Nicotine affects the nervous system through the action of nicotinic acetylcholine receptors (nAChRs) — ionotropic receptors that are widely distributed through the brain.
In the context of nicotine addiction, the involvement of the ventral tegmental area (VTA) has been extensively studied. The contribution of its dopamine (DA) and GABA (γ-aminobutyric acid) neurons, and their afferences and efferences, are crucially involved in the addiction process. Also, the contribution of glutamatergic transmission to this process has begun to gain prominence.
Nicotine activates nAChRs in DA neurons of the VTA, an activation that is followed by desensitization on continued exposure to nicotine. So, whereas the acute action might signal the rewarding effect of nicotine, the long-lasting desensitization might represent a cellular correlate of tolerance.
GABA neurons inhibit DA neurons in the VTA. But, whereas the acute effects of nicotine in the VTA predominantly affect GABA neurons, the nAChRs in these cells desensitize rapidly, leading to a long-lasting excitation of the DA neurons through removal of their inhibition. This shift would favour increased activity of the DA output pathways of the VTA.
Acetylcholine from brainstem nuclei might exert a profound modulatory effect on both populations of VTA neurons through the activation of nAChRs. In addition, it seems that the α7 subunit is a key component of the relevant receptors.
In addition to its rewarding properties, nicotine also has aversive properties. DA has been traditionally considered to relate only to the rewarding properties, but recent evidence indicates that its role might mediate its aversive properties. Moreover, a GABA system in the brainstem might have a previously unrecognized and prominent role in the rewarding effects of nicotine.
The shift from the acute effects of nicotine to the development of a dependence state might involve a switch in the balance between the role of DA and GABA neurons in the VTA. In the acute stage, the initial activation of GABA neurons in the VTA produces rewarding effects through a GABA system that projects to the brainstem. With repeated nicotine exposure, the GABA system becomes desensitized, leading to a shift in the action of nicotine to the DA neurons. This shift in balance might lead to a dysregulated DA signal in the VTA, which leads to the aversive effects of nicotine, and/or to the potentiation of the incentive salience of nicotine and its compulsive use.
Nicotine, the primary psychoactive component of tobacco smoke, produces diverse neurophysiological, motivational and behavioural effects through several brain regions and neurochemical pathways. Recent research in the fields of behavioural pharmacology, genetics and electrophysiology is providing an increasingly integrated picture of how the brain processes the motivational effects of nicotine. The emerging characterization of separate dopamine- and GABA (γ-aminobutyric acid)-dependent neural systems within the ventral tegmental area (VTA), which can mediate the acute aversive and rewarding psychological effects of nicotine, is providing new insights into how functional interactions between these systems might determine vulnerability to nicotine use.
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Peto, R. et al. Mortality from smoking worldwide. Br. Med. Bull. 52, 12–21 (1996).
Annual, smoking-attributable mortality, years of potential life lost, and economic costs — United States, 1995–1999. MMWR Morb. Mortal. Wkly. Rep. 51, 300–303 (2002).
Dani, J. A., Daoyun, J. & Zhou, F. Synaptic plasticity and nicotine addiction. Neuron 31, 349–352 (2001).
Corrigall, W. A. & Coen, K. M. Selective dopamine antagonists reduce nicotine self-administration. Psychopharmacology 104, 171–176 (1991). First experimental demonstration that systemic blockade of DA-mediated transmission could strongly inhibit the intravenous self-administration of nicotine in rodents.
Corrigall, W. A., Franklin, K. B., Coen, K. M. & Clarke, P. B. The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine. Psychopharmacology 107, 285–289 (1992).
Corrigall, W. A., Coen, K. M. & Adamson, K. L. Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area. Brain Res. 653, 278–284 (1994).
Picciotto, M. & Corrigall, W. A. Neuronal systems underlying behaviors related to nicotine addiction: neural circuits and molecular genetics. J. Neurosci. 22, 3338–3341 (2002).
Laviolette, S. R. & van der Kooy, D. Blockade of mesolimbic dopamine transmission dramatically increases sensitivity to the rewarding effects of nicotine in the ventral tegmental area. Mol. Psychiatry 8, 50–59 (2003). First experimental demonstration that a single brain region (the VTA) can mediate both the acute rewarding and aversive effects of nicotine, and that DA receptor blockade can potentiate nicotine reward signals in the VTA.
Mansvelder, H. B. & McGehee, D. S. Cellular and synaptic mechanisms of nicotine addiction. J. Neurobiol. 53, 606–617 (2002).
Shoaib, M. et al. The role of nicotinic receptor β-2 subunits in nicotine discrimination and conditioned taste aversion. Neuropharmacology 42, 530–539 (2002).
Salamone, F. & Zhou, M. Aberrations in nicotinic acetylcholine receptor structure, function and expression: implications in disease. McGill J. Med. 5, 90–97 (2000).
McGehee, D. S. & Role, L. W. Physiological diversity of nicotinic acetylcholine receptors expressed by vertebrate neurons. Annu. Rev. Physiol. 57, 521–546 (1995).
Role, L. W. & Berg, D. K. Nicotinic receptors in the development and modulation of CNS synapses. Neuron 16, 1077–1085 (1996).
Jones, S., Sudweeks, S. & Yakel, J. L. Nicotinic receptors in the brain: correlating physiology with function. Trends Neurosci. 22, 555–561 (1999).
Gotti, C., Fornasari, D. & Clementi, F. Human neuronal nicotinic receptors. Prog. Neurobiol. 53, 199–237 (1997).
Yu, C. R. & Role, L. W. Functional contribution of the α7 subunit to multiple subtypes of nicotinic receptors in embryonic chick sympathetic neurons. J. Physiol. (Lond.) 509, 651–665 (1998).
Woolterton, J. R. A., Pidoplichko, V. I., Broide, R. S. & Dani, J. A. Differential desensitization and distribution of nicotinic acetylcholine receptor subtypes in midbrain dopamine neurons. J. Neurosci. 23, 3176–3185 (2003).
Rogers, M., Colquhon, L. M., Patrick, J. W. & Dani, J. A. Calcium flux through predominantly independent purinergic ATP and nicotinic acetylcholine receptors. J. Neurophysiol. 77, 1407–1417 (1997).
Philips, P. E., Stuber, G. D., Heien, M. L., Wightman, R. M. & Carelli, R. M. Subsecond dopamine release promotes cocaine seeking. Nature 10, 614–618 (2003).
Diana, M. et al. Enduring effects of chronic ethanol in the CNS: basis for alcoholism. Alcohol. Clin. Exp. Res. 27, 354–361 (2003).
Nader, K. & van der Kooy, D. Deprivation state switches the neurobiological substrates mediating opiate reward in the ventral tegmental area. J. Neurosci. 17, 383–390 (1997).
Carlezon, W. A. et al. Distinct sites of opiate reward or aversion within the midbrain identified using a herpes simplex virus vector expressing GluR1. J. Neurosci. 20, RC62 (2000).
Corrigall, W. A., Coen, K. M., Adamson, K. L., Chow, B. L. C. & Zhang, J. Response of nicotine self-administration in the rat to manipulations of μ-opioid and γ-aminobutyric acid receptors in the ventral tegmental area. Psychopharmacology 149, 107–114 (2000).
Nisell, M., Nomikos, G. G. & Svensson, T. H. Systemic nicotine-induced dopamine release in the rat nucleus accumbens is regulated by nicotinic receptors in the ventral tegmental area. Synapse 16, 36–44 (1994).
Kalivas, P. W. Neurotransmitter regulation of dopamine neurons in the ventral tegmental area. Brain Res. Brain Res. Rev. 18, 75–113 (1993).
Steininger, T. L., Rye, D. B. & Wainer, B. H. Afferent projections to the cholinergic pedunculopontine tegmental nucleus and adjacent midbrain regions in the albino rat. 1. Retrograde tracing studies. J. Comp. Neurol. 321, 515–543 (1992).
Semba, K. & Fibiger, H. Afferent connections of the laterodorsal and pedunculopontine tegmental nuclei in the rat: a retro and anterograde transport and immunohistochemical study. J. Comp. Neurol. 323, 387–410 (1992).
Laviolette, S. R. & van der Kooy, D. GABAA receptors in the ventral tegmental area control bidirectional reward signaling through dopaminergic and non-dopaminergic neural motivational systems. Eur. J. Neurosci. 13, 1009–1015 (2001).
Steffensen, S. C., Lee, R. S., Stobbs, S. H. & Henriksen, S. J. Responses of ventral tegmental area GABA neurons to brain stimulation reward. Brain Res. 906, 190–197 (2001).
Garzon, M., Vaughn, R. A., Uhl, G. R., Kuhar, M. J. & Pickel, V. M. Cholinergic axon terminals in the ventral tegmental area target a subpopulation of neurons expressing low levels of the dopamine transporter. J. Comp. Neurol. 410, 197–210 (1999).
Charara, A., Smith, Y. & Parent, A. Glutamatergic inputs from the pedunculopontine tegmental nucleus to midbrain dopaminergic neurons in primates: Phaseolus vulgaris-leucoagglutinin anterograde labeling combined with post embedding glutamate and GABA immunohistochemistry. J. Comp. Neurol. 364, 254–266 (1996).
Yin, R. & French, E. D. A comparison of the effects of nicotine on dopamine and non-dopamine neurons in the rat ventral tegmental area: an electrophysiological study. Brain Res. Bull. 51, 507–514 (2000).
Mansvelder, H. D. & McGehee, D. S. Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas. Neuron 33, 905–919 (2002). The first in vitro study to examine the synaptic organization and time course of the functional interactions between GABA, DA and glutamate in the VTA in response to nicotine.
Charpantier, E., Barneoud, P., Moser, P., Besnard, F. & Sgard, F. Nicotinic acetylcholine subunit mRNA expression in dopaminergic neurons of the rat substantia nigral and ventral tegmental area. Neuroreport 9, 3097–3101 (1998).
Klink, R., de Kerchove d'Exaerde, A., Zoli, M. & Changeux, J. P. Molecular and physiological diversity of nicotinic acetylcholine receptors in the midbrain dopaminergic nuclei. J. Neurosci. 21, 1452–1463 (2001). A comprehensive study examining the anatomical distribution and nAChR receptor subunit within the substantia nigra and VTA DA cell groups in the midbrain.
Imperato, A., Mulas, A. & Di Chiara, G. Nicotine preferentially stimulates dopamine release in the limbic system of freely moving rats. Eur. J. Pharmacol. 132, 337–338 (1986).
Pidoplichko, V. I., DeBiasis, M., Williams, J. T. & Dani, J. A. Nicotine activates and desensitizes midbrain dopamine neurons. Nature 390, 401–404 (1997). First in vitro investigation to examine the direct actions of nicotine on VTA DA neurons using nicotine concentrations that are comparable to those obtained by human smokers, and the first study to look at the time course of nicotine-induced nAChR desensitization on VTA DA neurons.
Wickelgren, I. Getting the brain's attention. Science 278, 35–37 (1997).
Horvitz, J. C. Mesolimbocortical and nigrostriatal dopamine responses to salient non-reward events. Neuroscience 96, 651–656 (2000). A comprehensive review that examines the evidence for a role for DA-mediated transmission in signalling both aversive and emotionally salient, non-reward-related behavioural events.
Erhardt, S., Schweiler, L. & Engberg, G. Excitatory and inhibitory responses of dopamine neurons in the ventral tegmental area to nicotine. Synapse 43, 227–237 (2002).
Girod, R., Barazangi, N., McGehee, D. & Role, L. W. Facilitation of glutamatergic neurotransmission by presynaptic nicotinic acetylcholine receptors. Neuropharmacology 39, 2715–2725 (2000).
McGehee, D. S., Heath, M. J. S., Gelber, S., Devay, P. & Role, L. W. Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors. Science 269, 1692–1696 (1995). An important study on the role of nanomolar nicotine concentrations in the enhancement of glutamatergic and cholinergic transmission through presynaptic α7–containing nAChRs.
Schilstrom, B. et al. Putative role of presynaptic α7 nicotinic receptors in nicotine stimulated increases of extracellular levels of glutamate and aspartate in the ventral tegmental area. Synapse 38, 375–383 (2000).
Schilstrom, B., Svennson, H. M., Svennson, T. H. & Nomikos, G. G. Nicotine and food-induced dopamine release in the nucleus accumbens of the rat: putative role of α7 nicotinic receptors in the ventral tegmental area. Neuroscience 85, 1005–1009 (1998).
Mesulman, M. M., Mufson, E. J., Wainer, B. H. & Levey, A. I. Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1–Ch6). Neuroscience 10, 1185–1201 (1983).
Forster, G. L. & Blaha, C. D. Pedunculopontine tegmental stimulation evokes striatal dopamine efflux by activation of acetylcholine and glutamate receptors in the midbrain and pons of the rat. Eur. J. Neurosci. 17, 751–762 (2003).
Forster, G. L. & Blaha, C. D. Laterodorsal tegmental stimulation elicits dopamine efflux in the rat nucleus accumbens by activation of acetylcholine and glutamate receptors in the ventral tegmental area. Eur. J. Neurosci. 12, 3596–3604 (2000).
Yeomans, J. S. et al. Brain stimulation reward thresholds raised by antisense oligonucleotides for the M5 muscarinic receptor infused near dopamine cells. J. Neurosci. 20, 8861–8867 (2000).
Yeomans, J. S. & Baptista, M. Both nicotinic and muscarinic receptors in the ventral tegmental area contribute to brain stimulation reward. Pharmacol. Biochem. Behav. 57, 915–921 (1997).
Rose, J. E. & Corrigall, W. A. Nicotine self-administration in animals and humans: similarities and differences. Psychopharmacology 130, 28–40 (1997).
Jorenby, D. E., Steinpreis, R. E., Sherman, J. E. & Baker, T. B. Aversion instead of preference learning indicated by nicotine place conditioning in rats. Psychopharmacology 101, 533–538 (1990).
Shoaib, M. & Stolerman, I. P. Conditioned taste aversion in rats after intracerebral administration of nicotine. Behav. Pharmacol. 6, 375–385 (1995).
File, S. E., Cheeta, S. & Kenny, P. J. Neurobiological mechanisms by which nicotine mediates different types of anxiety. Eur. J. Pharmacol. 393, 231–236 (2000).
Ouagazzal, A. M., Kenny, P. J. & File, S. E. Stimulation of nicotinic receptors in the lateral septal nucleus increases anxiety. Eur. J. Neurosci. 11, 3957–3962 (1999).
Tucci, S., Genn, R. F., Marco, E. & File, S. E. Do different mechanisms underlie two anxiogenic effects of systemic nicotine? Behav. Pharmacol. 14, 323–329 (2003).
Kozlowski, L. T. & Harford, M. R. On the significance of never using a drug: an example from cigarette smoking. J. Abnorm. Psych. 85, 433–434 (1976)
Pomerleau, O. F. Individual differences in sensitivity to nicotine: implications for genetic research on nicotine dependence. Behav. Genet. 25, 161–177 (1995).
Iwamoto, E. T. & Williamson, E. C. Nicotine-induced taste aversion: characterization and pre-exposure effects in rats. Pharmacol. Biochem. Behav. 21, 527–532 (1984).
Pomerleau, O. F., Pomerleau, C. S. & Namenek, R. J. Early experiences with tobacco among women smokers, ex-smokers and never smokers. Addiction 93, 595–599 (1998).
Pomerleau, O. F. Why some people smoke and others do not: new perspectives. J. Consult. Clin. Psych. 61, 723–731 (1993).
Wise, R. A. The anhedonia hypothesis. Behav. Brain Sci. 8, 178–186 (1985). A classic treatise that postulated a central role for DA in the transmission of both natural and drug-related neural reward signals.
Schultz, W. Getting formal with dopamine and reward. Neuron 36, 241–263 (2002).
Picciotto, M. et al. Acetylcholine receptors containing the β2 subunit are involved in the reinforcing properties of nicotine. Nature 391, 173–177 (1998). The first study to show that deletion of a specific nAChR subunit was vital for the reinforcing effects of intravenously self-administered nicotine and that this behavioural effect was correlated with a blockade of nicotine-induced DA release.
Clarke, P. B. S. & Fibiger, H. C. Apparent absence of nicotine-induced conditioned place preference in rats. Psychopharmacology 92, 84–88 (1987).
Museo, E. & Wise, R. A. Place preference conditioning with ventral tegmental injections of cytisine. Life Sci. 55, 1179–1186 (1994).
Xi, Z. X. & Stein, E. A. Nucleus accumbens dopamine release modulation by mesolimbic GABAA receptors — an in vivo electrochemical study. Brain Res. 798, 156–165 (1998)
Westerink, B. H., Enrico, P., Feimann, J. & De Vries, J. B. The pharmacology of mesocortical dopamine neurons: a dual probe microdialysis study in the ventral tegmental area and prefrontal cortex of the rat. J. Pharmacol. Exp. Ther. 285, 143–154 (1998).
Fadda, P, Scherma, M., Fresu, A., Collu, M. & Fratta, W. Baclofen antagonizes nicotine, cocaine and morphine-induced dopamine release in the nucleus accumbens of rat. Synapse. 50, 1–6 (2003).
Laviolette, S. R., Alexson, T. O. & van der Kooy, D. Lesions of the tegmental pedunculopontine nucleus block the rewarding effects and reveal the aversive effects of nicotine in the ventral tegmental area. J. Neurosci. 22, 8653–8660 (2003).
Bechara, A. & van der Kooy, D. A single brainstem substrate mediates the motivational effects of both opiates and food in non-deprived rats but not in deprived rats. Behav. Neurosci. 106, 351–363 (1992).
Olmstead, M. C., Munn, E. M., Franklin, K. B. & Wise, R. A. Effects of pedunculopontine tegmental nucleus lesions on responding for intravenous heroin under different schedules of reinforcement. J. Neurosci. 18, 5035–5044 (1998).
Kippen, T. E. & van der Kooy, D. Blockade of sexually-rewarded conditioned place preference by tegmental pedunculopontine nucleus lesions. Behav. Pharmacol. 12, S52 (2001).
Parker, J. L. & van der Kooy, D. Tegmental pedunculopontine nucleus lesions do not block cocaine reward. Pharm. Biochem. Behav. 52, 77–83 (1995).
Oakman, S. A., Faris, P. L., Kerr, P. E., Cozzari, C. & Hartman, B. K. Distribution of pontomesencephalic cholinergic neurons projecting to the substantia nigra differ significantly from those projecting to the ventral tegmental area. J. Neurosci. 15, 5859–5869 (1995).
Lanca, J. A., Sanelli, T. R. & Corrigall, W. A. Nicotine-induced fos expression in the pedunculopontine mesencephalic tegmentum in the rat. Neuropharmacology 39, 2808–2817 (2000).
Nakahara, D., Ishida, Y., Nakamura, M., Furuno, N. & Nishimori, T. Intracranial self-stimulation induces fos expression in GABAergic neurons in the rat mesopontine tegmentum. Neuroscience 106, 633–641 (2001).
Lanca, A. J., Adamson, K. L., Coen, K. M., Chow, B. L. & Corrigall, W. A. The pedunculopontine tegmental nucleus and the role of cholinergic neurons in nicotine self-administration in the rat: a correlative neuroanatomical and behavioural study. Neuroscience 96, 735–742 (2000).
Corrigall, W. A, Coen, K. M., Zhang, J. & Adamson, K. L. GABA mechanisms in the pedunculopontine tegmental nucleus influence particular aspects of nicotine self-administration selectively in the rat. Psychopharmacology 158, 190–197 (2001).
Iwamoto, E. T. Nicotine conditions place preferences after intracerebral administration in rats. Psychopharmacology 100, 251–257 (1990).
Panagis, G., Kastellakis, G., Spyraki, C. & Nomikos, G. G. Effects of methyllycaconitine (MLA), an α7 nicotinic receptor antagonist, on nicotine and cocaine-induced potentiation of brain stimulation reward. Psychopharmacology 149, 388–396 (2000).
Grottick, A. J. et al. Evidence that nicotinic α7 receptors are not involved in the hyperlocomotor and rewarding effects of nicotine. J. Pharmacol. Exp. Ther. 294, 1112–1119 (2000)
Laviolette, S. R. & van der Kooy, D. The motivational valence of nicotine in the rat ventral tegmental area is switched from rewarding to aversive following blockade of the α7 subunit-containing nicotinic acetylcholine receptor. Psychopharmacology 166, 306–313 (2003).
Paterson, N. E., Semenova, S., Gasparini, F. & Markou, A. The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice. Psychopharmacology 167, 257–264 (2003).
Papp, M., Gruca, P. & Willner, P. Selective blockade of drug-induced place preference conditioning by ACPC, a functional NMDA receptor antagonist. Neuropsychopharmacology 27, 727–743 (2002).
Robinson, T. E. & Berridge, K. C. Incentive sensitization and addiction. Addiction 96, 103–114 (2001).
Berridge, K. C. & Robinson, T. E. What is the role of dopamine in reward: hedonic impact, reward learning or incentive salience? Brain Res. Brain Res. Rev. 28, 306–369 (1998). A comprehensive review and description of the incentive-salience theory of reward motivation.
Benwell, M. E. M. & Balfour, D. J. K. The effects of acute and repeated nicotine treatment on nucleus accumbens dopamine and locomotor activity. Br. J. Pharmacol. 105, 849–856 (1992).
Clarke, P. B. S., Fu, D. S., Jakubovic, A. & Fibiger, H. C. Evidence that mesolimbic dopaminergic activation underlies the locomotor stimulant action of nicotine in rats. J. Pharmacol. Exp. Ther. 246, 701–708 (1988).
Le Foll, B., Diaz, J. & Sokoloff, P. Increased dopamine D3 receptor expression accompanying behavioral sensitization to nicotine in rats. Synapse 47, 176–183 (2003).
Andreoli, M. et al. Selective antagonism at dopamine D3 receptors prevents nicotine-triggered relapse to nicotine-seeking behaviour. Neuropsychopharmacology 28, 1272–1280 (2003).
Gentry, C. L. & Lukas, R. J. Regulation of nicotinic acetylcholine receptor numbers and function by chronic nicotine exposure. Curr. Drug Targets CNS Neurol. Disord. 1, 359–385 (2002).
Olale, F., Gerzanich, V., Kuryatov, A., Wang, F. & Lindstrom, J. Chronic nicotine exposure differentially affects the function of human α3, α4 and α7 neuronal nicotinic receptor subtypes. J. Pharmacol. Exp. Ther. 283, 675–683 (1997).
Ryan, R. E. & Loiacono, R. E. Nicotine regulates α7 nicotinic receptor subunit mRNA: implications for nicotine dependence. Neuroreport 12, 569–572 (2001).
Brody, A. L. et al. Brain metabolic changes during cigarette craving. Arch. Gen. Psych. 59, 1162–1172 (2002).
Rada, P., Jensen, K. & Hoebel, B. G. Effects of nicotine and mecamylamine-induced withdrawal on extracellular dopamine and acetylcholine in the rat nucleus accumbens. Psychopharmacology 157,105–110 (2001).
Dagher, et al. Reduced dopamine D1 receptor binding in the ventral striatum of cigarette smokers. Synapse 42, 48–53 (2001).
Richmond, R. & Zwar, N. Review of bupropion for smoking cessation. Drug. Alcohol Rev. 22, 203–220 (2003).
Brauer, L. H., Cramblett, M. J., Paxton, D. A. & Rose, J. E. Haloperidol reduces smoking of both nicotine-containing and denicotinized cigarettes. Psychopharmacology 159, 31–37 (2001).
McEvoy, J. P. Freudenrich, O. & Wilson, W. H. Smoking and therapeutic response to clozapine in patients with schizophrenia. Biol. Psychiatry 46, 125–129 (1999).
Procyshyn, R. M., Ihsan, N. & Thompson, D. A comparison of smoking behaviours between patients treated with clozapine and depot neuroleptics. Int. Clin. Psychopharmacol. 16, 291–294 (2001).
Reuter, M., Netter, P., Toll, C. & Henning, J. Dopamine agonist and antagonist responders as related to types of nicotine craving and facets of extraversion. Prog. Neuropsychopharm. Biol. Psych. 26, 845–853 (2002).
Damsma, G., Day, J. & Fibiger, H. C. Lack of tolerance to nicotine-induced dopamine release in the nucleus accumbens. Eur. J. Pharmacol. 168, 363–368 (1989).
Zernig, G., O'Laughlin, I. A. & Fibiger, H. C. Nicotine and heroin augment cocaine-induced dopamine overflow in nucleus accumbens. Eur. J. Pharmacol. 337, 1–10 (1997).
Benwell, M. E., Balfour, D. J. & Khadra, L. F. Studies on the influence of nicotine infusions on mesolimbic dopamine and locomotor responses to nicotine. Clin. Invest. 72, 233–239 (1994).
McEvoy, J. P., Freudenreich, O., Levin, E. D. & Rose, J. E. Haloperidol increases smoking in patients with schizophrenia. Psychopharmacology 119, 124–126 (1995).
Dalack, G. W., Healy, D. J. & Meador-Woodruff, J. H. Nicotine dependence in schizophrenia: clinical phenomena and laboratory findings. Am. J. Psychiatry 155, 1490–1501 (1998).
Spanagel, R., Almeida, O. F. X. & Shippenberg, T. S. Long lasting changes in morphine-induced mesolimbic dopamine release after chronic morphine exposure. Synapse 14, 242–245 (1993).
Harris, G. C. & Aston-Jones, G. Involvement of D2 dopamine receptors in the nucleus accumbens in the opiate withdrawal syndrome. Nature 371, 155–157 (1994).
Zito, K. A., Bechara, A., Greenwood, C. & van der Kooy, D. The dopamine innervation of the visceral cortex mediates the aversive effects of opiates. Pharm. Biochem. Behav. 30, 693–699 (1988).
Laviolette, S. R., Nader, K. & van der Kooy, D. Motivational state determines the functional role of the mesolimbic dopamine system in the mediation of opiate reward processes. Behav. Brain Res. 129, 17–29 (2002).
Geier, A., Mucha, R. F. & Pauli, P. Appetitive nature of drug cues confirmed with physiological measures in a model using pictures of smoking. Psychopharmacology 150, 283–291 (2000).
The authors thank CIHR for their support.
The authors declare no competing financial interests.
A technique that allows the sampling of neurochemicals in the brain of live animals. It commonly uses a small U-shaped cannula that serves a dual function: it allows the injection of molecules of interest to test their effect, and it provides a pathway for the flow and subsequent collection of perfusate from a small brain area.
- ANTISENSE KNOCKDOWN
Oligonucleotides with a sequence that is complementary to the mRNA of a given molecule can be used to block its translation. The subsequent temporary elimination of the protein of interest often provides useful information on its biological function.
- MEDIAL FOREBRAIN BUNDLE
Complex fibre tract that runs through the diencephalon. It contains descending fibres from telencephalic structures such as the basal olfactory regions, the periamygdaloid region and the septal nuclei, and ascending fibres from the aminergic brainstem nuclei. Intracranial stimulation along this tract can simulate motivational states and reinforce behaviour.
- INCENTIVE SALIENCE
A psychological process whereby the perception of stimuli is transformed by increasing their salience, making them more attractive or wanted.
This term was originally coined to refer to the effects of early antipsychotic agents on cognition and behaviour.
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Laviolette, S., van der Kooy, D. The neurobiology of nicotine addiction: bridging the gap from molecules to behaviour. Nat Rev Neurosci 5, 55–65 (2004). https://doi.org/10.1038/nrn1298
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