Abstract
Rationale
Consistent sex differences are observed in human drug addiction, with females often exceeding males on drug intake. However, there is still a need for animal models for some aspects of addiction such as acquisition of drug self-administration and the subsequent development of drug-seeking.
Objectives
The present study examined sex differences in the acquisition and maintenance of self-administration of two widely used stimulants, cocaine and nicotine.
Methods
Male and female rats self-administered cocaine (0.4 mg/kg/infusion) or nicotine (0.03 mg/kg/infusion) daily under a fixed-ratio 1 (FR 1) schedule until acquisition criteria were met (maximum of 30 sessions). The self-administration criterion for cocaine was ≥20 infusions in a 2-h session and ≥5 infusions in a 1-h session for nicotine. Sex differences were assessed by examining the percentage of rats that met acquisition criteria, the number of sessions to meet criteria, and the number of infusions earned during the maintenance phase.
Results
A significantly higher percentage of male rats acquired both cocaine and nicotine self-administration than females, and males met acquisition criteria in fewer sessions. However, after criteria were met, females self-administered more cocaine than males during the first 5 days of maintenance. There were no sex differences in nicotine infusions post-acquisition.
Conclusions
Differences in acquisition amongst sexes can reveal factors that are integral to initiation of drug use, an often overlooked phase of drug addiction.
Similar content being viewed by others
References
Alexander BK, Coambs RB, Hadaway PF (1978) The effect of housing and gender on morphine self-administration in rats. Psychopharmacology (Berl) 58(2):175–179
Anker JJ, Carroll ME (2010) The role of progestins in the behavioral effects of cocaine and other drugs of abuse: human and animal research. Neurosci Biobehav Rev 35(2):315–333
Anker JJ, Carroll ME (2011) Females are more vulnerable to drug abuse than males: evidence from preclinical studies and the role of ovarian hormones. In Biological Basis of Sex Differences in Psychopharmacology: pp. 73–96. Springer Berlin Heidelberg
Anker JJ, Larson EB, Gliddon LA, Carroll ME (2007) Effects of progesterone on the reinstatement of cocaine-seeking behavior in female rats. Exp Clin Psychopharmacol 15(5):472
Anker JJ, Zlebnik NE, Navin SF, Carroll ME (2011) Responding during signaled availability and nonavailability of iv cocaine and food in rats: age and sex differences. Psychopharmacology (Berl) 215(4):785–799
Becker JB, Hu M (2008) Sex differences in drug abuse. Front Neuroendocrinol 29(1):36–47
Becker JB, Perry AN, Westenbroek C (2012) Sex differences in the neural mechanisms mediating addiction: a new synthesis and hypothesis. Biol Sex Differ 3(1):1–35
Caine SB, Bowen CA, Yu G, Zuzga D, Negus SS, Mello NK (2004) Effect of gonadectomy and gonadal hormone replacement on cocaine self-administration in female and male rats. Neuropsychopharmacol 29(5):929–42
Campbell UC, Morgan AD, Carroll ME (2002) Sex differences in the effects of baclofen on the acquisition of intravenous cocaine self-administration in rats. Drug Alcohol Depend 66(1):61–69
Carroll ME, Anker JJ (2010) Sex differences and ovarian hormones in animal models of drug dependence. Horm Behav 58(1):44–56
Carroll ME, Meisch RA (2011) Acquisition of drug self-administration. In Animal Models of Drug Addiction pp. 237–265. Humana Press
Carroll ME, Morgan AD, Lynch WJ, Campbell UC, Dess NK (2002) Intravenous cocaine and heroin self-administration in rats selectively bred for differential saccharin intake: phenotype and sex differences. Psychopharmacology (Berl) 161(3):304–313
Cason AM, Grigson PS (2013) Prior access to a sweet is more protective against cocaine self-administration in female rats than in male rats. Physiol Behav 112:96–103
Chambers RA, Taylor JR, Potenza MN (2014) Developmental neurocircuitry of motivation in adolescence: a critical period of addiction vulnerability. Am J Psychiatry 160(6):1041–52
Chaudhri N, Caggiula AR, Donny EC, Booth S, Gharib MA, Craven LA, Sved AF, Perkins KA (2005) Sex differences in the contribution of nicotine and nonpharmacological stimuli to nicotine self-administration in rats. Psychopharmacology (Berl) 180(2):258–266
Cicero TJ, Aylward SC, Meyer ER (2003) Gender differences in the intravenous self-administration of mu opiate agonists. Pharmacol Biochem Behav 74(3):541–549
Clemens KJ, Caillé S, Cador M (2010) The effects of response operandum and prior food training on intravenous nicotine self-administration in rats. Psychopharmacology (Berl) 211(1):43–54
Cosgrove KP, Hunter RG, Carroll ME (2002) Wheel-running attenuates intravenous cocaine self-administration in rats: sex differences. Pharmacol Biochem Behav 73(3):663–671
Cummings JA, Gowl BA, Westenbroek C, Clinton SM, Akil H, Becker JB (2011) Effects of a selectively bred novelty-seeking phenotype on the motivation to take cocaine in male and female rats. Biol Sex Differ 2(3)
DeVito EE, Herman AI, Waters AJ, Valentine GW, Sofuoglu M (2014) Subjective, physiological, and cognitive responses to intravenous nicotine: effects of sex and menstrual cycle phase. Neuropsychopharmacol 39(6):1431–1440
DiFranza JR, Savageau JA, Rigotti NA, Fletcher K, Ockene JK, McNeill AD, Coleman M, Wood C (2002) Development of symptoms of tobacco dependence in youths: 30 month follow up data from the DANDY study. Tob Control 11(3):228–235
Donny EC, Caggiula AR, Rowell PP, Gharib MA, Maldovan V, Booth S, Mielke MM, Hoffman A, McCallum S (2000) Nicotine self-administration in rats: estrous cycle effects, sex differences and nicotinic receptor binding. Psychopharmacology (Berl) 151(4):392–405
Donny EC, Chaudhri N, Caggiula AR, Evans-Martin FF, Booth S, Gharib MA, Sved AF (2003) Operant responding for a visual reinforcer in rats is enhanced by noncontingent nicotine: implications for nicotine self-administration and reinforcement. Psychopharmacology (Berl) 169(1):68–76
Evans SM, Haney M, Foltin RW (2002) The effects of smoked cocaine during the follicular and luteal phases of the menstrual cycle in women. Psychopharmacology (Berl) 159(4):397–406
Fattore L, Spano MS, Altea S, Angius F, Fadda P, Fratta W (2007) Cannabinoid self‐administration in rats: sex differences and the influence of ovarian function. Brit J Pharmacol 152(5):795–804
Fattore L, Altea S, Fratta W (2008) Sex differences in drug addiction: a review of animal and human studies. Womens Health 4:51–65
Fattore L, Fadda P, Fratta W (2009) Sex differences in the self-administration of cannabinoids and other drugs of abuse. Psychoneuroendocrinol 34:227–236
Fattore L, Melis M, Fadda P, Fratta W (2014) Sex differences in addictive disorders. Front Neuroendocrinol 35(3):272–284
Feltenstein MW, Ghee SM, See RE (2012) Nicotine self-administration and reinstatement of nicotine-seeking in male and female rats. Drug Alcohol Depend 121(3):240–246
Fuchs RA, Evans KA, Mehta RH, Case JM, See RE (2005) Influence of sex and estrous cyclicity on conditioned cue-induced reinstatement of cocaine-seeking behavior in rats. Psychopharmacology (Berl) 179(3):662–672
Grebenstein P, Burroughs D, Zhang Y, LeSage MG (2013) Sex differences in nicotine self-administration in rats during progressive unit dose reduction: implications for nicotine regulation policy. Pharmacol Biochem Behav 114:70–81
Haas AL, Peters RH (2000) Development of substance abuse problems among drug-involved offenders: evidence for the telescoping effect. J Subst Abuse 12(3):241–253
Hadaway PF, Alexander BK, Coambs RB, Beyerstein B (1979) The effect of housing and gender on preference for morphine-sucrose solutions in rats. Psychopharmacology (Berl) 66(1):87–91
Harris AC, Burroughs D, Pentel PR, LeSage MG (2008) Compensatory nicotine self-administration in rats during reduced access to nicotine: an animal model of smoking reduction. Exp Clin Psychopharmacol 16(1):86
Heppner CC, Kemble ED, Cox WM (1986) Effects of food deprivation on caffeine consumption in male and female rats. Pharmacol Biochem Behav 24(6):1555–1559
Hu M, Crombag HS, Robinson TE, Becker JB (2004) Biological basis of sex differences in the propensity to self-administer cocaine. Neuropsychopharmacol 29(1):81–85
Jackson LR, Robinson TE, Becker JB (2006) Sex differences and hormonal influences on acquisition of cocaine self-administration in rats. Neuropsychopharmacol 31(1):129–138
Jarvis MJ, Cohen JE, Delnevo CD, Giovino GA (2013) Dispelling myths about gender differences in smoking cessation: population data from the USA, Canada and Britain. Tob Control 22(5):356–360
Klein LC, Popke EJ, Grunberg NE (1997) Sex differences in effects of predictable and unpredictable footshock on fentanyl self-administration in rats. Exp Clin Psychopharmacol 5(2):99
Kosten TA, Zhang XY (2008) Sex differences in non-reinforced responding for cocaine. Am J Drug Alcohol Abuse 34(4):473–488
Kosten TA, Gawin FH, Kosten TR, Rounsaville BJ (1993) Gender differences in cocaine use and treatment response. J Subst Abuse Treat 10(1):63–66
Kosten TA, Sanchez H, Zhang XY, Kehoe P (2004) Neonatal isolation enhances acquisition of cocaine self-administration and food responding in female rats. Behav Brain Res 151(1):137–149
Lancaster FE, Spiegel KS (1992) Sex differences in pattern of drinking. Alcohol 9(5):415–420
Lozano OM, Domingo-Salvany A, Martinez-Alonso M, Brugal MT, Alonso J, de la Fuente L, ITINERE Investigators (2008) Health-related quality of life in young cocaine users and associated factors. Qual Life Res 17(7):977–985
Lynch WJ (2008) Acquisition and maintenance of cocaine self-administration in adolescent rats: effects of sex and gonadal hormones. Psychopharmacology (Berl) 197(2):237–246
Lynch WJ (2009) Sex and ovarian hormones influence vulnerability and motivation for nicotine during adolescence in rats. Pharmacol Biochem Behav 94(1):43–50
Lynch WJ, Carroll ME (1999) Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats. Psychopharmacology (Berl) 144(1):77–82
Lynch WJ, Arizzi MN, Carroll ME (2000) Effects of sex and the estrous cycle on regulation of intravenously self-administered cocaine in rats. Psychopharmacology (Berl) 152(2):132–139
Lynch WJ, Roth ME, Carroll ME (2002) Biological basis of sex differences in drug abuse: preclinical and clinical studies. Psychopharmacology (Berl) 164(2):121–137
McCance‐Katz EF, Carroll KM, Rounsaville BJ (1999) Gender differences in treatment‐seeking cocaine abusers—implications for treatment and prognosis. Am J Addict 8(4):300–311
Morse AC, Erwin VG, Jones BC (1993) Strain and housing affect cocaine self-selection and open-field locomotor activity in mice. Pharmacol Biochem Behav 45(4):905–912
National Research Council (2011) Guidelines for the Care and Use of Laboratory Animals, 8th edn. The National Academic Press, Washington, DC
Perkins KA (2001) Smoking cessation in women. CNS Drugs 15(5):391–411
Perkins KA (2009) Sex differences in nicotine reinforcement and reward: influences on the persistence of tobacco smoking. In The motivational impact of nicotine and its role in tobacco use. Springer US 143–169
Perry AN, Westenbroek C, Becker JB (2013) Impact of pubertal and adult estradiol treatments on cocaine self-administration. Horm Behav 64(4):573–578
Peterson AB, Hivick DP, Lynch WJ (2014) Dose-dependent effectiveness of wheel running to attenuate cocaine-seeking: impact of sex and estrous cycle in rats. Psychopharmacology (Berl) 31(13):2661–2670
Pogun S, Yararbas G (2009) Sex differences in nicotine action. In: Nicotine Psychopharmacology. Springer, Berlin, pp 261–291
Quinones-Jenab V, Jenab S (2012) Influence of sex differences and gonadal hormones on cocaine addiction. ILAR J 53(1):14–22
Rezvani AH, Eddins D, Slade S, Hampton DS, Christopher NC, Petro A, Horton K, Johnson M, Levin ED (2008) Neonatal 6-hydroxydopamine lesions of the frontal cortex in rats: persisting effects on locomotor activity, learning and nicotine self-administration. Neuroscience 154(3):885–897
Roberts DCS, Bennett S, Vickers GJ (1989) The estrous cycle affects cocaine self-administration on a progressive ratio schedule in rats. Psychopharmacology (Berl) 98(3):408–411
Roth ME, Carroll ME (2004) Sex differences in the acquisition of IV methamphetamine self-administration and subsequent maintenance under a progressive ratio schedule in rats. Psychopharmacology (Berl) 172(4):443–449
Sartor CE, Kranzler HR, Gelernter J (2014) Rate of progression from first use to dependence on cocaine or opioids: a cross-substance examination of associated demographic, psychiatric, and childhood risk factors. Addict Behav 39(2):473–479
Smith PH, Kasza KA, Hyland A, Fong GT, Borland R, Brady K, Carpenter MJ, Hartwell K, Cummings KM, McKee SA (2015) Gender differences in medication use and cigarette smoking cessation: results from the International Tobacco Control Four Country Survey. Nicotine Tob Res 17(4):463–472
Waldron I (1991) Patterns and causes of gender differences in smoking. Soc Sci Med 32(9):989–1005
Westenbroek C, Perry AN, Becker JB (2013) Pair housing differentially affects motivation to self-administer cocaine in male and female rats. Behav Brain Res 252:68–71
Acknowledgments
The authors are grateful to Dr. Natalie Zlebnik and Heather Veglahn for their assistance with data collection. This study was supported by NIH/NIDA P50 DA033942 (MEC) and NIDA training grant T32 DA007097 (JRS; Dr. Thomas Molitor, PI).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Compliance with ethical standards
All experiments were approved by the Institutional Animal Care and Use Committee (Protocol #1307-30762A), and the research was conducted in accordance with the Principles of Laboratory Animal Care.
Rights and permissions
About this article
Cite this article
Swalve, N., Smethells, J.R. & Carroll, M.E. Sex differences in the acquisition and maintenance of cocaine and nicotine self-administration in rats. Psychopharmacology 233, 1005–1013 (2016). https://doi.org/10.1007/s00213-015-4183-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-015-4183-8