Abstract
This study assessed the role of stress systems in the nucleus accumbens (NAc) in promoting sex differences in the reinforcing effects of nicotine. Intravenous self-administration (IVSA) of various doses of nicotine was compared following overexpression of corticotropin-releasing factor (CRF) in the NAc of female and male rats. Ovariectomized (OVX) females were also included to assess the role of ovarian hormones in promoting nicotine reinforcement. Rats received intra-NAc administration of an adeno-associated vector that overexpressed CRF (AAV2/5-CRF) or green fluorescent protein (AAV2/5-GFP). All rats were then given extended access (23 h/day) to an inactive and an active lever that delivered nicotine. Separate groups of rats received intra-NAc AAV2/5-CRF and saline IVSA. Rats were also allowed to nose-poke for food and water during IVSA testing. At the end of the study, the NAc was dissected and rt-qPCR methods were used to estimate CRF overexpression and changes in CRF receptors (CRFr1, CRFr2) and the CRF receptor internalizing protein, β-arrestin2 (Arrb2). Overexpression of CRF in the NAc increased nicotine IVSA to a larger extent in intact female versus male and OVX females. Food intake was increased to a larger extent in intact and OVX females as compared to males. The increase in CRF gene expression was similar across all groups; however, in females, overexpression of CRF resulted in a larger increase in CRFr1 and CRFr2 relative to males. In males, overexpression of CRF produced a larger increase in Arrb2 than females, suggesting greater CRF receptor internalization. Our results suggest that stress systems in the NAc promote the reinforcing effectiveness of nicotine in female rats in an ovarian hormone-dependent manner.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Samet JM. Tobacco smoking: the leading cause of preventable disease worldwide. Thorac Surg Clin. 2013;23:103–12.
Perkins KA, Donny E, Caggiula AR. Sex differences in nicotine effects and self-administration: review of human and animal evidence. Nicotine Tob Res. 1999;1:301–15.
Perkins KA, Giedgowd GE, Karelitz JL, Conklin CA, Lerman C. Smoking in response to negative mood in men versus women as a function of distress tolerance. Nicotine Tob Res. 2012;14:1418–25.
Perkins KA, Karelitz JL, Giedgowd GE, Conklin CA. Negative mood effects on craving to smoke in women versus men. Addict Behav. 2013;38:1527–31.
Mykletun A, Overland S, Aaro LE, Liabo HM, Stewart R. Smoking in relation to anxiety and depression: evidence from a large population survey: the HUNT study. Eur Psychiatry. 2008;23:77–84.
Brook JS, Zhang C, Brook DW, Koppel J, Whiteman M. Psychosocial predictors of nicotine dependence among women during their mid-sixties. Am J Addict. 2012;21:302–12.
Dedert EA, Calhoun PS, Harper LA, Dutton CE, McClernon FJ, Beckham JC. Smoking withdrawal in smokers with and without posttraumatic stress disorder. Nicotine Tob Res. 2012;14:372–6.
Langdon KJ, Leventhal AM. Posttraumatic stress symptoms and tobacco abstinence effects in a non-clinical sample: evaluating the mediating role of negative affect reduction smoking expectancies. J Psychopharmacol. 2014;28:1009–17.
Childs E, de Wit H. Hormonal, cardiovascular, and subjective responses to acute stress in smokers. Psychopharmacol (Berl). 2009;203:1–12.
Feltenstein MW, Ghee SM, See RE. Nicotine self-administration and reinstatement of nicotine-seeking in male and female rats. Drug Alcohol Depend. 2012;121:240–6.
Buczek Y, Le AD, Wang A, Stewart J, Shaham Y. Stress reinstates nicotine seeking but not sucrose solution seeking in rats. Psychopharmacol (Berl). 1999;144:183–8.
Leao RM, Cruz FC, Planeta CS. Exposure to acute restraint stress reinstates nicotine-induced place preference in rats. Behav Pharmacol. 2009;20:109–13.
Zislis G, Desai TV, Prado M, Shah HP, Bruijnzeel AW. Effects of the CRF receptor antagonist D-Phe CRF(12-41) and the alpha2-adrenergic receptor agonist clonidine on stress-induced reinstatement of nicotine-seeking behavior in rats. Neuropharmacology. 2007;53:958–66.
Bruijnzeel AW, Prado M, Isaac S. Corticotropin-releasing factor-1 receptor activation mediates nicotine withdrawal-induced deficit in brain reward function and stress-induced relapse. Biol Psychiatry. 2009;66:110–7.
Swanson LW, Sawchenko PE, Rivier J, Vale WW. Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study. Neuroendocrinology. 1983;36:165–86.
Albrechet-Souza L, Hwa LS, Han X, Zhang EY, DeBold JF, Miczek KA. Corticotropin releasing factor binding protein and CRF2 receptors in the ventral tegmental area: modulation of ethanol binge drinking in C57BL/6J mice. Alcohol Clin Exp Res. 2015;39:1609–18.
Lemos JC, Wanat MJ, Smith JS, Reyes BA, Hollon NG, Van Bockstaele EJ, et al. Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive. Nature. 2012;490:402–6.
Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. 7th ed. Cambridge, MA: Academic Press; 2013.
Qi X, Shan Z, Ji Y, Guerra V, Alexander JC, Ormerod BK, et al. Sustained AAV-mediated overexpression of CRF in the central amygdala diminishes the depressive-like state associated with nicotine withdrawal. Transl Psychiatry. 2014;4:e385.
Natividad LA, Torres OV, Friedman TC, O’Dell LE. Adolescence is a period of development characterized by short- and long-term vulnerability to the rewarding effects of nicotine and reduced sensitivity to the anorectic effects of this drug. Behav Brain Res. 2013;257:275–85.
Chen SA, O’Dell LE, Hoefer ME, Greenwell TN, Zorrilla EP, Koob GF. Unlimited access to heroin self-administration: independent motivational markers of opiate dependence. Neuropsychopharmacology. 2006;31:2692–707.
Sidhu KS. Basis for body weight exponent (0.75) as a scaling factor in energy metabolism and risk assessment. J Appl Toxicol. 1992;12:309–10.
Torres OV, Gentil LG, Natividad LA, Carcoba LM, O’Dell LE. Behavioral, biochemical, and molecular indices of stress are enhanced in female versus male rats experiencing nicotine withdrawal. Front Psychiatry. 2013;4:38.
Khan AM, Walker EM, Dominguez N, Watts AG. Neural input is critical for arcuate hypothalamic neurons to mount intracellular signaling responses to glycemic challenges in male rats: implications for communication within feeding and metabolic control networks. Endocrinology. 2014;155:405–16.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–8.
Sierra-Fonseca JA, Najera O, Martinez-Jurado J, Walker EM, Varela-Ramirez A, Khan AM, et al. Nerve growth factor induces neurite outgrowth of PC12 cells by promoting Gbetagamma-microtubule interaction. BMC Neurosci. 2014;15:132.
Donny EC, Caggiula AR, Mielke MM, Booth S, Gharib MA, Hoffman A, et al. Nicotine self-administration in rats on a progressive ratio schedule of reinforcement. Psychopharmacol (Berl). 1999;147:135–42.
Chaudhri N, Caggiula AR, Donny EC, Booth S, Gharib MA, Craven LA, et al. Sex differences in the contribution of nicotine and nonpharmacological stimuli to nicotine self-administration in rats. Psychopharmacol (Berl). 2005;180:258–66.
Rezvani AH, Eddins D, Slade S, Hampton DS, Christopher NC, Petro A, et al. Neonatal 6-hydroxydopamine lesions of the frontal cortex in rats: persisting effects on locomotor activity, learning and nicotine self-administration. Neuroscience. 2008;154:885–97.
Sanchez V, Moore CF, Brunzell DH, Lynch WJ. Sex differences in the effect of wheel running on subsequent nicotine-seeking in a rat adolescent-onset self-administration model. Psychopharmacol (Berl). 2014;231:1753–62.
Pittenger ST, Swalve N, Chou S, Smith MD, Hoonakker AJ, Pudiak CM, et al. Sex differences in neurotensin and substance P following nicotine self-administration in rats. Synapse. 2016;70:336–46.
Swalve N, Smethells JR, Carroll ME. Sex differences in the acquisition and maintenance of cocaine and nicotine self-administration in rats. Psychopharmacol (Berl). 2016;233:1005–13.
O’Dell LE, Chen SA, Smith RT, Specio SE, Balster RL, Paterson NE, et al. Extended access to nicotine self-administration leads to dependence: Circadian measures, withdrawal measures, and extinction behavior in rats. J Pharm Exp Ther. 2007;320:180–93.
Flores RJ, Uribe KP, Swalve N, O’Dell LE. Sex differences in nicotine intravenous self-administration: a meta-analytic review. Physiol Behav. 2019;203:42–50.
O’Dell LE, Koob GF. ‘Nicotine deprivation effect’ in rats with intermittent 23-hour access to intravenous nicotine self-administration. Pharm Biochem Behav. 2007;86:346–53.
Cohen A, Treweek J, Edwards S, Leao RM, Schulteis G, Koob GF, et al. Extended access to nicotine leads to a CRF1 receptor dependent increase in anxiety-like behavior and hyperalgesia in rats. Addict Biol. 2015;20:56–68.
Flores RJ, Pipkin JA, Uribe KP, Perez A, O’Dell LE. Estradiol promotes the rewarding effects of nicotine in female rats. Behav Brain Res. 2016;307:258–63.
Torres OV, Natividad LA, Tejeda HA, Van Weelden SA, O’Dell LE. Female rats display dose-dependent differences to the rewarding and aversive effects of nicotine in an age-, hormone-, and sex-dependent manner. Psychopharmacol (Berl). 2009;206:303–12.
Flores RJ, Cruz B, Uribe KP, Carcoba LM, O’Dell LE. Sex differences and the role of ovarian hormones in modulating the behavioral effects of nicotine in rodent models. In: Becker JB, Tollkuhn J, editors. Sex differences in the brain: balancing sex in preclinical research. Washington, DC: Society of Neuroscience; 2018. p. 59–67.
Pecina S, Schulkin J, Berridge KC. Nucleus accumbens corticotropin-releasing factor increases cue-triggered motivation for sucrose reward: paradoxical positive incentive effects in stress? BMC Biol. 2006;4:8.
Torres OV, Pipkin JA, Ferree P, Carcoba LM, O’Dell LE. Nicotine withdrawal increases stress-associated genes in the nucleus accumbens of female rats in a hormone-dependent manner. Nicotine Tob Res. 2015;17:422–30.
Salamone JD, Correa M, Farrar A, Mingote SM. Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits. Psychopharmacol (Berl). 2007;191:461–82.
Nicola SM. Reassessing wanting and liking in the study of mesolimbic influence on food intake. Am J Physiol Regul Integr Comp Physiol. 2016;311:R811–40.
Volkow ND, O’Brien CP. Issues for DSM-V: should obesity be included as a brain disorder? Am J Psychiatry. 2007;164:708–10.
Volkow ND, Wang GJ, Tomasi D, Baler RD. Obesity and addiction: neurobiological overlaps. Obes Rev. 2013;14:2–18.
Nair SG, Gray SM, Ghitza UE. Role of food type in yohimbine- and pellet-priming-induced reinstatement of food seeking. Physiol Behav. 2006;88:559–66.
Schepers ST, Bouton ME. Stress as a context: stress causes relapse of inhibited food seeking if it has been associated with prior food seeking. Appetite. 2019;132:131–8.
Reed SJ, Lafferty CK, Mendoza JA, Yang AK, Davidson TJ, Grosenick L, et al. Coordinated reductions in excitatory input to the nucleus accumbens underlie food consumption. Neuron. 2018;99:1260–73 e1264.
Bangasser DA, Curtis A, Reyes BA, Bethea TT, Parastatidis I, Ischiropoulos H, et al. Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology. Mol Psychiatry. 2010;15:896–904.
Valentino RJ, Bangasser D, Van Bockstaele EJ. Sex-biased stress signaling: the corticotropin-releasing factor receptor as a model. Mol Pharmacol. 2013;83:737–45.
Valentino RJ, Van Bockstaele E, Bangasser D. Sex-specific cell signaling: the corticotropin-releasing factor receptor model. Trends Pharm Sci. 2013;34:437–44.
Hauger RL, Risbrough V, Oakley RH, Olivares-Reyes JA, Dautzenberg FM. Role of CRF receptor signaling in stress vulnerability, anxiety, and depression. Ann N Y Acad Sci. 2009;1179:120–43.
Bangasser DA, Dong H, Carroll J, Plona Z, Ding H, Rodriguez L, et al. Corticotropin-releasing factor overexpression gives rise to sex differences in Alzheimer’s disease-related signaling. Mol Psychiatry. 2017;22:1126–33.
Lal S, Allan A, Markovic D, Walker R, Macartney J, Europe-Finner N, et al. Estrogen alters the splicing of type 1 corticotropin-releasing hormone receptor in breast cancer cells. Sci Signal. 2013;6:ra53.
Becker JB, Hu M. Sex differences in drug abuse. Front Neuroendocrinol. 2008;29:36–47.
Becker JB, Perry AN, Westenbroek C. Sex differences in the neural mechanisms mediating addiction: a new synthesis and hypothesis. Biol Sex Differ. 2012;3:14.
Mermelstein PG, Becker JB, Surmeier DJ. Estradiol reduces calcium currents in rat neostriatal neurons via a membrane receptor. J Neurosci. 1996;16:595–604.
Hu M, Watson CJ, Kennedy RT, Becker JB. Estradiol attenuates the K+-induced increase in extracellular GABA in rat striatum. Synapse. 2006;59:122–4.
Pogun S. Sex differences in brain and behavior: emphasis on nicotine, nitric oxide and place learning. Int J Psychophysiol. 2001;42:195–208.
Qi X, Guzhva L, Yang Z, Febo M, Shan Z, Wang KKW, et al. Overexpression of CRF in the BNST diminishes dysphoria but not anxiety-like behavior in nicotine withdrawing rats. Eur Neuropsychopharmacol. 2016;26:1378–89.
Tobiansky DJ, Will RG, Lominac KD, Turner JM, Hattori T, Krishnan K, et al. Estradiol in the preoptic area regulates the dopaminergic response to cocaine in the nucleus accumbens. Neuropsychopharmacol. 2016;41:1897–906.
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Uribe, K.P., Correa, V.L., Pinales, B.E. et al. Overexpression of corticotropin-releasing factor in the nucleus accumbens enhances the reinforcing effects of nicotine in intact female versus male and ovariectomized female rats. Neuropsychopharmacol. 45, 394–403 (2020). https://doi.org/10.1038/s41386-019-0543-0
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41386-019-0543-0
