Skip to main content Accessibility help
Hostname: page-component-768ffcd9cc-727vs Total loading time: 0.442 Render date: 2022-12-02T01:10:57.569Z Has data issue: true Feature Flags: { "useRatesEcommerce": false } hasContentIssue true

Sex- and age-dependent differences in nicotine susceptibility evoked by developmental exposure to tobacco smoke and/or ethanol in mice

Published online by Cambridge University Press:  09 December 2020

André Luiz Nunes-Freitas
Laboratório de Neurofisiologia, Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Av. Prof. Manuel de Abreu 444, 5 andar – Vila Isabel, Rio de Janeiro, RJ, 20550-170, Brazil
Alex C. Manhães
Laboratório de Neurofisiologia, Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Av. Prof. Manuel de Abreu 444, 5 andar – Vila Isabel, Rio de Janeiro, RJ, 20550-170, Brazil
Ana Carolina Dutra-Tavares
Laboratório de Neurofisiologia, Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Av. Prof. Manuel de Abreu 444, 5 andar – Vila Isabel, Rio de Janeiro, RJ, 20550-170, Brazil
Pedro Henrique Leal-Rocha
Laboratório de Neurofisiologia, Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Av. Prof. Manuel de Abreu 444, 5 andar – Vila Isabel, Rio de Janeiro, RJ, 20550-170, Brazil
Claudio C. Filgueiras
Laboratório de Neurofisiologia, Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Av. Prof. Manuel de Abreu 444, 5 andar – Vila Isabel, Rio de Janeiro, RJ, 20550-170, Brazil
Anderson Ribeiro-Carvalho
Departamento de Ciências, Faculdade de Formação de Professores da Universidade do Estado do Rio de Janeiro, São Gonçalo, RJ, 24435-005, Brazil
Yael Abreu-Villaça*
Laboratório de Neurofisiologia, Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Av. Prof. Manuel de Abreu 444, 5 andar – Vila Isabel, Rio de Janeiro, RJ, 20550-170, Brazil
Address for correspondence: Yael Abreu-Villaça, Laboratório de Neurofisiologia, Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Centro Biomédico, Universidade do Estado do Rio de Janeiro, Av. Prof. Manuel de Abreu 444, 5 andar, Vila Isabel, Rio de Janeiro, RJ, 20550-170, Brazil. Emails:;


Either tobacco smoking or alcohol consumption during pregnancy sex-selectively increases susceptibility to drugs of abuse later in life. Considering that pregnant smoking women are frequently intermittent consumers of alcoholic beverages, here, we investigated whether a short-term ethanol exposure restricted to the brain growth spurt period when combined with chronic developmental exposure to tobacco smoke aggravates susceptibility to nicotine in adolescent and adult mice. Swiss male and female mice were exposed to tobacco smoke (SMK; research cigarettes 3R4F, whole-body exposure, 8 h/daily) or ambient air during the gestational period and until the tenth postnatal day (PN). Ethanol (ETOH, 2 g/Kg, 25%, i.p.) or saline was injected in the pups every other day from PN2 to PN10. There were no significant differences in cotinine (nicotine metabolite) and ethanol serum levels among SMK, ETOH and SMK + ETOH groups. During adolescence (PN30) and adulthood (PN90), nicotine (NIC, 0.5 mg/Kg) susceptibility was evaluated in the conditioned place preference and open field tests. NIC impact was more evident in females: SMK, ETOH and SMK + ETOH adolescent females were equally more susceptible to nicotine-induced place preference than control animals. At adulthood, SMK and SMK + ETOH adult females exhibited a nicotine-evoked hyperlocomotor profile in the open field, with a stronger effect in the SMK + ETOH group. Our results indicate that ethanol exposure during the brain growth spurt, when combined to developmental exposure to tobacco smoke, increases nicotine susceptibility with stronger effects in adult females. This result represents a worsened outcome from the early developmental dual exposure and may predispose nicotine use/abuse later in life.

Original Article
© Non-Gov. entity and The Author(s), 2020. Published by Cambridge University Press in association with International Society for Developmental Origins of Health and Disease

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)


Mullen, PD. How can more smoking suspension during pregnancy become lifelong abstinence? Lessons learned about predictors, interventions, and gaps in our accumulated knowledge. Nicotine Tob Res. 2004; 6(Suppl. 2). doi: 10.1080/14622200410001669150 CrossRefGoogle ScholarPubMed
Herzberg, J, Barrier, B, Sprague, DJ, Vinson, DC. Substance use in women of reproductive age. Mo Med. 2016; 113(3), 182186.Google ScholarPubMed
Denny, CH, Tsai, J, Floyd, RL, Green, PP. Alcohol use among pregnant and nonpregnant women of childbearing age – United States, 1991–2005. Morb Mortal Wkly Rep. 2009; 58(19), 529532.Google Scholar
Reitan, T, Callinan, S. Changes in smoking rates among pregnant women and the general female population in Australia, Finland, Norway, and Sweden. Nicotine Tob Res. 2017; 19(3), 282289. doi: 10.1093/ntr/ntw188 Google Scholar
McHugh, RK, Wigderson, S, Greenfield, SF. Epidemiology of substance use in reproductive-age women. Obstet Gynecol Clin North Am. 2014; 41(2), 177189. doi: 10.1016/j.ogc.2014.02.001 CrossRefGoogle ScholarPubMed
Hammer, JH, Parent, MC, Spiker, DA, World Health Organization. Global status report on alcohol and health 2018. Vol. 65; 2018. doi:10.1037/cou0000248 CrossRefGoogle Scholar
Meschke, LL, Holl, JA, Messelt, S. Assessing the risk of fetal alcohol syndrome: understanding substance use among pregnant women. Neurotoxicol Teratol. Published online 2003. doi: 10.1016/ CrossRefGoogle ScholarPubMed
Pauly, JR, Slotkin, TA. Maternal tobacco smoking, nicotine replacement and neurobehavioural development. Acta Paediatr Int J Paediatr. 2008; 97(10), 13311337. doi: 10.1111/j.1651-2227.2008.00852.x CrossRefGoogle ScholarPubMed
Bruin, JE, Gerstein, HC, Holloway, AC. Long-term consequences of fetal and neonatal nicotine exposure: a critical review. Toxicol Sci. 2010; 116(2), 364374. doi: 10.1093/toxsci/kfq103 CrossRefGoogle ScholarPubMed
Tong, VT, Dietz, PM, Morrow, B, et al. Trends in smoking before, during, and after pregnancy – pregnancy risk assessment monitoring system, United States, 40 sites, 2000-2010. MMWR Surveill Summ. 2013; 62(6), 119.Google ScholarPubMed
Mendelsohn, C, Gould, GS, Oncken, C. Management of smoking in pregnant women. Aust Fam Physician. 2014; 43(1), 4651.Google ScholarPubMed
Curtin, SC, Matthews, TJ. Smoking prevalence and cessation before and during pregnancy: data from the birth certificate, 2014. Natl Vital Stat Rep. 2016; 65(1), 114.Google ScholarPubMed
Senecky, Y, Weiss, N, Shalev, SA, et al. Alcohol consumption during pregnancy among women in israel. Can J Clin Pharmacol. 2011; 18(2), 261272.Google ScholarPubMed
Balachova, T, Bonner, B, Chaffin, M, et al. Women’s alcohol consumption and risk for alcohol-exposed pregnancies in Russia. Addiction. 2012; 107(1), 109117. doi: 10.1111/j.1360-0443.2011.03569.x CrossRefGoogle ScholarPubMed
Balachova, T, Shaboltas, A, Nasledov, A, et al. Alcohol and HIV risk among Russian women of childbearing age. AIDS Behav. 2017; 21(7), 18571867. doi: 10.1007/s10461-016-1542-3 CrossRefGoogle ScholarPubMed
Spohr, HL, Willms, J, Steinhausen, HC. Fetal alcohol spectrum disorders in young adulthood. J Pediatr. Published online 2007. doi: 10.1016/j.jpeds.2006.11.044 CrossRefGoogle ScholarPubMed
Welch-Carre, E. The neurodevelopmental consequences of prenatal alcohol exposure. Adv Neonatal Care. 2005; 5(4), 217229. doi: 10.1016/j.adnc.2005.04.007 CrossRefGoogle ScholarPubMed
Kuja-Halkola, R, D’Onofrio, BM, Larsson, H, Lichtenstein, P. Maternal smoking during pregnancy and adverse outcomes in offspring : genetic and environmental sources of covariance. Behav Genet. 2014; 44(5), 456467. doi: 10.1007/s10519-014-9668-4 CrossRefGoogle ScholarPubMed
Eskenazf, B, Trupln, LS. Passive and active maternal smoking during pregnancy, as measured by Serum Cotinine, and postnatal smoke exposure. II. Effects on neurodevelopment at age 5 years. Am Joumal Epidemiol. 1995; 142(9).Google Scholar
Fergusson, D, Woodward, L, Horwood, J. Maternal smoking during pregnancy and psychiatric adjustment in youngf adulthood. Arch Gen Psychiatry. 1998; 55(8), 721727.CrossRefGoogle Scholar
Burd, L, Klug, MG, Martsolf, JT, Kerbeshian, J. Fetal alcohol syndrome: Neuropsychiatric phenomics. Neurotoxicol Teratol. 2003; 25(6), 697705. doi: 10.1016/ CrossRefGoogle ScholarPubMed
Rasmussen, C. Executive functioning and working memory in fetal alcohol spectrum disorder. Alcohol Clin Exp Res. 2005; 29(8), 13591367. doi: 10.1097/01.alc.0000175040.91007.d0 CrossRefGoogle ScholarPubMed
England, LJ, Aagaard, K, Bloch, M, et al. Developmental toxicity of nicotine: a transdisciplinary synthesis and implications for emerging tobacco products. Neurosci Biobehav Rev. 2017; 72, 176189. doi: 10.1016/j.neubiorev.2016.11.013 CrossRefGoogle ScholarPubMed
Marquardt, K, Brigmana, JL. The impact of prenatal alcohol exposure on social, cognitive and affective behavioral domains: insights from rodent models. Physiol Behav. 2016; 51(1), 115. doi: 10.1016/j.physbeh.2017.03.040 Google ScholarPubMed
Sabzalizadeh, M, Afarinesh, MR, Mafi, F, et al. Alcohol and nicotine co-Administration during pregnancy and lactation periods alters sensory discrimination of adult NMRI mice offspring. Physiol Behav. 2020; 213(October 2019). doi: 10.1016/j.physbeh.2019.112731 CrossRefGoogle ScholarPubMed
Stephen, JM, Ph, D, Kodituwakku, PW, et al. Delays in auditory processing identified in preschool children with FASD Julia. Alcohol Clin Exp Res. 2012; 36(10), 17201727. doi: 10.1111/j.1530-0277.2012.01769.x.Delays CrossRefGoogle Scholar
Mccartney, JS, Fried, PA, Watkinson, B. Central auditory processing in school-age children prenatally exposed to cigarette smoke. Neurotoxicol Teratol. 1994; 16(3), 269276. doi: 10.1016/0892-0362(94)90048-5 CrossRefGoogle ScholarPubMed
Kandel, DB, Wu, P, Davies, M. Maternal smoking during pregnancy and smoking by adolescent daughters. Am J Public Health. 1994; 84(9), 14071413. doi: 10.2105/AJPH.84.9.1407 CrossRefGoogle ScholarPubMed
Buka, SL, Shenassa, ED, Niaura, R. Elevated risk of tobacco dependence among offspring of mothers who smoked during pregnancy: A 30-year prospective study. Am J Psychiatry. 2003; 160(11), 19781984. doi: 10.1176/appi.ajp.160.11.1978 CrossRefGoogle ScholarPubMed
Oncken, C, McKee, S, Krishnan-Sarin, S, O’Malley, S, Mazure, C. Gender effects of reported in utero tobacco exposure on smoking initiation, progression and nicotine dependence in adult offspring. Nicotine Tob Res. 2004; 6(5), 829833. doi: 10.1080/1462220042000282555 CrossRefGoogle ScholarPubMed
Wang, TW, Gentzke, A, Sharapova, S, Cullen, KA, Ambrose, BK, Jamal, A. Tobacco use among middle and high school students - United States, 2011-2016 Morbidity and Mortality Weekly Report Tobacco. Morb Mortal Wkly Rep. 2018; 66(28), 765.Google Scholar
Gentzke, AS, Creamer, M, Cullen, KA, et al. Vital signs: tobacco product use among middle and high school students – United States, 2011–2018. Morb Mortal Wkly Rep. 2019; 68(6), 157164. doi: 10.15585/mmwr.mm6839a2 CrossRefGoogle ScholarPubMed
Miliano, C, Scott, ER, Murdaugh, LB, et al. Modeling drug exposure in rodents using e-cigarettes and other electronic nicotine delivery systems. J Neurosci Methods. 2019; 330, 108458. doi: 10.1016/j.jneumeth.2019.108458 CrossRefGoogle ScholarPubMed
Kaleta, D, Niedzin, M, Jankowska, A, Polańska, K. Predictors of e-cigarette use susceptibility—A study of young people from a socio-economically disadvantaged rural area in Poland. Int J Environ Res Public Health. 2019; 16(20), 111. doi: 10.3390/ijerph16203935 CrossRefGoogle ScholarPubMed
Baer, JS, Barr, HM, Bookstein, FL, Sampson, PD, Streissguth, AP. Prenatal alcohol exposure and family history of alcoholism in the etiology of adolescent alcohol problems. J Stud Alcohol. 1998; 59(5), 533543. doi: 10.15288/jsa.1998.59.533 CrossRefGoogle ScholarPubMed
Baer, JS, Sampson, PD, Barr, HM, Connor, PD, Streissguth, AP. A 21-year longitudinal analysis of the effects of prenatal alcohol exposure on young adult drinking. Arch Gen Psychiatry. 2003; 60(4), 377385. doi:10.1001/archpsyc.60.4.377\r60/4/377[pii]CrossRefGoogle ScholarPubMed
Yates, WR, Cadoret, RJ, Troughton, EP, Stewart, M, Giunta, TS. Effect of fetal alcohol exposure on adult symptoms of nicotine, alcohol, and drug dependence. Alcohol Clin Exp Res. 1998; 22(4), 914920. doi: 10.1111/j.1530-0277.1998.tb03889.x CrossRefGoogle Scholar
Levin, ED, Lawrence, S, Petro, A, Horton, K, Seidler, FJ, Slotkin, TA. Increased nicotine self-administration following prenatal exposure in female rats. Pharmacol Biochem Behav. 2006; 85(3), 669674. doi: 10.1016/j.pbb.2006.11.006 CrossRefGoogle ScholarPubMed
Schneider, S, Schutz, J. Who smokes during pregnancy? A systematic literature review of population-based surveys conducted in developed countries between 1997 and 2006. Eur J Contracept Reprod Heal Care. 2008; 13(2), 138147. doi: 10.1080/13625180802027993 CrossRefGoogle ScholarPubMed
Chotro, MG, Arias, C, Laviola, G. Increased ethanol intake after prenatal ethanol exposure: Studies with animals. Neurosci Biobehav Rev. 2007; 31(2), 181191. doi: 10.1016/j.neubiorev.2006.06.021 CrossRefGoogle ScholarPubMed
Slater, ME, Haughwout, SP, Castle, IP. Trends in substance use among reproductive-age females in the United States, 2002–2013. 2015.Google Scholar
Delgado-Lobete, L, Montes-Montes, R, Vila-Paz, A, et al. Individual and environmental factors associated with tobacco smoking, alcohol abuse and illegal drug consumption in university students: A mediating analysis. Int J Environ Res Public Health. 2020; 17(9), 47. doi: 10.3390/ijerph17093019 CrossRefGoogle ScholarPubMed
Dierker, L, Lloyd-Richardson, E, Stolar, M, et al. The proximal association between smoking and alcohol use among first year college students. Drug Alcohol Depend. Published online 2006. doi: 10.1016/j.drugalcdep.2005.05.012 CrossRefGoogle ScholarPubMed
Weitzman, ER, Chen, YY. The co-occurrence of smoking and drinking among young adults in college: national survey results from the United States. Drug Alcohol Depend. Published online 2005. doi: 10.1016/j.drugalcdep.2005.05.008 CrossRefGoogle ScholarPubMed
Walker, MJ, Al-Sahab, B, Islam, F, Tamim, H. The epidemiology of alcohol utilization during pregnancy: an analysis of the Canadian Maternity Experiences Survey (MES). BMC Pregnancy Childbirth. 2011; 11(1), 52. doi: 10.1186/1471-2393-11-52 CrossRefGoogle Scholar
Abreu-Villaça, Y, Carvalho-Graca, AC, Skinner, G, et al. Hyperactivity and memory/learning deficits evoked by developmental exposure to nicotine and/or ethanol are mitigated by cAMP and cGMP signaling cascades activation. Neurotoxicology. 2018; 66(2010), 150159. doi: 10.1016/j.neuro.2018.04.003 CrossRefGoogle ScholarPubMed
Ribeiro-Carvalho, A, Lima, CS, Medeiros, AH, et al. Combined exposure to nicotine and ethanol in adolescent mice: effects on the central cholinergic systems during short and long term withdrawal. Neuroscience. 2009; 162(4), 11741186. doi: 10.1016/j.neuroscience.2009.05.032 CrossRefGoogle Scholar
Maggio, SE, Saunders, MA, Nixon, K, et al. An improved model of ethanol and nicotine co-use in female P rats: Effects of naltrexone, varenicline, and the selective nicotinic α6β2* antagonist r-bPiDI. Drug Alcohol Depend. 2018; 193, 154–151. doi: 10.1016/j.drugalcdep.2018.09.008 CrossRefGoogle ScholarPubMed
Abreu-Villaça, Y, Filgueiras, CC, Guthierrez, M, et al. Exposure to tobacco smoke containing either high or low levels of nicotine during adolescence: Differential effects on choline uptake in the cerebral cortex and hippocampus. Nicotine Tob Res. 2010; 12(7), 776780. doi: 10.1093/ntr/ntq075 CrossRefGoogle ScholarPubMed
Abreu-Villaça, Y, Filgueiras, CC, Correa-Santos, M, et al. Tobacco smoke containing high or low levels of nicotine during adolescence: effects on novelty-seeking and anxiety-like behaviors in mice. Psychopharmacology (Berl). 2015; 232(10), 16931703. doi: 10.1007/s00213-014-3801-1 CrossRefGoogle ScholarPubMed
Abreu-Villaça, Y, Correa-Santos, M, Dutra-Tavares, AC, et al. A ten fold reduction of nicotine yield in tobacco smoke does not spare the central cholinergic system in adolescent mice. Int J Dev Neurosci. 2016; 52, 93103. doi: 10.1016/j.ijdevneu.2016.06.002 CrossRefGoogle Scholar
Abreu-Villaça, Y, Guimarães, VMS, Nunes-Freitas, A, et al. Tobacco smoke and ethanol during adolescence: Both combined- and single-drug exposures lead to short- and long-term disruption of the serotonergic system in the mouse brain. Brain Res Bull. 2019; 146(October 2018), 94103. doi: 10.1016/j.brainresbull.2018.12.007 CrossRefGoogle Scholar
Anthenelli, RM. Recent advances in the treatment of tobacco dependence. Clin Neurosci Res. 2005; 5(2–4), 175183. doi: 10.1016/j.cnr.2005.08.014 CrossRefGoogle Scholar
Belluzzi, JD, Wang, R, Leslie, FM. Acetaldehyde enhances acquisition of nicotine self-administration in adolescent rats. Neuropsychopharmacology. 2005; 30(4), 705712. doi: 10.1038/sj.npp.1300586 CrossRefGoogle ScholarPubMed
Brennan, KA, Putt, F, Truman, P. Nicotine-, tobacco particulate matter- and methamphetamine-produced locomotor sensitisation in rats. Psychopharmacology (Berl). 2013; 228(4), 659672. doi: 10.1007/s00213-013-3071-3 CrossRefGoogle ScholarPubMed
Bruijnzeel, AW, Ford, J, Rogers, JA, et al. Blockade of CRF1 receptors in the central nucleus of the amygdala attenuates the dysphoria associated with nicotine withdrawal in rats. Pharmacol Biochem Behav. 2012; 101(1), 6268. doi: 10.1016/j.pbb.2011.12.001 CrossRefGoogle ScholarPubMed
Hall, BJ, Wells, C, Allenby, C, et al. Differential effects of non-nicotine tobacco constituent compounds on nicotine self-administration in rats. Pharmacol Biochem Behav. 2014; 120, 103108. doi: 10.1016/j.pbb.2014.02.011 CrossRefGoogle ScholarPubMed
Hoffman, AC, Evans, SE. Abuse potential of non-nicotine tobacco smoke components: acetaldehyde, nornicotine, cotinine, and anabasine. Nicotine Tob Res. 2013; 15(3), 622632. doi: 10.1093/ntr/nts192 CrossRefGoogle ScholarPubMed
Pickworth, WB, Fant, R V., Nelson, RA, Rohrer, MS, Henningfield, JE. Pharmacodynamic effects of new de-nicotinized cigarettes. Nicotine Tob Res. 1999; 1(4), 357364. doi: 10.1080/14622299050011491 CrossRefGoogle ScholarPubMed
Villégier, AS, Gallager, B, Heston, J, Belluzzi, JD, Leslie, FM. Age influences the effects of nicotine and monoamine oxidase inhibition on mood-related behaviors in rats. Psychopharmacology (Berl). 2010; 208(4), 593601. doi: 10.1007/s00213-009-1760-8 CrossRefGoogle ScholarPubMed
Chadi, N, Hadland, SE, Harris, SK. Understanding the implications of the “vaping epidemic” among adolescents and young adults: a call for action. Subst Abus. 2019; 40(1), 710. doi: 10.1080/08897077.2019.1580241 CrossRefGoogle Scholar
Cavallo, DA, Krishnan-Sarin, S. Nicotine use disorders in adolescents. Pediatr Clin North Am. 2019; 66(6), 10531062. doi: 10.1016/j.pcl.2019.08.002 CrossRefGoogle ScholarPubMed
Kandel, ER, Kandel, DB. A molecular basis for nicotine as a gateway drug. N Engl J Med. 2014; 371(10), 932943. doi: 10.1056/NEJMsa1405092 CrossRefGoogle ScholarPubMed
Schramm-Sapyta, NL, Walker, QD, Caster, JM, Levin, ED, Kuhn, CM. Are adolescents more vulnerable to drug addiction than adults? Evidence from animal models. Psychopharmacology (Berl). 2009; 206(1), 121. doi: 10.1007/s00213-009-1585-5 CrossRefGoogle ScholarPubMed
Yuan, M, Cross, SJ, Loughlin, SE, Leslie, FM. Nicotine and the adolescent brain. J Physiol. 2015; 593(16), 33973412. doi: 10.1113/JP270492 CrossRefGoogle ScholarPubMed
Keyes, KM, Grant, BF, Hasin, DS. Evidence for a closing gender gap in alcohol use, abuse, and dependence in the United States population. Drug Alcohol Depend. 2008; 93(1-2), 2129. doi: 10.1016/j.drugalcdep.2007.08.017 CrossRefGoogle ScholarPubMed
Dazzi, L, Seu, E, Cherchi, G, Barbieri, PP, Matzeu, A, Biggio, G. Estrous cycle-dependent changes in basal and ethanol-induced activity of cortical dopaminergic neurons in the rat. Neuropsychopharmacology. 2007; 32(4), 892901. doi: 10.1038/sj.npp.1301150 CrossRefGoogle ScholarPubMed
Lynch, WJ. Sex differences in vulnerability to drug self-administration. Exp Clin Psychopharmacol. 2006; 14(1), 3441. doi: 10.1037/1064-1297.14.1.34 CrossRefGoogle ScholarPubMed
Lynch, WJ, Sofuoglu, M. Role of progesterone in nicotine addiction: evidence from initiation to relapse. Exp Clin Psychopharmacol. 2010; 18(6), 451461. doi: 10.1037/a0021265.Role CrossRefGoogle Scholar
Tanapat, P, Hastings, NB, Reeves, AJ, Gould, E. Estrogen stimulates a transient increase in the number of new neurons in the dentate gyrus of the adult female rat. J Neurosci. 1999; 19(14), 57925801. doi: 10.1523/JNEUROSCI.19-14-05792.1999 CrossRefGoogle ScholarPubMed
Abreu-Villaça, Y, Cavina, CC, Ribeiro-Carvalho, A, et al. Combined exposure to tobacco smoke and ethanol during adolescence leads to short- and long-term modulation of anxiety-like behavior. Drug Alcohol Depend. 2013; 133(1), 5260. doi: 10.1016/j.drugalcdep.2013.05.033 CrossRefGoogle Scholar
Abreu-Villaça, Y, de Carvalho Graça, AC, Ribeiro-Carvalho, A, de Freitas Naiff, V, Manhães, AC, Filgueiras, CC. Combined exposure to tobacco smoke and ethanol in adolescent mice elicits memory and learning deficits both during exposure and withdrawal. Nicotine Tob Res. 2013; 15(7), 12111221. doi: 10.1093/ntr/nts250 CrossRefGoogle ScholarPubMed
Christensen, LH, Høyer, BB, Pedersen, HS, et al. Prenatal smoking exposure, measured as maternal serum cotinine, and children’s motor developmental milestones and motor function: A follow-up study. Neurotoxicology. 2016; 53, 236245. doi: 10.1016/j.neuro.2016.02.007 CrossRefGoogle ScholarPubMed
Król, MK, Florek, E, Piekoszewski, W, Bokiniec, R, Kornacka, MK. The impact of intrauterine tobacco exposure on the cerebral mass of the neonate based on the measurement of head circumference. Brain Behav. 2012; 2(3), 243248. doi: 10.1002/brb3.49 CrossRefGoogle ScholarPubMed
Mamsen, LS, Jönsson, BAG, Lindh, CH, et al. Concentration of perfluorinated compounds and cotinine in human foetal organs, placenta, and maternal plasma. Sci Total Environ. 2017; 596–597, 97105. doi: 10.1016/j.scitotenv.2017.04.058 CrossRefGoogle ScholarPubMed
Wrześniak, M, Królik, M, Kepinska, M, Milnerowicz, H. The influence of maternal smoking on transferrin sialylation and fetal biometric parameters. Environ Toxicol Pharmacol. 2016; 47, 100107. doi: 10.1016/j.etap.2016.09.008 CrossRefGoogle ScholarPubMed
Livy, DJ, Maier, SE, West, JR. Fetal alcohol exposure and temporal vulnerability: Effects of binge-like alcohol exposure on the ventrolateral nucleus of the thalamus. Alcohol Clin Exp Res. 2001; 25(5), 774780. doi: 10.1111/j.1530-0277.2001.tb02278.x CrossRefGoogle ScholarPubMed
Nunes, F, Ferreira-Rosa, K, Pereira, M dos S, et al. Acute administration of vinpocetine, a phosphodiesterase type 1 inhibitor, ameliorates hyperactivity in a mice model of fetal alcohol spectrum disorder. Drug Alcohol Depend. 2011; 119(1–2), 8187. doi: 10.1016/j.drugalcdep.2011.05.024 CrossRefGoogle Scholar
Tokunaga, S, Silvers, JM, Matthews, DB. Chronic intermittent ethanol exposure during adolescence blocks ethanol-induced inhibition of spontaneously active hippocampal pyramidal neurons. Alcohol Clin Exp Res. 2006; 30(1), 16. doi: 10.1111/j.1530-0277.2006.00020.x CrossRefGoogle ScholarPubMed
White, AM, Ghia, AJ, Levin, ED, Scott Swartzwelder, H. Binge pattern ethanol exposure in adolescent and adult rats: Differential impact on subsequent responsiveness to ethanol. Alcohol Clin Exp Res. 2000; 24(8), 12511256. doi: 10.1111/j.1530-0277.2000.tb02091.x CrossRefGoogle Scholar
Filgueiras, CC, Krahe, TE, Medina, AE. Phosphodiesterase type 1 inhibition improves learning in rats exposed to alcohol during the third trimester equivalent of human gestation. Neurosci Lett. 2010; 473(3), 202207. doi: 10.1016/j.neulet.2010.02.046 CrossRefGoogle ScholarPubMed
Eckardt, MJ, File, SE, Gessa, GL, et al. Effects of moderate alcohol consumption on the central nervous system. Alcohol Clin Exp Res. 1998; 22(5), 9981040. doi: 10.1111/j.1530-0277.1998.tb03695.x CrossRefGoogle ScholarPubMed
Clancy, B, Finlay, BL, Darlington, RB, Anand, K. Extrapolating brain development from experimental species to humans. Neurotoxicology. 2007; 28(5), 931937. doi: 10.1016/j.neuro.2007.01.014.EXTRAPOLATING CrossRefGoogle ScholarPubMed
Quinn, GE. The “ideal” management of retinopathy of prematurity. Eye. 2005; 19(10), 10441049. doi: 10.1038/sj.eye.6701960 CrossRefGoogle ScholarPubMed
Bandeira, F, Lent, R, Herculano-Houzel, S. Changing numbers of neuronal and non-neuronal cells underlie postnatal brain growth in the rat. Proc Natl Acad Sci U S A. 2009; 106(33), 1410814113. doi: 10.1073/pnas.0804650106 CrossRefGoogle ScholarPubMed
Dobbing, J, Sands, J. Comparative aspects of the brain growth spurt. Early Hum Dev. 1979; 3(1), 7983. doi: 10.1016/0378-3782(79)90022-7 CrossRefGoogle ScholarPubMed
Dwyer, JB, McQuown, SC, Leslie, FM. The dynamic effects of nicotine on the developing brain. Pharmacol Ther. 2009; 122(2), 125139. doi: 10.1038/jid.2014.371 CrossRefGoogle ScholarPubMed
Ethen, MK, Ramadhani, TA, Scheuerle, AE, et al. Alcohol consumption by women before and during pregnancy. Matern Child Heal J. 2009; 13(2), 274285. doi: 10.1007/s10995-008-0328-2 CrossRefGoogle ScholarPubMed
Gil-Mohapel, J, Boehme, F, Kainer, L, Christie, BR. Hippocampal cell loss and neurogenesis after fetal alcohol exposure: Insights from different rodent models. Brain Res Rev. 2010; 64(2), 283303. doi: 10.1016/j.brainresrev.2010.04.011 CrossRefGoogle ScholarPubMed
Olney, JW, Tenkova, T, Dikranian, K, Qin, YQ, Labruyere, J, Ikonomidou, C. Ethanol-induced apoptotic neurodegeneration in the developing C57BL/6 mouse brain. Dev Brain Res. 2002; 133(2), 115126. doi: 10.1016/S0165-3806(02)00279-1 CrossRefGoogle ScholarPubMed
Thomas, JD, Fleming, SL, Riley, EP. MK-801 can exacerbate or attenuate behavioral alterations associated with neonatal alcohol exposure in the rat, depending on the timing of administration. Alcohol Clin Exp Res. 2001; 25(5), 764773. doi: 10.1111/j.1530-0277.2001.tb02277.x CrossRefGoogle ScholarPubMed
Tzschentke, TM. Measuring reward with the conditioned place preference paradigm: A comprehensive review of drug effects, recent progress and new issues. Prog Neurobiol. 1998; 56(6), 613672. doi: 10.1016/S0301-0082(98)00060-4 CrossRefGoogle ScholarPubMed
Yararbas, G, Keser, A, Kanit, L, Pogun, S. Nicotine-induced conditioned place preference in rats: Sex differences and the role of mGluR5 receptors. Neuropharmacology. 2010; 58(2), 374382. doi: 10.1016/j.neuropharm.2009.10.001 CrossRefGoogle ScholarPubMed
Mineur, YS, Brunzell, DH, Grady, SR, et al. Localized low-level re-expression of high-affinity mesolimbic nicotinic acetylcholine receptors restores nicotine-induced locomotion but not place conditioning. Genes, Brain Behav. 2009; 8(3), 257266. doi: 10.1111/j.1601-183X.2008.00468.x CrossRefGoogle Scholar
Museo, E, Wise, RA. Sensitization of locomotion following repeated ventral tegmental injections of cytisine. Pharmacol Biochem Behav. 1994; 48(2), 521524. doi: 10.1016/0091-3057(94)90563-0 CrossRefGoogle ScholarPubMed
Abreu-Villaça, Y, Medeiros, AH, Lima, CS, Faria, FP, Filgueiras, CC, Manhães, AC. Combined exposure to nicotine and ethanol in adolescent mice differentially affects memory and learning during exposure and withdrawal. Behav Brain Res. 2007; 181(1), 136146. doi: 10.1016/j.bbr.2007.03.035 CrossRefGoogle ScholarPubMed
Slotkin, TA, Skavicus, S, Ko, A, Levin, ED, Seidler, FJ. Corrigendum to: The developmental neurotoxicity of tobacco smoke can be mimicked by a combination of nicotine and benzo[a]pyrene: Effects on cholinergic and serotonergic systems (Toxicological Sciences (2019) 167, 1 (293-304) DOI: 10.1093/toxsci/kfy241). Toxicol Sci. 2019; 168(1), 280. doi: 10.1093/toxsci/kfy304 CrossRefGoogle Scholar
Wainwright, PE. Issues of design and analysis relating to the use of multiparous species in developmental nutritional studies. J Nutr. 1998 Mar; 128(3), 661–3. doi: 10.1093/jn/128.3.661 CrossRefGoogle Scholar
Ivorra, C, García-Vicent, C, Ponce, F, Ortega-Evangelio, G, Fernández-Formoso, JA, Lurbe, E. High cotinine levels are persistent during the first days of life in newborn second hand smokers. Drug Alcohol Depend. 2014; 134(1), 275279. doi: 10.1016/j.drugalcdep.2013.10.017 CrossRefGoogle ScholarPubMed
Audrain-Mcgovern, J, Benowitz, NL. Cigarette smoking, nicotine, and body weight. Clin Pharmacol Ther. 2011; 90(1), 164168. doi: 10.1038/clpt.2011.105 CrossRefGoogle ScholarPubMed
Valdomero, A, Bussolino, DF, Orsingher, OA, Cuadra, GR. Perinatal protein malnutrition enhances rewarding cocaine properties in adult rats. Neuroscience. 2006; 137(1), 221229. doi: 10.1016/j.neuroscience.2005.08.055 CrossRefGoogle ScholarPubMed
Velazquez, EE, Valdomero, A, Orsingher, OA, Cuadra, GR. Perinatal undernutrition facilitates morphine sensitization and cross-sensitization to cocaine in adult rats: a behavioral and neurochemical study. Neuroscience. 2010; 165(2), 475484. doi: 10.1016/j.neuroscience.2009.10.061 CrossRefGoogle ScholarPubMed
Dutra-Tavares, AC, Manhães, AC, Silva, JO, et al. Locomotor response to acute nicotine in adolescent mice is altered by maternal undernutrition during lactation. Int J Dev Neurosci. 2015; 47(Pt B), 278285. doi: 10.1016/j.ijdevneu.2015.10.002 CrossRefGoogle ScholarPubMed
Goldani, MZ, Haeffner, LSB, Agranonik, M, Barbieri, MA, Bettiol, H, da Silva, AAM. Do early life factors influence body mass index in adolescents? Brazilian J Med Biol Res. 2007; 40(9), 12311236. doi: 10.1590/S0100-879X2006005000131 CrossRefGoogle ScholarPubMed
Oliveira, E, Moura, EG, Santos-Silva, AP, et al. Short- and long-term effects of maternal nicotine exposure during lactation on body adiposity, lipid profile, and thyroid function of rat offspring. J Endocrinol. 2009; 202(3), 397405. doi: 10.1677/JOE-09-0020 CrossRefGoogle Scholar
Lkhagvadorj, K, Meyer, KF, Verweij, LP, et al. Prenatal smoke exposure induces persistent Cyp2a5 methylation and increases nicotine metabolism in the liver of neonatal and adult male offspring. Epigenetics. 2020; 23, 116. doi: 10.1080/15592294.2020.1782655 Google Scholar
Ni, S, Wang, X, Wang, J, et al. Effects of intrauterine undernutrition on the expression of CYP3A23/3A1, PXR, CAR and HNF4alpha in neonate rats. Biopharm Drug Dispos. 2008; 29(9), 501510. doi: 10.1002/bdd.635 CrossRefGoogle ScholarPubMed
Soo, JY, Wiese, MD, Berry, MJ, McMillen, IC, Morrison, JL. Intrauterine growth restriction may reduce hepatic drug metabolism in the early neonatal period. Pharmacol Res. 2018; 134, 6878. doi: 10.1016/j.phrs.2018.06.003 CrossRefGoogle ScholarPubMed
Zhu, ZW, Ni, SQ, Wang, XM, Wang, J, Zeng, S, Zhao, ZY. Hepatic CYP3A expression and activity in low birth weight developing female rats. World J Pediatr. 2013; 9(3), 266272. doi: 10.1007/s12519-013-0429-x CrossRefGoogle ScholarPubMed
Benowitz, NL. Nicotine addiction. N Engl J Med. 2010; 362(24), 22952303. doi: 10.1056/NEJMra0809890 CrossRefGoogle ScholarPubMed
Ho, MK, Mwenifumbo, JC, Al Koudsi, N, et al. Association of nicotine metabolite ratio and CYP2A6 genotype with smoking cessation treatment in African-American light smokers. Clin Pharmacol Ther. 2009; 85(6), 635643. doi: 10.1038/clpt.2009.19 CrossRefGoogle ScholarPubMed
Grant, KA. Emerging neurochemical concepts in the actions of ethanol at ligand-gated ion channels. Behav Pharmacol. 1994; 5(4–5), 383404. doi: 10.1097/00008877-199408000-00003 CrossRefGoogle ScholarPubMed
Abreu-Villaça, Y, Filgueiras, CC, Manhães, AC. Developmental aspects of the cholinergic system. Behav Brain Res. 2011; 221(2), 367378. doi: 10.1016/j.bbr.2009.12.049 CrossRefGoogle ScholarPubMed
Abreu-Villaça, Y, Manhães, AC, Krahe, TE, Filgueiras, CC, Ribeiro-Carvalho, A. Tobacco and alcohol use during adolescence: Interactive mechanisms in animal models. Biochem Pharmacol. 2017; 144, 117. doi: 10.1016/j.bcp.2017.06.113 CrossRefGoogle ScholarPubMed
Levin, ED, Abreu-Villaça, Y. Developmental neurotoxicity of nicotine and tobacco. In Handbook of Developmental Neurotoxicology, Vol 1, 2nd ed., (eds. William Slikker, J, Paule, MG, Wang, C), 2018; 439452. Academic Press. doi: 10.1016/C2015-0-04830-4 CrossRefGoogle Scholar
Lotfullina, N, Khazipov, R. Ethanol and the developing brain: inhibition of neuronal activity and neuroapoptosis. Neuroscientist. 2018; 24(2), 130141. doi: 10.1177/1073858417712667 CrossRefGoogle ScholarPubMed
Carneiro, LMV, Diógenes, JPL, Vasconcelos, SMM, et al. Behavioral and neurochemical effects on rat offspring after prenatal exposure to ethanol. Neurotoxicol Teratol. 2005; 27(4), 585592. doi: 10.1016/ CrossRefGoogle ScholarPubMed
Oliff, HS, Gallardo, KA. [Frontiers in Bioscience 4, d883-897, December 1, 1999] the effect of nicotine on developing brain catecholamine systems Heather S. Oliff and Kathy A. Gallardo. Published online 1999, 883897.CrossRefGoogle Scholar
Klein, LC, Stine, MM, Pfaff, DW, Vandenbergh, DJ. Maternal nicotine exposure increases nicotine preference in periadolescent male but not female C57B1/6J mice. Nicotine Tob Res. 2003; 5(1), 117124. doi: 10.1080/14622200307257 CrossRefGoogle Scholar
Fu, Y, Matta, SG, Gao, W, Sharp, BM. Local α-bungarotoxin-sensitive nicotinic receptors in the nucleus accumbens modulate nicotine-stimulated dopamine secretion in vivo. Neuroscience. 2000; 101(2), 369375. doi: 10.1016/S0306-4522(00)00371-7 CrossRefGoogle ScholarPubMed
Blomqvist, O, Söderpalm, B, Engel, JA. Ethanol-induced locomotor activity: involvement of central nicotinic acetylcholine receptors? Brain Res Bull. 1992; 29(2), 173178. doi: 10.1016/0361-9230(92)90023-Q CrossRefGoogle ScholarPubMed
Söderpalm, B, Ericson, M, Olausson, P, Blomqvist, O, Engel, JA. Nicotinic mechanisms involved in the dopamine activating and reinforcing properties of ethanol. Behav Brain Res. 2000; 113(1–2), 8596. doi: 10.1016/S0166-4328(00)00203-5 CrossRefGoogle ScholarPubMed
Matta, SG, Elberger, AJ. Combined exposure to nicotine and ethanol throughout full gestation results in enhanced acquisition of nicotine self-administration in young adult rat offspring. Psychopharmacology (Berl). 2007; 193(2), 199213. doi: 10.1007/s00213-007-0767-2 CrossRefGoogle ScholarPubMed
Roguski, EE, Sharp, BM, Chen, H, Matta, SG. Full-gestational exposure to nicotine and ethanol augments nicotine self-administration by altering ventral tegmental dopaminergic function due to NMDA receptors in adolescent rats. J Neurochem. 2014; 128(5), 701712. doi: 10.1111/jnc.12504 CrossRefGoogle ScholarPubMed
Smith, TT, Schaff, MB, Rupprecht, LE, et al. Effects of MAO inhibition and a combination of minor alkaloids, β-carbolines, and acetaldehyde on nicotine self-administration in adult male rats. Drug Alcohol Depend. 2015; 155, 243252. doi: 10.1016/j.drugalcdep.2015.07.002 CrossRefGoogle Scholar
Papp-Peka, A, Tong, M, Kril, JJ, De La Monte, SM, Sutherland, GT. The Differential Effects of Alcohol and Nicotine-Specific Nitrosamine Ketone on White Matter Ultrastructure. Alcohol Alcohol. 2017; 52(2), 165171. doi: 10.1093/alcalc/agw067 Google ScholarPubMed
Zabala, V, Silbermann, E, Re, E, et al. Potential co-factor role of tobacco specific nitrosamine exposures in the pathogenesis of fetal alcohol spectrum disorder. Gynecol Obstet Res. 2016; 2(5), 112125. doi: 10.17140/GOROJ-2-125 Google ScholarPubMed
Cross, SJ, Linker, KE, Leslie, FM. Sex dependent effects of nicotine on the developing brain. J Neurosci Res. 2017; 95(1–2), 422436. doi: 10.1002/jnr.23878 CrossRefGoogle ScholarPubMed
Valera, S, Ballivet, M, Bertrand, D. Progesterone modulates a neuronal nicotinic acetylcholine receptor. Proc Natl Acad Sci U S A. 1992; 89(20), 99499953. doi: 10.1073/pnas.89.20.9949 CrossRefGoogle ScholarPubMed
Romero-grimaldi, C, Moreno-lo, B. Age-dependent effect of Nitric Oxide on Subventricular Zone and Olfactory Bulb. J Comp Neurol. 2008; 346(October 2007), 339346. doi: 10.1002/cne CrossRefGoogle Scholar
Barbieri, RL, Gochberg, J, Ryan, KJ. Nicotine, cotinine, and anabasine inhibit aromatase in human trophoblast in vitro. J Clin Invest. 1986; 77(6), 17271733. doi: 10.1172/JCI112494 CrossRefGoogle ScholarPubMed
von Ziegler, NI, Schlumpf, M, Lichtensteiger, W. Prenatal nicotine exposure selectively affects perinatal forebrain aromatase activity and fetal adrenal function in male rats. Dev Brain Res. 1991; 62(1), 2331. doi: 10.1016/0165-3806(91)90186-M CrossRefGoogle ScholarPubMed
Sarasin, A, Schlumpf, M, Müller, M, Fleischmann, I, Lauber, ME, Lichtensteiger, W. Adrenal-mediated rather than direct effects of nicotine as a basis of altered sex steroid synthesis in fetal and neonatal rat. Reprod Toxicol. 2003; 17(2), 153162. doi: 10.1016/S0890-6238(02)00119-3 CrossRefGoogle ScholarPubMed
Comeau, WL, Lee, K, Anderson, K, Weinberg, J. Prenatal alcohol exposure and adolescent stress increase sensitivity to stress and gonadal hormone influences on cognition in adult female rats. Physiol Behav. 2015; 148, 157165. doi: 10.1016/j.physbeh.2015.02.033 CrossRefGoogle ScholarPubMed
Marques, AA, Bevilaqua, MC, da Fonseca, AM, Nardi, AE, Thuret, S, Dias, GP. Gender differences in the neurobiology of anxiety: focus on adult hippocampal neurogenesis. Neural Plast. 2016; 2016, 5026713. doi: 10.1155/2016/5026713 CrossRefGoogle ScholarPubMed
Songtachalert, T, Roomruangwong, C, Carvalho, AF, Bourin, M, Maes, M. Anxiety disorders: sex differences in serotonin and tryptophan metabolism. Curr Top Med Chem. 2018; 18(19), 17041715. doi: 10.2174/1568026618666181115093136 CrossRefGoogle ScholarPubMed
Supplementary material: PDF

Nunes-Freitas et al. supplementary material

Nunes-Freitas et al. supplementary material

Download Nunes-Freitas et al. supplementary material(PDF)

Save article to Kindle

To save this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the or variations. ‘’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Sex- and age-dependent differences in nicotine susceptibility evoked by developmental exposure to tobacco smoke and/or ethanol in mice
Available formats

Save article to Dropbox

To save this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you used this feature, you will be asked to authorise Cambridge Core to connect with your Dropbox account. Find out more about saving content to Dropbox.

Sex- and age-dependent differences in nicotine susceptibility evoked by developmental exposure to tobacco smoke and/or ethanol in mice
Available formats

Save article to Google Drive

To save this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you used this feature, you will be asked to authorise Cambridge Core to connect with your Google Drive account. Find out more about saving content to Google Drive.

Sex- and age-dependent differences in nicotine susceptibility evoked by developmental exposure to tobacco smoke and/or ethanol in mice
Available formats

Reply to: Submit a response

Please enter your response.

Your details

Please enter a valid email address.

Conflicting interests