Susan Wonnacott (2001) Nicotinic Receptors in Relation to Nicotine Addiction. Psycoloquy: 12(006) Nicotine Addiction (6)

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PSYCOLOQUY (ISSN 1055-0143) is sponsored by the American Psychological Association (APA).
Psycoloquy 12(006): Nicotinic Receptors in Relation to Nicotine Addiction

NICOTINIC RECEPTORS IN RELATION TO NICOTINE ADDICTION
Target Article on Nicotine-Addiction

Susan Wonnacott
Department of Biology & Biochemistry
University of Bath, Bath BA2 7AY

bsssw@bath.ac.uk

Abstract

The first step in processing nicotine's effects on the brain is the drug's interaction with neuronal nicotinic receptors (nAChR). The diversity of nAChR subtypes, their various modes of response (activation, desensitisation, prolonged inactivation), and the complex pharmacokinetics of nicotine delivery conspire to make this a complex issue that is difficult to unravel. The alpha4beta2 nAChR subtype has the highest affinity for nicotine and is the primary candidate for mediating nicotine's central effects. Chronic nicotine exposure (in both humans, animals and cell culture systems) leads to an increase in numbers of alpha4beta2 nAChR (upregulation), with functional implications for withdrawal. However, there is little evidence presently that nAChR upregulation is pertinent to the induction or maintenance of dependence. However, the particular characteristics of the alpha7 subtype of nAChR suggest that it may participate in long term changes in synaptic efficacy that could be relevant to nicotine dependence.

Keywords

Nicotine, nicotinic receptors, receptor desensitisation, nicotinic receptor upregulation.
    The target article below was today published in PSYCOLOQUY, a
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    INTRODUCTION FOR NICOTINE ADDICTION WORKSHOP BY MARCUS MUNAFO AND
    MIKE MURPHY: The ICRF General Practice Research Group in Oxford
    recently hosted a workshop on the theme of "Neuroscience, molecular
    genetics and nicotine addiction". It was chaired by Professor Neal
    Benowitz from the University of California at San Francisco, a
    specialist in the field of nicotine pharmacology spending an
    invited week in the University to work with the Group, and included
    about 30 other experts from groups around the UK and Sweden,
    including the ICRF Molecular Pharmacology Unit in Dundee and the
    ICRF Health Behaviour unit in London. Their backgrounds included
    neuroscience, molecular genetics, genetic epidemiology,
    pharmacology, psychology and clinical medicine, but they were
    united in a belief about the importance of tobacco control.

    It is now recognised that addiction to nicotine lies at the heart
    of the tobacco control problem. Without the marketing of tobacco
    its use would dwindle. But while it is so widely promoted smoking
    research focuses heavily on factors affecting why people continue
    smoking after trying it and how to get them to stop with
    psychological support and the use of effective drugs. Although
    tobacco use is rightly viewed as a social and psychological problem
    we also need to see it as a pharmacological one with a potential
    genetic contribution to the addictive process. The need to
    integrate knowledge about the brain chemistry underlying addiction,
    the molecular genetics of these cellular processes, and how the
    drugs which are effective work, was the workshop's subject.

    Each of the meeting's 4 sessions kicked off with a brief
    introduction by speakers who had precirculated draft papers. The
    sessions considered in turn: (1)how nicotine is metabolised and
    cleared from the body (2)the brain receptors in which nicotine
    "docks" to exert its effects (3)the brain pathways involving the
    neurotransmitter,dopamine,which are thought to contribute to the
    rewarding properties of nicotine which reinforce a smoker's desire
    to smoke (4)other non-dopamine pathways that are activated by
    nicotine and may underly such effects as nicotine withdrawal
    symptoms.

    Understanding how the drugs which are effective (Nicotine
    Replacement Therapy and some antidepressants) interact with the
    expression of individual genotypes in the brain and elsewhere to
    predict success in quitting smoking will help to shed light on
    which bits of the brain are important in nicotine addiction at both
    the anatomical and cellular level. The workshop participants
    emerged pleased to have caught up with advances in fields which
    were not their speciality and with a strong sense that more
    enduring closer contact and cooperation will be possible in the
    future.

I. INTRODUCTION

1.The contribution that nAChRs might make to the addiction process will depend on factors such as:

    -where nAChRs are localised in the brain
    -their sensitivity to nicotine
    -nAChR activation versus desensitisation
    -altered responses after chronic exposure to nicotine

These properties will vary for the different subtypes of nAChR, but as nAChR subtypes have not been fully characterised with respect to their constituent subunits, many aspects of their functional contributions remain poorly defined.

II. ANATOMICAL LOCALISATION OF nAChR SUBTYPES IN THE BRAIN

2. nAChR are widely expressed throughout the CNS, albeit at low levels (10-100 times lower than muscarinic receptors), but different subunits show distinct anatomical localisations. The association of nAChR with dopamine pathways is perhaps most relevant to the psychomotor stimulant properties of nicotine. The ventral tegmental area (VTA) and substantia nigra (SN) express mRNAs for a large portfolio of nAChR subunits: alpha3, alpha4, alpha5, alpha6, alpha7, beta2, beta3, (but probably not alpha2 or beta4) (Wada et al., 1989; Le Novere et al., 1996). This suggests that dopaminergic neurones contain multiple nAChR subtypes, and there is pharmacological evidence for both alpha3beta2* and alpha4beta2 subunit combinations (Sharples et al., 2000) (where * denotes the possible presence of other subunits, Lukas et al., 2000). Particularly intriguing is the high expression of alpha6 and beta3 subunits in VTA and SN (Le Novere et al., 1996; Goldner et al., 1997). The expression of these subunits in the brain is very restricted but they are found in high abundance in catacholaminergic nuclei, suggesting a particular relationship with dopamine and noradrenaline systems. The properties conferred by the inclusion of alpha6 and/or beta3 to nAChR function or regulation are generally not known at the present time.

III. SENSITIVITY TO NICOTINE: ACTIVATION VS DESENSITISATION

3. Different subtypes of nAChR differ in their sensitivity to agonists, including nicotine. This will determine which nAChR subtypes could be activated during smoking. The alpha4beta2 subunit combination has the greatest sensitivity to nicotine, with an EC50 value of 1-5 microM for the human alpha4beta2 subtype (Gotti et al., 1997). This is the only major nAChR subtype that can be identified by the binding of tritiated nicotine: [3H]nicotine binding is completely absent from the brains of transgenic mice lacking beta2 subunit (Picciotto et al., 1995) and largely absent (except for the interpeduncular nucleus) from those lacking the alpha4 subunit (Marubio et al., 1999). (Although all nAChR recognise nicotine by definition, only the alpha4beta2 subtype has sufficient affinity for nicotine for it to be useful as a radioligand - see below).

4. However, it is important to remember that agonists (including nicotine) can also lead to the desensitisation (short term) or inactivation (longer term) of nAChRs. Agonist binding can result in the transient activation of the nAChR, with a conformational charge causing the central ion channel to open, allowing a flow of cations. But the open state of the channel has a finite lifetime and automatically closes as the nAChR adopts another conformation: the desensitised state (of which there are multiple configurations), in which the channel is closed, the nAChR is refractory to activation but can still bind agonist, now with higher affinity than when in the open state. Subsequently, the nAChR reverts to the resting state, with channel closed but no agonist bound: in this state it is receptive to activation again (Changeux & Edelstein, 1998). For example, for the alpha4beta2 nAChR, nicotine concentrations greater than approx. 0.1 microM will activate the nAChR, converting it to the open state, whereas the desensitised conformation binds nicotine with about 100 times higher affinity (i.e., lower concentration), in the range 1-10 nM. A further complication is that sustained low concentrations of nicotine (1-10nM for alpha4beta2 nAChR) can convert the nAChR to the desensitised state without prior activation. Radiolabelled agonists will stabilise the desensitised (high affinity) state in ligand binding assays (because the tissue is exposed to the agonist for a long time: minutes - hours). Hence equilibrium binding constants reflect the desensitised state of the nAChR (Lippiello et al., 1987).

5. Cigarette smoking is characterised by the repeated inhalation of tobacco smoke which generates boli of nicotine delivered to the brain, superimposed on a relatively stable basal level of plasma nicotine maintained throughout the smoking day. This basal level of nicotine will keep a proportion of nAChR in the desensitised state, while the remaining population of nAChR will be available for activation by nicotine boli, if appropriate concentrations are achieved. Thus we can see how smokers may manipulate their plasma nicotine profiles to achieve a balance of desensitisation versus activation that suits them, c.f. anecdotal smoking for relaxation versus smoking for stimulation. This will also explain why the first cigarette of the day is the most satisfying, as overnight abstinence will have allowed substantial recovery of nAChR from desensitisation.

6. Given that the resting - active - desensitised relationship will differ between nAChR subtypes, and that the concentration of nicotine delivered to the brain is subtly controlled by the smoker, a very complex picture of nAChR responses emerges.

IV. CHRONIC EXPOSURE TO NICOTINE AND THE DEVELOPMENT OF DEPENDENCE

7. It is well documented that the numbers of [3H]nicotine binding sites (alpha4beta2 nAChR) are increased in the brains of smokers examined post mortem (Benwell et al., 1988; Breese et al., 1997), and in the brains of rodents given doses of nicotine daily for a few days (Wonnacott, 1990). This effect can also be produced in cell culture, even when nAChR are expressed heterologously in non-neuronal cells (e.g., Whiteaker et al., 1998). Other nAChR subtypes may also be upregulated but only at higher concentrations of nicotine. The 'upregulation' of receptors was unexpected but is probably a response to desensitisation of the receptor by chronic nicotine exposure (Fenster et al., 1999). There are conflicting reports about the functional status of nAChR after chronic nicotine treatment, with increased, decreased and unchanged levels of responsiveness being reported (Marshall et al., 1997; Hsu et al., 1996). Chronic exposure to nicotine not only transiently desensitises nAChR but can also result in permanent inactivation. alpha4beta2 nAChR are more prone to inactivation than alpha3beta2 * nAChR (Kuryatov et al., 2000). Long lasting inactivation has been seen in native systems, e.g., nicotine-evoked dopamine release from striatal synaptosomes shows partial dose- and time-dependent inactivation (no recovery after one hour; Rowell & Duggan, 1998). Both alpha4beta2 * and alpha3beta2 * nAChR mediate this response (Sharples et al., 2000). Inactivation may reflect the removal of nAChR from the cell surface into an intracellular compartment where the nAChR can still bind hydrophobic ligands.

8. The consensus view is that upregulation of nAChR numbers is an attempt to compensate for the loss of nAChR function through desensitisation, but that compensation may be inadequate (or confounded by removal of nAChR to a functionally irrelevant compartment). However, under circumstances in which nicotine is cleared from the system and desensitisation is reversed, the increased number of receptors could produce an excessive (rebound) response to agonist (including the endogenous agonist acetylcholine). Thus nAChR upregulation may contribute to withdrawal symptoms on quitting smoking.

9. The exact cause and mechanisms of upregulation remain controversial. However, we may ask if this response is relevant to the development of nicotine dependence. Clearly the first step in developing dependence must be the interaction of nicotine with its receptors: indeed, absence of the beta2 subunit in transgenic mice abolishes nicotine self-administration (Picciotto et al., 1998). However, the reversible nature of nAChR upregulation (with a return to normal levels in just a few days in animal models (Wonnacott, 1990), and normal levels are found in ex-smokers (Breese et al., 1997)) is at odds with the long term susceptibility to relapse of smokers after quitting, suggesting that there are other, long term changes in the brain. Rats treated chronically with nicotine by a variety of methods (daily injection, slow release from implanted minipumps, oral consumption) show upregulation of [3H]nicotine binding sites. Dependence, on the other hand, is highly correlated with the rate of access of drug to the brain. Although the nicotine administration routes by injection and minipump are widely used as models of chronic nicotine exposure, neither method adequately models the complex pattern of nicotine delivery achieved by cigarette smoking. It seems probable that peak doses of nicotine delivered to the brain by smokers provoke long-lasting changes downstream from nAChR activation, in dopamine neurones or in brain circuitry.

10. However, there is one nAChR subtype that may be a candidate for long term changes underlying the addiction process. This is the alpha7 nAChR. This subtype is highly calcium permeable (Seguela et al., 1993), has been proposed to participate in synaptic changes akin to long term potentiation (Hunter et al., 1994), is often associated with terminals containing the major excitatory transmitter glutamate (Gray et al., 1996), and is proposed to modulate glutamate synapses onto dopamine neurones in the VTA (Schilstrom et al., 1998). Thus nicotine might influence synaptic remodelling through the alpha7 subtype. It is not very sensitive to nicotine (EC50 = 40 microM; Gotti et al., 1997) and desensitises rapidly, but one study has suggested that 100 nM nicotine may be sufficient to elicit modulation of glutamate transmission via alpha7 nAChR (Gray et al., 1996). Further study of the role of alpha7 nAChR in models of nicotine dependence are warranted, to establish if this nAChR subtype plays a role in the long term changes that underpin drug addiction.

REFERENCES

Benwell M, Balfour D and Anderson J Evidence that tobacco smoking increases the density of (-)[3H]nicotine binding sites in human brain. J. Neurochem. 50: 1243-1247 (1988).

Breese, C.R., Marks M.J., Logel, J., Adams, C.E., Sullivan, B., Collins, A.C. and Leonard, S. Effect of smoking history on [3H]nicotine binding in human postmortem brain. J. Pharmacol. Exp. Ther. 282: 7-13 (1997).

Changeux, J.-P. and Edelstein, S.J. Allosteric receptors after 30 years. Neuron 21: 959-980 (1998).

Fenster C, Whitworth T, Sheffield E, Quick M and Lester R Upregulation of surface alpha4beta2 nicotinic receptors is initiated by receptor desensitization after chronic exposure to nicotine. J. Neurosci. 19: 4804-4814 (1999).

Goldner, F.M., Dineley, K.T. and Patrick, J.W. Immunohistochemical localisation of the nicotinic acetylcholine receptor subunit alpha6 to dopaminergic neurons in the substantia nigra and ventral tegmental area. NeuroReport 8: 2739-2742 (1997).

Gotti, C., Fornasari, D. and Clementi, F. Human neuronal nicotinic receptors. Prog. Neurobiol. 53: 199-237 (1997).

Gray, R., Rajan, A.S., Radcliffe, K.A., Yakehiro, M. and Dani, J.A. Hippocampal synaptic transmission enhanced by low concentrations of nicotine. Nature 383: 713-716 (1996).

Hsu Y, Amin J, Weiss D and Wecker L Sustained nicotine exposure differentially affects alpha3beta2 and alpha4beta2 neuronal nicotinic receptors expressed in Xenopus oocytes. J. Neurochem. 66: 667-675 (1996)

Hunter B, de Fiebre C, Papke R, Kem W and Meyer E A novel nicotinic agonist facilitates induction of long-term potentiation in the rat hippocampus. Neurosci Lett 168: 130-134 (1994)

Kuryatov A, Olale F, Choi C and Lindstrom J Acetylcholine receptor extracellular domain determines sensitivity to nicotine-induced inactivation. Eur. J. Pharmacol. 393: 11-21 (2000)

Lippiello, P.M., Sears, S.B. and Fernandess, K.G. Kinetics and mechanism of L-[3H]nicotine binding to putative high affinity receptor sites in brain. Mol. Pharmacol. 31: 392-400 (1987).

Le Novere, N., Zoli, M. and Changeux, J.P. Neuronal nicotinic receptor alpha6 subunit mRNA is selectively concentrated in catecholaminergic nuclei of the rat brain. Eur. J. Neurosci. 8: 2428-2439 (1996).

Lukas, R.J. et al. International Union of Pharmacology Document: Current status of the nomenclature for nicotinic acetylcholine receptors and their subunits. Pharmacol. Rev. 51: 397-401 (2000).

Marshall D, Redfern P and Wonnacott S Presynaptic nicotinic modulation of dopamine release in the three ascending pathways studied by in vivo microdialysis: comparison of naive and chronic nicotine-treated rats. J Neurochem 68:1511-1519 (1997).

Marubio L, Arroyo-Jimenez M, Codero-Erausquin M, Lena C, Le Novere N, Huchet M, Damaj M and Changeux J Reduced antinociception in mice lacking neuronal nicotinic receptors subunits. Nature 398: 805-808 (1999).

Picciotto, M.R., Zoli, M., Lena, C., Bessis, A., Lallemand, Y., LeNovere, N., Vincent, P., Pich, E.M., Brulet, P., and Changeux, J-P. Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain. Nature 374: 65-67 (1995).

Picciotto, M.R., Zoli, M., Rimondini, R., Lena, C., Marubio, L., Pich, E.M., Fuxe, K. and Changeux, J-P. Beta2-subunit-containing acetylcholine receptors are involved in the reinforcing properties of nicotine. Nature 391: 173-176 (1998).

Rowell, R.P. and Duggan D Long-lasting inactivation of nicotinic receptor function in vitro by treatment with high concentrations of nicotine. Neuropharmacol. 37: 103-111 (1988).

Schilstrom B, Svensson H, Svensson T and Nomikos G Nicotine and food induced dopamine release in the nucleus accumbens of the rat: putative role of Alpha7 nicotinic receptors in the ventral tegmental area. Neuroscience 85: 1005-1009 (1998).

Seguela, P., Wadiche, J., Dineley-Miller, K., Dani, J.A. and Patrick, J.W. Molecular cloning, functional properties, and distribution of rat brain Alpha7: A nicotinic cation channel highly permeable to calcium. J. Neurosci., 13, 596-604 (1993).

Sharples CGV, Kaiser S, Soliakov L, Marks MJ, Collins AC, Washburn M, Wright E, Spencer JA, Gallagher T, Whiteaker P and Wonnacott S UB-165: a novel nicotinic agonist with subtype selectivity implicates the alpha4beta2 subtype in the modulation of dopamine release from rat striatal synaptosomes. J Neurosci. 20: 2783-2791 (2000)

Wada E., Wada K., Boulter J., Deneris E., Heinemann S., Patrick J., and Swanson L. W. Distribution of alpha 2, alpha 3, alpha 4, and beta 2 neuronal nicotinic receptor subunit mRNAs in the central nervous system: a hybridization histochemical study in the rat. J. Comp. Neurol. 284, 314-335 (1989)

Whiteaker, P., Sharples, C.G.V. and Wonnacott, S. Agonist-induced upregulation of alpha4beta2 nicotinic acetylcholine receptors in M10 cells: pharmacological and spatial definition. Mol. Pharmacol. 53: 950-962 (1998)

Wonnacott, S. The paradox of nicotinic acetylcholine receptor upregulation by nicotine. Trends Pharmacol. Sci. 11: 216-219 (1990).


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