Intermittent nicotine exposure upregulates nAChR s in VTA dopamine neurons and sensitises locomotor responding to the drug
Open accessAbstract
Dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NA cc) mediate the behavioral and motivational effects of many drugs of abuse, including nicotine. Repeated intermittent administration of these drugs, a pattern often associated with initial drug exposure, sensitises the reactivity of dopamine (DA) neurons in this pathway, enhances the locomotor behaviors the drugs emit, and promotes their pursuit and self‐administration. Here we show that activation of nicotinic acetylcholine receptors (n AC h R s) in the VTA, but not the NA cc, is essential for the induction of locomotor sensitisation by nicotine. Repeated intermittent nicotine exposure (4 × 0.4 mg/kg, base, i.p., administered over 7 days), a regimen leading to long‐lasting locomotor sensitisation, also produced upregulation of nAChR s in the VTA, but not the NA cc, in the hours following the last exposure injection. Functional nAChR upregulation was observed selectively in DA but not GABA neurons in the VTA. These effects were followed by long‐term potentiation of excitatory inputs to these cells and increased nicotine‐evoked DA overflow in the NA cc. Withdrawal symptoms were not observed following this exposure regimen. Thus, intermittent activation and upregulation by nicotine of nAChR s in DA neurons in the VTA may contribute to the development of behavioral sensitisation and increased liability for nicotine addiction.
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For nicotine, animal studies have shown that repeated intermittent injections of nicotine typically cause sensitization or enhancement of the drug's locomotor activating effects.
“For nicotine, animal studies have shown that repeated intermittent injections of nicotine typically cause sensitization or enhancement of the drug’s locomotor activating effects (L. K. Baker et al., 2013; Benwell & Balfour, 1992; Clarke & Kumar, 1983; Vezina, McGehee, & Green, 2007).”
From Cued for Risk: Evidence for an Incentive Sensitization Framework to Explain the Interplay between Stress and Anxiety, Substance Abuse, and Reward Uncertainty in Disordered Gambling Behavior (2019) · cites this paper as L. K. Baker et al., 2013
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Cites
The Rat Brain in Stereotaxic Coordinates
Paxinos, G., & Watson, C. (1983) · Elsevier eBooks · doi:10.1016/c2009-0-63235-9 · Cited by 28,585 · see citing works
The neural basis of drug craving: An incentive-sensitization theory of addiction
Robinson, T. (1993) · Brain Research Reviews · doi:10.1016/0165-0173(93)90013-p · Cited by 7,346 · see citing works
Drug abuse: hedonic homeostatic dysregulation
Koob, G. F., & Moal, M. L. (1997) · Science · doi:10.1126/science.278.5335.52 · Cited by 2,535 · see citing works
Robinson, T. G., & BECKER, J. (1986) · Brain Research · doi:10.1016/s0006-8993(86)80193-7 · Cited by 2,110 · see citing works
Drugs of Abuse and Stress Trigger a Common Synaptic Adaptation in Dopamine Neurons
Saal, D., Dong, Y., Bonci, A., & Malenka, R. C. (2003) · Neuron · doi:10.1016/s0896-6273(03)00021-7 · Cited by 1,147 · see citing works
Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons
Ungless, M. A., Whistler, J. L., Malenka, R. C., & Bonci, A. (2001) · Nature · doi:10.1038/35079077 · Cited by 1,106 · see citing works
Long-term potentiation of excitatory inputs to brain reward areas by nicotine
Mansvelder, H. D., & McGehee, D. S. (2000) · Neuron · doi:10.1016/s0896-6273(00)00042-8 · Cited by 720 · see citing works
Self-citationSynaptic mechanisms underlie nicotine-induced excitability of brain reward areas
Mansvelder, H. D., Keath, J. R., & McGehee, D. S. (2002) · Neuron · doi:10.1016/s0896-6273(02)00625-6 · Cited by 701 · see citing works
Self-citationDramatic decreases in brain reward function during nicotine withdrawal
Epping-Jordan, M. P., Watkins, S. S., Koob, G. F., & Markou, A. (1998) · Nature · doi:10.1038/30001 · Cited by 674 · see citing works
Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors
Maskos, U., Molles, B. E., Pons, S., Besson, M., Guiard, B. P., Guilloux, J.-P., Evrard, A., Cazala, P., Cormier, A., Mameli-Engvall, M., et al. (2005) · Nature · doi:10.1038/nature03694 · Cited by 566 · see citing works
Vezina, P. (2004) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2003.11.001 · Cited by 515 · see citing works
Self-citationNicotine addiction and nicotinic receptors: lessons from genetically modified mice
Changeux, J.-P. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2849 · Cited by 453 · see citing works
Frequency-dependent modulation of dopamine release by nicotine
Zhang, H., & Sulzer, D. (2004) · Nature Neuroscience · doi:10.1038/nn1243 · Cited by 361 · see citing works
Chronic Exposure to Nicotine Upregulates the Human α4β2 Nicotinic Acetylcholine Receptor Function
Buisson, B., & Bertrand, D. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-06-01819.2001 · Cited by 361 · see citing works
Büttner‐Ennever, J. A. (1997) · Journal of Anatomy · doi:10.1046/j.1469-7580.1997.191203153.x · Cited by 360 · see citing works
Preexposure to amphetamine and nicotine predisposes rats to self-administer a low dose of cocaine
Horger, B. A., Giles, M. K., & Schenk, S. (1992) · Psychopharmacology · doi:10.1007/bf02245147 · Cited by 344 · see citing works
Govind, A. P., Vezina, P., & Green, W. N. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.06.011 · Cited by 338 · see citing works
Self-citationElevated levels of GluR1 in the midbrain: a trigger for sensitization to drugs of abuse?
Carlezon, W. A., & Nestler, E. J. (2002) · Trends in Neurosciences · doi:10.1016/s0166-2236(02)02289-0 · Cited by 281 · see citing works
Nashmi, R., Xiao, C., Deshpande, P., McKinney, S., Grady, S. R., Whiteaker, P., Huang, Q., McClure-Begley, T., Lindstrom, J. M., Labarca, C., et al. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.2199-07.2007 · Cited by 274 · see citing works
Synaptic Plasticity and Nicotine Addiction
Dani, J. A., Ji, D., & Zhou, F.-M. (2001) · Neuron · doi:10.1016/s0896-6273(01)00379-8 · Cited by 266 · see citing works
Gotti, C., Guiducci, S., Tedesco, V., Corbioli, S., Zanetti, L., Moretti, M., Zanardi, A., Rimondini, R., Mugnaini, M., Clementi, F., et al. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.5095-09.2010 · Cited by 226 · see citing works
Characterization of the locomotor stimulant action of nicotine in tolerant rats
Clarke, P. B. S., & Kumar, R. C. (1983) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1983.tb10733.x · Cited by 222 · see citing works
Sensitization of Midbrain Dopamine Neuron Reactivity Promotes the Pursuit of Amphetamine
Vezina, P., Lorrain, D. S., Arnold, G. M., Austin, J. D., & Suto, N. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-11-04654.2002 · Cited by 206 · see citing works
Self-citationWolf, M., White, F., & Hu, X. (1994) · Journal of Neuroscience · doi:10.1523/jneurosci.14-03-01735.1994 · Cited by 202 · see citing works
Chronic Nicotine Exposure Upregulates Nicotinic Receptors by a Novel Mechanism
Vallejo, Y. F. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.5240-04.2005 · Cited by 201 · see citing works
Nisell, M., Nomikos, G. G., & Svensson, T. H. (1994) · Pharmacology & Toxicology · doi:10.1111/j.1600-0773.1994.tb00373.x · Cited by 201 · see citing works
Psychostimulant-Induced Behavioral Sensitization Depends on Nicotinic Receptor Activation
Schoffelmeer, A. N. M., Vries, T. J. D., Wardeh, G., van de Ven, H. W. M., & Vanderschuren, L. J. M. J. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-08-03269.2002 · Cited by 157 · see citing works
Diminished nicotine withdrawal in adolescent rats: implications for vulnerability to addiction
O’Dell, L. E., Bruijnzeel, A. W., Smith, R. T., Parsons, L. H., Merves, M. L., Goldberger, B. A., Richardson, H. N., Koob, G. F., & Markou, A. (2006) · Psychopharmacology · doi:10.1007/s00213-006-0383-6 · Cited by 153 · see citing works
Exposure to nicotine and sensitization of nicotine-induced behaviors
Vezina, P., McGehee, D. S., & Green, W. N. (2007) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2007.08.038 · Cited by 151 · see citing works
Self-citationChronic nicotine and locomotor activity: influences of exposure dose and test dose
Ksir, C. J., Hakan, R. L., & Kellar, K. J. (1987) · Psychopharmacology · doi:10.1007/bf00215474 · Cited by 146 · see citing works
Ferrari, R., Le Novère, N., Picciotto, M. R., Changeux, J. P., & Zoli, M. (2002) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2001.02009.x · Cited by 132 · see citing works
Dose‐Response Relationship for Nicotine‐Induced Up‐Regulation of Rat Brain Nicotinic Receptors
Rowell, P. P., & Li, M. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.68051982.x · Cited by 124 · see citing works
Govind, A. P., Walsh, H., & Green, W. N. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.5438-11.2012 · Cited by 116 · see citing works
Self-citationRahman, S., Zhang, J., Engleman, E. A., & Corrigall, W. A. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.08.010 · Cited by 110 · see citing works
Zhang, T. A., Placzek, A. N., & Dani, J. A. (2010) · Neuropharmacology · doi:10.1016/j.neuropharm.2010.06.004 · Cited by 100 · see citing works
Brunzell, D. H., Boschen, K. E., Hendrick, E. S., Beardsley, P. M., & McIntosh, J. M. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2009.171 · Cited by 95 · see citing works
Skjei, K. L., & Markou, A. (2003) · Psychopharmacology · doi:10.1007/s00213-003-1414-1 · Cited by 93 · see citing works
Panagis, G., Kastellakis, A., Spyraki, C., & Nomikos, G. G. (2000) · Psychopharmacology · doi:10.1007/s002130000384 · Cited by 93 · see citing works
Nicotine Potentiation of Excitatory Inputs to Ventral Tegmental Area Dopamine Neurons
Mao, D., Gallagher, K., & McGehee, D. S. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.5671-10.2011 · Cited by 90 · see citing works
Self-citationMugnaini, M., Tessari, M., Tarter, G., Merlo Pich, E., Chiamulera, C., & Bunnemann, B. (2002) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2002.02220.x · Cited by 88 · see citing works
Vezina, P., & Queen, A. L. (2000) · Psychopharmacology · doi:10.1007/s002130000463 · Cited by 88 · see citing works
Self-citationUp-regulation of Nicotinic Receptors by Nicotine Varies with Receptor Subtype
Walsh, H., Govind, A. P., Mastro, R., Hoda, J. C., Bertrand, D., Vallejo, Y., & Green, W. N. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m703432200 · Cited by 87 · see citing works
Self-citationYang, K., Buhlman, L. M., Khan, G. M., Nichols, R. A., Jin, G.-Z., McIntosh, J. M., Whiteaker, P., Lukas, R. J., & Wu, J. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.3003-10.2011 · Cited by 85 · see citing works
Crawford, C. A., Choi, F., Kohutek, J. L., Yoshida, S. T., & McDougall, S. A. (2003) · Synapse · doi:10.1002/syn.10301 · Cited by 83 · see citing works
Collins, A. C., Romm, E., & Wehner, J. M. (1990) · Brain Research Bulletin · doi:10.1016/0361-9230(90)90222-l · Cited by 79 · see citing works
Nicotine tolerance: an analysis of the time course of its development and loss in the rat
Collins, A. C., Romm, E., & Wehner, J. M. (1988) · Psychopharmacology · doi:10.1007/bf02431526 · Cited by 66 · see citing works
Bruijnzeel, A. W., & Markou, A. (2004) · Neuropharmacology · doi:10.1016/j.neuropharm.2004.05.005 · Cited by 60 · see citing works
Snell, L. D., & Johnson, K. M. (1989) · Synapse · doi:10.1002/syn.890030204 · Cited by 59 · see citing works
Enhanced Nicotinic Receptor Function and Drug Abuse Vulnerability
Fagen, Z. M., Mitchum, R. D., Vezina, P., & McGehee, D. S. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.2017-06.2007 · Cited by 40 · see citing works
Self-citationCortright, J. J., Sampedro, G. R., Neugebauer, N. M., & Vezina, P. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2012.80 · Cited by 27 · see citing works
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Allain, F., Minogianis, E.-A., Roberts, D. C. S., & Samaha, A.-N. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.06.012 · Cited by 192 · see citing works
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de Kloet, S. F., Mansvelder, H. D., & De Vries, T. J. (2015) · Biochemical Pharmacology · doi:10.1016/j.bcp.2015.07.014 · Cited by 69 · see citing works
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“For nicotine, animal studies have shown that repeated intermittent injections of nicotine typically cause sensitization or enhancement of the drug’s locomotor activating effects (L. K. Baker et al., 2013; Benwell & Balfour, 1992; Clarke & Kumar, 1983; Vezina, McGehee, & Green, 2007).”
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- Authors
- Baker, L. K., Mao, D., Chi, H., Govind, A. P., Vallejo, Y. F., Iacoviello, M., Herrera, S., Cortright, J. J., Green, W. N., McGehee, D. S., & Vezina, P.
- Affiliations
- University of Chicago (US)
- Corresponding author
- Vezina, Paul
- Venue
- European Journal of Neuroscience
- Publisher
- Wiley
- Published
- 2013-01-21
- Volume
- 37
- Issue
- 6
- Pages
- 1004-1011
- ISSN
- 0953-816X (ISSN-L)
- 1460-9568
- PMC
- PMC3604051
- OpenAlex
- W1996574732
- Cited by
- 39
- References
- 50
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 1 · 2021: 3 · 2020: 4 · 2019: 2 · 2018: 5 · 2017: 2 · 2016: 3 · 2015: 10 · 2014: 2 · 2013: 3
- FWCI
- 2.69
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- European Journal of Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Drug Abuse (T32-DA07255, R01DA015918, P01DA019695, T32DA007255)
- National Institute of Neurological Disorders and Stroke (R01NS043782)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Keywords
- nicotine, nicotinic acetylcholine receptors, ventral tegmental area, dopaminergic neurons, nicotine dependence, nucleus accumbens, receptor up-regulation, long-term potentiation, nicotine withdrawal, drugs of abuse
- MeSH terms
- Animals, Dopamine, Locomotion, Male, Nicotine, Nucleus Accumbens, Receptors, Nicotinic, Up-Regulation, Rats, Sprague-Dawley, Ventral Tegmental Area, Long-Term Potentiation, Nicotinic Agonists, Rats, Dopaminergic Neurons, GABAergic Neurons, Central Nervous System Sensitization
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