Preclinical studies indicate that gonadal hormones are important determinants of drug self-administration. To date, little is known about the influence of sex and estrous cycle on drug self-administration in ecologically relevant social contexts.
The objective of this study was to examine the role of sex and estrous cycle in a rat model during cocaine and heroin self-administration with male-female and female-female social dyads.
Male and female virgin rats were trained to self-administer cocaine and heroin in operant conditioning chambers that permitted two rats to self-administer concurrently, but prevented physical contact. Experiment 1 examined cocaine self-administration on a progressive ratio schedule in male-female dyads. Experiments 2 and 3 examined heroin self-administration on a fixed ratio schedule in male-female dyads at constant and varying doses, respectively. Experiment 4 examined heroin self-administration in female-female dyads on a fixed ratio schedule.
Cocaine-maintained breakpoints increased by ∼17 % in females during estrus, but remained consistent in males. Heroin self-administration decreased by ∼70 % during proestrus in females whether they were isolated, housed with males, or housed with females. Heroin self-administration was lower in males than females under some conditions and was not consistently associated with the responding of females.
Cocaine and heroin self-administration is influenced by the estrous cycle in females when in the presence of a male partner. As a novel finding, these data illustrate that heroin self-administration is reduced in females during proestrus regardless of the social context tested. Finally, these data suggest that drug self-administration in males is only minimally influenced by the hormonal status of a female partner.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Anglin MD, Hser YI, McGlothlin WH (1987) Sex differences in addict careers. 2. Becoming addicted. Am J Drug Alcohol Abuse 13:59–71
Anker JJ, Carroll ME (2010) Sex differences in the effects of allopregnanolone on yohimbine-induced reinstatement of cocaine seeking in rats. Drug Alcohol Depend 107:264–267
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 15:472–480
Anker JJ, Holtz NA, Zlebnik N, Carroll ME (2009) Effects of allopregnanolone on the reinstatement of cocaine-seeking behavior in male and female rats. Psychopharmacology (Berl) 203:63–72
Anker JJ, Zlebnik NE, Carroll ME (2010) Differential effects of allopregnanolone on the escalation of cocaine self-administration and sucrose intake in female rats. Psychopharmacology (Berl) 212:419–429
Arnold JM, Roberts DC (1997) A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement. Pharmacol Biochem Behav 57:441–447
Becker JB, Arnold AP, Berkley KJ, Blaustein JD, Eckel LA, Hampson E, Herman JP, Marts S, Sadee W, Steiner M, Taylor J, Young E (2005) Strategies and methods for research on sex differences in brain and behavior. Endocrinology 146:1650–1673
Bot SM, Engels RC, Knibbe RA, Meeus WH (2005) Friend’s drinking behaviour and adolescent alcohol consumption: the moderating role of friendship characteristics. Addict Behav 30:929–947
Brady KT, Randall CL (1999) Gender differences in substance use disorders. Psychiatr Clin North Am 22:241–252
Brady KT, Back SE, Greenfield SF (2009) Women and addiction: a comprehensive handbook. Guilford Publications, New York
Butcher RL, Collins WE, Fugo NW (1974) Plasma concentration of LH, FSH, prolactin, progesterone and estradiol-17beta throughout the 4-day estrous cycle of the rat. Endocrinology 94:1704–1708
Caggiula AR, Donny EC, White AR, Chaudhri N, Booth S, Gharib MA, Hoffman A, Perkins KA, Sved AF (2002) Environmental stimuli promote the acquisition of nicotine self-administration in rats. Psychopharmacology (Berl) 163:230–237
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. Neuropsychopharmacology 29:929–942
Campbell UC, Carroll ME (2000) Acquisition of drug self-administration: environmental and pharmacological interventions. Exp Clin Psychopharmacol 8:312–325
Carroll ME, Smethells JR (2015) Sex differences in behavioral dyscontrol: role in drug addiction and novel treatments. Front Psychiatry 6:175
Carroll ME, Lynch WJ, Roth ME, Morgan AD, Cosgrove KP (2004) Sex and estrogen influence drug abuse. Trends Pharmacol Sci 25:273–279
Center for Behavioral Health Statistics and Quality (2015) 2014 National Survey on Drug Use and Health. Substance Abuse and Mental Health Services Administration. Rockville, MD
Cicero TJ, Aylward SC, Meyer ER (2003) Gender differences in the intravenous self-administration of mu opiate agonists. Pharmacol Biochem Behav 74:541–549
Clayton JA, Collins FS (2014) Policy: NIH to balance sex in cell and animal studies. Nature 509:282–283
Cooper ZD, Truong YN, Shi YG, Woods JH (2008) Morphine deprivation increases self-administration of the fast- and short-acting mu-opioid receptor agonist remifentanil in the rat. J Pharmacol Exp Ther 326:920–929
Dick DM, Pagan JL, Holliday C, Viken R, Pulkkinen L, Kaprio J, Rose RJ (2007) Gender differences in friends’ influences on adolescent drinking: a genetic epidemiological study. Alcohol Clin Exp Res 32:2012–2019
Dunphy DC (1963) The social structure of urban adolescent peer groups. Sociometry 26:230–246
Evans SM, Foltin RW (2006) Exogenous progesterone attenuates the subjective effects of smoked cocaine in women, but not in men. Neuropsychopharmacology 31:659–674
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) 159:397–406
Feltenstein MW, See RE (2007) Plasma progesterone levels and cocaine-seeking in freely cycling female rats across the estrous cycle. Drug Alcohol Depend 89:183–189
Feltenstein MW, Byrd EA, Henderson AR, See RE (2009) Attenuation of cocaine-seeking by progesterone treatment in female rats. Psychoneuroendocrinology 34:343–352
Festa ED, Quinones-Jenab V (2004) Gonadal hormones provide the biological basis for sex differences in behavioral responses to cocaine. Horm Behav 46:509–519
Goldman JM, Murr AS, Cooper RL (2007) The rodent estrous cycle: characterization of vaginal cytology and its utility in toxicological studies. Birth Defects Res B Dev Reprod Toxicol 80:84–97
Grasing K, Li N, He S, Parrish C, Delich J, Glowa J (2003) A new progressive ratio schedule for support of morphine self-administration in opiate dependent rats. Psychopharmacology (Berl) 168:387–396
Green TA, Gehrke BJ, Bardo MT (2002) Environmental enrichment decreases intravenous amphetamine self-administration in rats: dose-response functions for fixed- and progressive-ratio schedules. Psychopharmacology (Berl) 162:373–378
Greenfield SF, Back SE, Lawson K, Brady KT (2010) Substance Abuse in Women. Psychiatr Clin North Am 33:339–355
Grimm JW, See RE (1997) Cocaine self-administration in ovariectomized rats is predicted by response to novelty, attenuated by 17-beta estradiol, and associated with abnormal vaginal cytology. Physiol Behav 61:755–761
Holly EN, Shimamoto A, DeBold JF, Miczek KA (2012) Sex differences in behavioral and neural cross-sensitization and escalated cocaine taking as a result of episodic social defeat stress in rats. Psychopharmacology (Berl) 224:179–188
Hser YI, Anglin MD, Booth MW (1987) Sex differences in addict careers. 3. Addiction. Am J Drug Alcohol Abuse 13:231–251
Hu M, Crombag HS, Robinson TE, Becker JB (2004) Biological basis of sex differences in the propensity to self-administer cocaine. Neuropsychopharmacology 29:81–85
Hubscher CH, Brooks DL, Johnson JR (2005) A quantitative method for assessing stages of the rat estrous cycle. Biotech Histochem 80:79–87
Institute of Laboratory Animal Resources (2011) Guide for the care and use of laboratory animals NIH publication. U.S. Dept. of Health and Human Services, Public Health Service, Bethesda, Md, p v
Jackson LR, Robinson TE, Becker JB (2006) Sex differences and hormonal influences on acquisition of cocaine self-administration in rats. Neuropsychopharmacology 31:129–138
Justice AJ, de Wit H (1999) Acute effects of d-amphetamine during the follicular and luteal phases of the menstrual cycle in women. Psychopharmacology (Berl) 145:67–75
Kosten TA, Gawin FH, Kosten TR, Rounsaville BJ (1993) Gender differences in cocaine use and treatment response. J Subst Abuse Treat 10:63–66
Lacy RT, Strickland JC, Brophy MK, Witte MA, Smith MA (2014a) Exercise decreases speedball self-administration. Life Sci 114:86–92
Lacy RT, Strickland JC, Smith MA (2014b) Cocaine self-administration in social dyads using custom-built operant conditioning chambers. J Neurosci Methods 236:11–18
Larson EB, Roth ME, Anker JJ, Carroll ME (2005) Effect of short- vs. long-term estrogen on reinstatement of cocaine-seeking behavior in female rats. Pharmacol Biochem Behav 82:98–108
Larson EB, Anker JJ, Gliddon LA, Fons KS, Carroll ME (2007) Effects of estrogen and progesterone on the escalation of cocaine self-administration in female rats during extended access. Exp Clin Psychopharmacol 15:461–471
Liu Y, Roberts DC, Morgan D (2005) Effects of extended-access self-administration and deprivation on breakpoints maintained by cocaine in rats. Psychopharmacology (Berl) 179:644–651
Lynch WJ (2006) Sex differences in vulnerability to drug self-administration. Exp Clin Psychopharmacol 14:34–41
Lynch WJ (2008) Acquisition and maintenance of cocaine self-administration in adolescent rats: effects of sex and gonadal hormones. Psychopharmacology (Berl) 197:237–246
Lynch WJ, Carroll ME (1999) Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats. Psychopharmacology (Berl) 144:77–82
Lynch WJ, Roth ME, Mickelberg JL, Carroll ME (2001) Role of estrogen in the acquisition of intravenously self-administered cocaine in female rats. Pharmacol Biochem Behav 68:641–646
Lynch WJ, Roth ME, Carroll ME (2002) Biological basis of sex differences in drug abuse: preclinical and clinical studies. Psychopharmacology (Berl) 164:121–137
Marcondes FK, Bianchi FJ, Tanno AP (2002) Determination of the estrous cycle phases of rats: some helpful considerations. Braz J Biol 62:609–614
Marusich JA, Craft RM, Lefever TW, Wiley JL (2015) The impact of gonadal hormones on cannabinoid dependence. Exp Clin Psychopharmacol 23:206–216
Molly LE, Gest SD, Feinberg ME, Osgood DW (2014) Emergence of mixed-sex friendship groups during adolescence: developmental associations with substance use and delinquency. Dev Psychol 50:2449–2461
Mrug S, Borch C, Cillessen AHN (2011) Other-sex friendships in late adolescence: risky associations for substance use and sexual debut? J Youth Adolescence 40:875–888
Poulin F, Pederson S (2007) Developmental changes in gender composition of friendship networks in adolescent girls and boys. Dev Psychol 43: 1484–1496
Quinones-Jenab V, Ho A, Schlussman SD, Franck J, Kreek MJ (1999) Estrous cycle differences in cocaine-induced stereotypic and locomotor behaviors in Fischer rats. Behav Brain Res 101:15–20
Richardson NR, Roberts DC (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66:1–11
Roberts DC, Bennett SA (1993) Heroin self-administration in rats under a progressive ratio schedule of reinforcement. Psychopharmacology (Berl) 111:215–218
Roberts DC, Bennett SA, Vickers GJ (1989) The estrous cycle affects cocaine self-administration on a progressive ratio schedule in rats. Psychopharmacology (Berl) 98:408–411
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) 172:443–449
Roth ME, Casimir AG, Carroll ME (2002) Influence of estrogen in the acquisition of intravenously self-administered heroin in female rats. Pharmacol Biochem Behav 72:313–318
Roth ME, Cosgrove KP, Carroll ME (2004) Sex differences in the vulnerability to drug abuse: a review of preclinical studies. Neurosci Biobehav Rev 28:533–546
Salvy SJ, Pedersen ER, Miles JN, Tucker JS, D’Amico EJ (2014) Proximal and distal social influence on alcohol consumption and marijuana use among middle school adolescents. Drug Alcohol Depend 144:93–101
Segarra AC, Torres-Diaz YM, Silva RD, Puig-Ramos A, Menendez-Delmestre R, Rivera-Bermudez JG, Amadeo W, Agosto-Rivera JL (2014) Estrogen receptors mediate estradiol’s effect on sensitization and CPP to cocaine in female rats: role of contextual cues. Horm Behav 65:77–87
Shimamoto A, Holly EN, Boyson CO, DeBold JF, Micezk KA (2015) Individual differences in anhedonic and accumbal dopamine responses to chronic social stress and their link to cocaine self-administration in female rats. Psychopharmacology (Berl) 232:825–834
Smith MA (2012) Peer influences on drug self-administration: social facilitation and social inhibition of cocaine intake in male rats. Psychopharmacology (Berl) 224:81–90
Smith MA, Schmidt KT, Iordanou JC, Mustroph ML (2008) Aerobic exercise decreases the positive-reinforcing effects of cocaine. Drug Alcohol Depend 98:129–135
Smith MA, Lacy RT, Strickland JC (2014) The effects of social learning on the acquisition of cocaine self-administration. Drug Alcohol Depend 141:1–8
Stewart J, Woodside B, Shaham Y (1996) Ovarian hormones do not affect the initiation and maintenance of intravenous self-administration of heroin in the female rat. Psychobiology 24:154–159
Strickland JC, Smith MA (2014) The effects of social contact on drug use: behavioral mechanisms controlling drug intake. Exp Clin Psychopharmacol 22:23–34
Strickland JC, Smith MA (2015) Animal models of social contact and drug self-administration. Pharmacol Biochem Behav 136:47–54
Westermeyer J, Kopka S, Nugent S (1997) Course and severity of substance abuse among patients with comorbid major depression. Am J Addict 6:284–292
White TL, Justice AJ, de Wit H (2002) Differential subjective effects of D-amphetamine by gender, hormone levels and menstrual cycle phase. Pharmacol Biochem Behav 73:729–741
Wissman AM, McCollum AF, Huang GZ, Nikrodhanond AA, Woolley CS (2011) Sex differences and effects of cocaine on excitatory synapses in the nucleus accumbens. Neuropharmacology 61:217–227
Yang H, Zhao W, Hu M, Becker JB (2007) Interactions among ovarian hormones and time of testing on behavioral sensitization and cocaine self-administration. Behav Brain Res 184:174–184
The authors thank Sarah Bills for expert technical assistance and the National Institute on Drug Abuse for supplying the study drugs.
This study was funded by NIH Grants DA027485 and DA031725.
Conflict of interests
The authors report no financial conflicts of interest.
About this article
Cite this article
Lacy, R.T., Strickland, J.C., Feinstein, M.A. et al. The effects of sex, estrous cycle, and social contact on cocaine and heroin self-administration in rats. Psychopharmacology 233, 3201–3210 (2016). https://doi.org/10.1007/s00213-016-4368-9