette can activate nAChRs and cause DA release. This activity leading to DA release and an associated reward could be the main mechanism that initiates nicotine abuse. It also must be considered, however, that the peaks of nicotine associated with each cigarette are superimposed on a steady-state nicotine level of ∼0.1 μM, which increases with repeated cigarette consumption during the day because nicotine has a long half-life of about 2 hr (1Benowitz N.L Porchet H Jacob III, P Prog. Brain Res. 1989; 79: 279-287Crossref PubMed Scopus (82) Google Scholar, 20Russell M.A.H Prog. Brain Res. 1989; 79: 289-302Crossref PubMed Scopus (54) Google Scholar). There is evidence that steady levels of nicotine can cause significant desensitization because, after one nicotine dose, there develops an acute tolerance to a second dose following within an hour. It is possible that nicotine-induced release of DA drives tobacco usage, while inactivation of nAChRs by low levels of nicotine may play a role in the processes of tolerance and withdrawal. Presumably a regular smoker has an excess number of nAChRs, but at the same time, the smoker maintains a low level of nicotine that may inactivate many of the nAChRs. After many hours of abstinence (such as overnight), a smoker's nicotine levels fall and the inactivated nAChRs begin to recover to a responsive state with a rate that may be dependent on the receptor subtype. As an excessive number of nAChRs become responsive, there might be heightened or abnormal potentiation of ordinary synaptic activity in some nonrewarding cholinergic pathways that could contribute to the agitation and discomfort (or withdrawal symptoms) that drive the smoker to the next cigarette. That next dose of nicotine would have at least two effects. First, after a night time of abstinence, a dose of nicotine could be more rewarding than normal, either by directly causing DA release within the mesolimbic system or by acting elsewhere on other pathways that provide reward or by indirectly activating reward pathways. This hypothesis is supported by reports from smokers that they receive the most pleasurable impact from the first cigarette of the day (20Russell M.A.H Prog. Brain Res. 1989; 79: 289-302Crossref PubMed Scopus (54) Google Scholar). Second, after the initial reward (nicotine dose), a longer term effect of subsequent cigarettes (nicotine doses) could be to desensitize the excess number of nAChRs back to their usual state of inactivation for a regular smoker. Thus, smokers report a relief from agitation and tension after they have consumed nicotine. This relief from withdrawal symptoms could be explained as follows: nicotine desensitizes the excess number of responsive nAChRs in nonreward pathways back to a lower more appropriate number of functional receptors for the smoker. This hypothesis is supported by the finding that nAChR antagonists can suppress drug-seeking behavior (5Corrigall W.A Coen K.M Psychopharmacology. 1989; 99: 473-478Crossref PubMed Scopus (506) Google Scholar, 6Corrigall W.A Franklin K.B Coen K.M Clarke P.B Psychopharmacology. 1992; 107: 285-289Crossref PubMed Scopus (726) Google Scholar, 9Goldberg S.R Henningfield J.E Pharmacol. Biochem. Behav. 1988; 30: 227-234Crossref PubMed Scopus (74) Google Scholar), possibly decreasing the drive for nicotine because the antagonist would be expected to inactivate the excess pool of functional nAChRs. This model of nicotine addiction can be tested in more detail by studying the activation and desensitization mechanisms induced by nicotine. A number of other questions need further investigation. What is the role of the many nicotinic receptor subtypes? Do specific nAChR subtypes mediate addiction? Is nicotine addiction mediated directly by the same reward pathways involved in other drug addictions? Does chronic nicotine induce long-term changes in the mesolimbic dopaminergic system beyond the increased number of nAChRs that have been seen in many areas of the brain, including the ventral tegmental area and the nucleus accumbens? A simplistic hypothesis can be put forward as a working basis for research (Figure 2). Upon smoking a cigarette, a small pulse of nicotine activates nAChRs that directly or indirectly induce DA release that provides a pleasurable effect. It is likely that the mesolimbic dopaminergic system mediates at least part of this reward. With continued use, nicotine builds up to a low steady-state concentration that causes significant nAChR desensitization and (over time) longer-term inactivation. There is evidence that nicotinic receptor turnover decreases following inactivation, leading to an increased number of nAChRs, which subsequently may lead to nicotinic cholinergic systems that are pathological. In between cigarettes, during sleep, or under conditions of abstinence while attempting to stop smoking, nicotine levels drop and a portion of the inactive nAChRs recover to a responsive state. Because of the increased number of nAChRs that have now become responsive in this pathological condition, some cholinergic systems other than the reward pathways become hyperexcitable to synaptically released ACh, contributing to the drive for the next cigarette. Thus, smokers medicate themselves with nicotine to regulate the number of functional nAChRs. Superimposed on this simplistic cycle of nicotine exposure, there may be long-term synaptic changes that result in the learned behaviors that are associated with smoking and with the context in which smoking takes place. Because these behaviors are reinforced by repeated variable rewards from cigarettes (especially after abstinence) and by associated sensory cues, the desire for cigarettes extinguishes slowly and sometimes incompletely. These factors coupled to the easy access of cigarettes and constant advertising contribute to the difficulty in breaking the nicotine habit.