Vulnerability to nicotine self-administration in adolescent mice correlates with age-specific expression of α4* nicotinic receptors
Abstract
The majority of smokers begin during adolescence, a developmental period with a high susceptibility to substance abuse. Adolescents are affected differently by nicotine compared to adults, with adolescents being more vulnerable to nicotine's rewarding properties. It is unknown if the age-dependent molecular composition of a younger brain contributes to a heightened susceptibility to nicotine addiction. Nicotine, the principle pharmacological component of tobacco, binds and activates nicotinic acetylcholine receptors (nAChRs) in the brain. The most prevalent is the widely expressed α4-containing (α4*) subtype which mediates reward and is strongly implicated in nicotine dependence. Exposing different age groups of mice, postnatal day (P) 44-86 days old, to a two bottle-choice oral nicotine self-administration paradigm for five days yielded age-specific consumption levels. Nicotine self-administration was elevated in the P44 group, peaked at P54-60 and was drastically lower in the P66 through P86 groups. We also quantified α4* nAChR expression via spectral confocal imaging of brain slices from α4YFP knock-in mice, in which the α4 nAChR subunit is tagged with a yellow fluorescent protein. Quantitative fluorescence revealed age-specific α4* nAChR expression in dopaminergic and GABAergic neurons of the ventral tegmental area. Receptor expression showed a strong positive correlation with daily nicotine dose, suggesting that α4* nAChR expression levels are age-specific and may contribute to the propensity to self-administer nicotine.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Nicotine self-administration is greater in male adolescent mice than in adults, correlated strongly with α4 nAchR expression in VTA.
“nicotine self-administration has been shown to be greater in male adolescent mice than in adults, which correlated strongly with α4 nAchR expression in the VTA [192].”
From Consequences of adolescent drug use (2023) · cites this paper as [192]
Expression of α4-containing nAChRs in the VTA peaks late in adolescence and is positively correlated with nicotine intake in an oral self-administration task.
“expression of α4- containing nAChRs in the VTA peaks late in adolescence, and is positively correlated with nicotine intake in an oral self-administration task (Fig. 2A) [60].”
From Adolescent nicotine exposure and persistent neurocircuitry changes: unveiling lifelong psychiatric risks (2025) · cites this paper as [60]
Cites
Picciotto, M. R., Zoli, M., Rimondini, R., Léna, C., Marubio, L. M., Pich, E. M., Fuxe, K., & Changeux, J.-P. (1998) · Nature · doi:10.1038/34413 · Cited by 1,320 · see citing works
Adverse Childhood Experiences and Smoking During Adolescence and Adulthood
Anda, R. F. (1999) · JAMA · doi:10.1001/jama.282.17.1652 · Cited by 1,256 · see citing works
Adolescent cortical development: A critical period of vulnerability for addiction
Crews, F., He, J., & Hodge, C. (2007) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2006.12.001 · Cited by 1,091 · see citing works
Clarke, P. B. S., Schwartz, R., Paul, S. M., Cb, P., & Pert, A. (1985) · Journal of Neuroscience · doi:10.1523/jneurosci.05-05-01307.1985 · Cited by 1,037 · see citing works
Psychosocial factors related to adolescent smoking: a critical review of the literature
Tyas, S. L., & Pederson, L. L. (1998) · Tobacco Control · doi:10.1136/tc.7.4.409 · Cited by 899 · see citing works
The natural history of drug use from adolescence to the mid-thirties in a general population sample
Chen, K., & Kandel, D. B. (1995) · American Journal of Public Health · doi:10.2105/ajph.85.1.41 · Cited by 857 · see citing works
Dopamine neurons and their role in reward mechanisms
Schultz, W. (1997) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(97)80007-4 · Cited by 769 · 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
Nicotine Activation of α4* Receptors: Sufficient for Reward, Tolerance, and Sensitization
Tapper, A. R., McKinney, S. L., Nashmi, R., Schwarz, J., Deshpande, P., Labarca, C., Whiteaker, P., Marks, M. J., Collins, A. C., & Lester, H. A. (2004) · Science · doi:10.1126/science.1099420 · Cited by 686 · see citing works
Self-citationRole of dopamine in the behavioural actions of nicotine related to addiction
Chiara, G. D. (2000) · European Journal of Pharmacology · doi:10.1016/s0014-2999(00)00122-9 · Cited by 680 · see citing works
Food Intake, Water Intake, and Drinking Spout Side Preference of 28 Mouse Strains
Bachmanov, A. A., Reed, D. R., Beauchamp, G. K., & Tordoff, M. G. (2002) · Behavior Genetics · doi:10.1023/a:1020884312053 · Cited by 679 · see citing works
Toward a structural basis for the function of nicotinic acetylcholine receptors and their cousins
Karlin, A., & Akabas, M. H. (1995) · Neuron · doi:10.1016/0896-6273(95)90004-7 · Cited by 622 · see citing works
Endogenous nicotinic cholinergic activity regulates dopamine release in the striatum
Zhou, F.-M., Liang, Y., & Dani, J. A. (2001) · Nature Neuroscience · doi:10.1038/nn769 · Cited by 585 · 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
Nicotine binding and nicotinic receptor subunit RNA after chronic nicotine treatment
Marks, M., Pauly, Jr., Gross, S., Deneris, E., Hermans-Borgmeyer, I., Heinemann, S., & Collins, A. (1992) · The Journal of Neuroscience · doi:10.1523/jneurosci.12-07-02765.1992 · Cited by 551 · see citing works
Periadolescence: age-dependent behavior and psychopharmacological responsivity in rats
Spear, L. P., & Brake, S. C. (1983) · Developmental Psychobiology · doi:10.1002/dev.420160203 · Cited by 539 · see citing works
Structural and functional diversity of native brain neuronal nicotinic receptors
Gotti, C., Clementi, F., Fornari, A., Gaimarri, A., Guiducci, S., Manfredi, I., Moretti, M., Pedrazzi, P., Pucci, L., & Zoli, M. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.05.024 · Cited by 469 · see citing works
Chassin, L., Presson, C. C., Sherman, S. J., & Edwards, D. A. (1990) · Health Psychology · doi:10.1037//0278-6133.9.6.701 · Cited by 460 · see citing works
Chassin, L., Presson, C. C., Sherman, S. J., et al. (1990) · Health Psychology · doi:10.1037/0278-6133.9.6.701 · Cited by 348 · see citing works
Pons, S., Fattore, L., Cossu, G., Tolu, S., Porcu, E., McIntosh, J. M., Changeux, J. P., Maskos, U., & Fratta, W. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3918-08.2008 · Cited by 312 · 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
Self-citationAge of smoking initiation: implications for quitting.
Chen, J., & Millar, W. J. (1998) · PubMed · Cited by 273 · see citing works
Saccone, N. L., Wang, J. C. C., Breslau, N., Johnson, E. O., Hatsukami, D. K., Saccone, S. F., Grucza, R. A., Sun, L., Duan, W., Budde, J., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-0786 · Cited by 267 · see citing works
Nicotine addiction: the possible role of functional upregulation
Buisson, B., & Bertrand, D. (2002) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(00)01979-9 · Cited by 254 · see citing works
Nicotine-induced conditioned place preference in adolescent and adult rats
Vastola, B. J., Douglas, L. A., Varlinskaya, E. I., & Spear, L. P. (2002) · Physiology & Behavior · doi:10.1016/s0031-9384(02)00818-1 · Cited by 251 · see citing works
Perry, D. C., Xiao, Y., Nguyen, H. N., Musachio, J. L., Dávila‐García, M. I., & Kellar, K. J. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.00951.x · Cited by 246 · see citing works
Environmental stimuli promote the acquisition of nicotine self-administration in rats
Caggiula, A. R., Donny, E. C., White, A., Chaudhri, N., Booth, S., Gharib, M. A., Hoffman, A., Perkins, K. A., & Sved, A. F. (2002) · Psychopharmacology · doi:10.1007/s00213-002-1156-5 · Cited by 225 · see citing works
Are adolescents more vulnerable to drug addiction than adults? Evidence from animal models
Schramm-Sapyta, N. L., Walker, Q. D., Caster, J. M., Levin, E. D., & Kuhn, C. M. (2009) · Psychopharmacology · doi:10.1007/s00213-009-1585-5 · Cited by 215 · see citing works
Nicotine dependence and reward differ between adolescent and adult male mice
Kota, D., Martin, B. R., Robinson, S. E., & Damaj, M. I. (2007) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.121616 · Cited by 202 · see citing works
Shram, M. J., Funk, D., Li, Z., & Lê, A. D. (2006) · Psychopharmacology · doi:10.1007/s00213-006-0373-8 · Cited by 192 · see citing works
Nicotinic acetylcholine receptor β2 subunits in the medial prefrontal cortex control attention
Guillem, K., Bloem, B., Poorthuis, R. B., Loos, M., Smit, A. B., Maskos, U., Spijker, S., & Mansvelder, H. D. (2011) · Science · doi:10.1126/science.1207079 · Cited by 191 · see citing works
Nashmi, R., Dickinson, M. E., McKinney, S., Jareb, M., Labarca, C., Fraser, S. E., & Lester, H. A. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-37-11554.2003 · Cited by 188 · see citing works
Self-citationBehavioral and Neurochemical Vulnerability During Adolescence in Mice: Studies with Nicotine
Adriani, W., Granstrem, O., Macrı̀, S., Izykenova, G. A., Dambinova, S. A., & Giovanni Laviola, A. (2003) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300366 · Cited by 164 · 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
Levin, E. D., Lawrence, S. S., Petro, A., Horton, K., Rezvani, A. H., Seidler, F. J., & Slotkin, T. A. (2007) · Neurotoxicology and Teratology · doi:10.1016/j.ntt.2007.02.002 · Cited by 147 · see citing works
Whiting, P. J., Liu, R., Morley, B., & Lindstrom, J. M. (1987) · Journal of Neuroscience · doi:10.1523/jneurosci.07-12-04005.1987 · Cited by 138 · see citing works
Developmental regulation of nicotinic acetylcholine receptors within midbrain dopamine neurons
Azam, L., Chen, Y., & Leslie, F. M. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2006.11.011 · Cited by 138 · see citing works
Tobacco abstinence, smoking cues, and the reinforcing value of smoking
Perkins, K. A., Epstein, L. H., Grobe, J. E., & Fonte, C. A. (1994) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(94)90118-x · Cited by 129 · see citing works
Doura, M. B., Gold, A. B., Keller, A. B., & Perry, D. C. (2008) · Brain Research · doi:10.1016/j.brainres.2008.03.056 · Cited by 129 · see citing works
Xiao, C., Nashmi, R., McKinney, S. L., Cai, H., McIntosh, J. M., & Lester, H. A. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.2939-09.2009 · Cited by 115 · 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
Effects of lobeline, a nicotinic receptor agonist, on learning and memory
Decker, M. W., Majchrzak, M. J., & Arnerić, S. P. (1993) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(93)90508-q · Cited by 107 · see citing works
Age Interacts with Heaviness of Smoking in Predicting Success in Cessation of Smoking
Coambs, R. B., Li, S., & Kozlowski, L. T. (1992) · American Journal of Epidemiology · doi:10.1093/oxfordjournals.aje.a116277 · Cited by 101 · see citing works
Fowler, C. D., & Kenny, P. J. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.05.012 · Cited by 94 · see citing works
Brielmaier, J. M., McDonald, C. G., & Smith, R. F. (2007) · Neurotoxicology and Teratology · doi:10.1016/j.ntt.2006.09.023 · Cited by 90 · see citing works
Brunzell, D. H., Chang, J. R., Schneider, B., Olausson, P., Taylor, J. R., & Picciotto, M. R. (2006) · Psychopharmacology · doi:10.1007/s00213-005-0099-z · Cited by 71 · see citing works
Reducing substance use during adolescence: a translational framework for prevention
Stanis, J. J., & Andersen, S. L. (2014) · Psychopharmacology · doi:10.1007/s00213-013-3393-1 · Cited by 69 · see citing works
Rusted, J. M., & Warburton, D. M. (1992) · Psychopharmacology · doi:10.1007/bf02247420 · Cited by 68 · see citing works
Nicotine and Hippocampus-Dependent Learning: Implications for Addiction
Gould, T. J. (2006) · Molecular Neurobiology · doi:10.1385/mn:34:2:93 · Cited by 61 · see citing works
Enhanced nicotine reward in adulthood after exposure to nicotine during early adolescence in mice
Kota, D., Robinson, S. E., & Imad Damaj, M. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.06.099 · Cited by 59 · see citing works
Neurodevelopment During Adolescence
SPEAR, L. P. (2003) · Cambridge University Press eBooks · doi:10.1017/cbo9780511546365.005 · Cited by 58 · see citing works
Tan, H., Bishop, S. F., Lauzon, N. M., Sun, N., & Laviolette, S. R. (2008) · Neuropharmacology · doi:10.1016/j.neuropharm.2008.12.008 · Cited by 46 · see citing works
Counotte, D. S., Goriounova, N. A., Moretti, M., Smoluch, M. T., Irth, H., Clementi, F., Schoffelmeer, A. N. M., Mansvelder, H. D., Smit, A. B., Gotti, C., et al. (2012) · The FASEB Journal · doi:10.1096/fj.11-198994 · Cited by 44 · see citing works
Gallego, X., Molas, S., Amador‐Arjona, A., Marks, M. J., Robles, N., Murtra, P., Armengol, L., Fernández-Montes, R. D., Gratacòs, M., Pumarola, M. B., et al. (2011) · Amino Acids · doi:10.1007/s00726-011-1149-y · Cited by 40 · see citing works
Ngolab, J., Liu, L., Zhao-Shea, R., Gao, G., Gardner, P. D., & Tapper, A. R. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.4453-14.2015 · Cited by 32 · see citing works
Renda, A., & Nashmi, R. (2014) · BMC Neuroscience · doi:10.1186/1471-2202-15-89 · Cited by 31 · see citing works
Self-citationRenda, A., & Nashmi, R. (2012) · Journal of Visualized Experiments · doi:10.3791/3516 · Cited by 12 · see citing works
Self-citationNeurodevelopmental Mechanisms in Psychopathology
Fleisher, M. H. (2005) · American Journal of Psychiatry · doi:10.1176/appi.ajp.162.4.829 · Cited by 4 · see citing works
Andersen (2000) · doi:10.1002/1098-2396(200008)37:2
Flagged first, then by citations
Cited by
Sorted by citations
Consequences of adolescent drug use
Steinfeld, M. R., & Torregrossa, M. M. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02590-4 · Cited by 237 · see citing works
“For example, there is evidence that ACE induces a hyperdopaminergic state in the VTA [130].”
BackgroundInfluentialReynolds, L. M., Faure, P., & Barik, J. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03110-0 · Cited by 26 · see citing works
- Authors
- Renda, A., Penty, N., Komal, P., & Nashmi, R.
- Affiliations
- University of Victoria (CA)
- Corresponding author
- Nashmi, Raad
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 108
- Pages
- 49-59
- ISSN
- 0028-3908 (ISSN-L)
- OpenAlex
- W2338096289
- Cited by
- 17
- References
- 59
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 2
- FWCI
- 0.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Natural Sciences and Engineering Research Council of Canada
- NARSAD Young Investigator Award
- Victoria Foundation—Myre and Winifred Sim Fund
- Canadian Foundation for Innovation
- British Columbia Knowledge Development Fund
- Natural Sciences and Engineering Research Council of Canada Research Tools and Instrumentation Grant
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- nicotine self-administration, adolescent vulnerability, nicotinic acetylcholine receptors, alpha4 nAChR, nicotine dependence, ventral tegmental area, dopaminergic neurons, GABAergic neurons, nicotine reward, brain maturation
- MeSH terms
- Age Factors, Animals, Female, Hippocampus, Male, Mice, Inbred C57BL, Nicotine, Receptors, Nicotinic, Self Administration, Gene Expression, Ventral Tegmental Area, Mice, Gene Knock-In Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
