Abstract
Although more men than women are addicted to cocaine, it has been suggested that women may have an accelerated transition to addiction, and that once addicted they may be more vulnerable to relapse. Here we investigate the effects of extended access to cocaine under a 24-h/day discrete trial procedure on patterns of intake and subsequent motivation to use cocaine as assessed by responding under a progressive-ratio schedule in male and female rats. Rats were initially trained to self-administer cocaine (1.5 mg/kg/infusion) under a fixed-ratio 1 schedule until acquisition occurred, and then responding was assessed under a progressive schedule for three sessions. Subsequently, rats had 24-h access to intravenous cocaine infusions (1.5 mg/kg) that were available in discrete trials (4, 10 min trials/h) for 7 consecutive days. At 10 days after the last discrete trial session, responding was reassessed under a progressive-ratio schedule for three additional sessions to investigate changes in motivation to obtain cocaine. Prior to cocaine self-administration under the 24-h access discrete trial procedure, males and females did not differ on cocaine self-administration under the fixed-ratio or progressive-ratio schedules. However, sex differences emerged under the 24-h access discrete trial procedure with females self-administering higher levels of cocaine, for longer initial periods of time, and showing a greater disruption in the diurnal control over intake than did males. Additionally, following a 10-day forced abstinence period, females responded at higher levels under the progressive-ratio schedule to obtain cocaine infusions than did males. These findings suggest that extended access to cocaine under the discrete trial cocaine self-administration procedure produces sex-dependent patterns of intake and sex-specific changes in motivation to obtain cocaine as measured by progressive-ratio responding.
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
Ahmed SH, Koob GF (1998). Transition from moderate to excessive drug intake: change in hedonic set point. Science 282: 298–300.
Ahmed SH, Koob GF (1999). Long-lasting increase in the set point for cocaine self-administration after escalation in rats. Psychopharmacology 146: 303–312.
American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Press: Washington, DC; 1994.
Arnold JM, Roberts DCS (1997). A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement. Pharmacol Biochem Behav 57: 441–447.
Bowman BP, Vaughan SR, Walker QD, Davis SL, Little PJ, Scheffler, NM et al (1999). Effects of sex and gonadectomy on cocaine metabolism in the rat. J Pharmacol Exp Ther 290: 1316–1323.
Brady KT, Randall CL (1999). Gender differences in substance use disorders. Psychiatr Clin North Am 22: 241–252.
Campbell UC, Morgan AD, Carroll ME (2002). Sex differences in the effect of baclofen on the acquisition of cociane self-administration in rats. Drug Alcohol Depend 66: 61–69.
Carroll ME, Morgan AD, Campbell UC, Lynch WJ, Dess NK (2002). Influence of estrogen in the acquisition of intravenously self-administration in rats selectively bred for differential saccharin intake: phenotype and sex differences. Psychopharmacology 161: 304–313.
Dudish SA, Hatsukami DK (1996). Gender differences in crack users who are research volunteers. Drug Alcohol Depend 42: 55–63.
Elman I, Karlsgodt KH, Gastfriend DR (2001). Gender differences in cocaine craving among non-treatment-seeking individuals with cocaine dependence. Am J Drug Alcohol Abuse 27: 193–202.
Evans SM, Haney M, Fischman MW, Foltin RW (1999). Limited sex differences in response to ‘binge’ smoked cocaine use in humans. Neuropsychopharmacology 21: 445–454.
Fitch TE, Roberts DCS (1993). The effects of dose and access restrictions on the periodicity of cocaine self-administration in the rat. Drug Alcohol Depend 33: 119–128.
Freeman WM, Brebner K, Patel KM, Lynch WJ, Roberts DC, Vrana KE (2002). Repeated cocaine self-administration causes multiple changes in rat frontal cortex gene expression. Neurochem Res 1181–1192.
Gawin FH (1991). Cocaine addiction: psychology and neurophysiology. Science 2251: 1580–1586.
Glick SD, Hinds PA (1984). Sex differences in sensitization to cocaine-induced rotation. Eur J Pharmacol 99: 119–121.
Grimm JW, Hope BT, Wise RA, Shaham Y (2001). Neuroadaptation. Incubation of cocaine craving after withdrawal. Nature 412: 141–142.
Haney M, Castanon N, Cador M, Le Moal M, Mormede P (1994). Cocaine sensitivity in roman high and low avoidance rats is modulated by sex and gonadal hormone status. Brain Res 645: 179–185.
Haney M, Maccari S, Le Moal M, Simon H, Piazza PV (1995). Social stress increases the acquisition of cocaine self-administration in male and female rats. Brain Res 698: 46–52.
Hu M, Becker JB (2003). Effects of sex and estrogen on behavioral sensitization to cocaine in rats. J Neurosci 23: 693–699.
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.
Jentsch JD, Taylor JR (1999). Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacology 146: 373–390.
Koob GF (1992). Neural mechanisms of drug reinforcement. Ann NY Acad Sci 28: 171–191.
Kosten TR, Kosten TA, McDougle CJ, Hameedi FA, McCance EF et al (1996). Gender differences in response to intranasal cocaine administration to humans. Biol Psychiatry 39: 147–148.
Lynch WJ, Arizzi MN, Carroll ME (2000). Effects of sex and the estrous cycle on regulation of intravenously self-administered cocaine in rats. Psychopharmacology 152: 132–139.
Lynch WJ, Carroll ME (1999). Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats. Psychopharmacology 144: 77–82.
Lynch WJ, Carroll ME (2000). Reinstatement of cocaine self-administration in rats: sex differences. Psychopharmacology 148: 196–200.
Lynch WJ, Roberts DCS (2004). The effects of cocaine self-administration on food-reinforced responding using a discrete trial procedure. Neuropsychopharmacology, (in press).
Lynch WJ, Roth ME, Carroll ME (2002). Biological basis of sex differences in drug abuse: preclinical and clinical studies. Psychopharmacology 164: 121–137.
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.
Mello NK, Mendelson JH (2002). Cocaine, hormones, and behavior: clinical and preclinical studies. Horm Brain Behav 5: 665–745.
Morgan D, Brebner K, Lynch WJ, Roberts DCS (2002). Increases in the reinforcing efficacy of cocaine after particular histories of reinforcement. Behav Pharmacol 13: 389–396.
Morishima HO, Abe Y, Matsuo M, Akiba K, Masaoka T, Cooper TB (1993). Gender-related differences in cocaine toxicity in the rat. J Lab Clin Med 122: 157–163.
Robbins SJ, Ehrman RN, Childress AR, O’Brien CP (1999). Comparing levels of cocaine cue reactivity in male and female outpatients. Drug Alcohol Depend 53: 223–230.
Roberts DCS, Bennett SAL, Vickers GJ (1989). The estrous cycle affects cocaine self-administration on a progressive ratio schedule in rats. Psychopharmacology 98: 408–411.
Roberts DCS, Brebner K, Vincler M, Lynch WJ (2002). Patterns of cocaine self-administration in rats produced by various access conditions under a discrete trial procedure. Drug Alcohol Depend 67: 291–299.
Robinson TE, Berridge KC (2001). Incentive-sensitization and addiction. Addiction 96: 103–114.
Sell SL, Scalzitti JM, Thomas ML, Cunningham KA (2000). Influence of ovarian hormones and estrous cycle on the behavioral response to cocaine in female rats. J Pharmacol Exp Ther 293: 879–886.
Sircar R, Kim D (1999). Female gonadal hormones differentially modulate cocaine-induced behavioral sensitization in Fischer, Lewis, and Spraque–Dawley rats. J Pharmacol Exp Ther 289: 54–65.
Sofuoglu M, Dudish-Poulsen S, Nelson D, Pentel PR, Hatsukami DK (1999). Sex and menstrual cycle differences in the subjective effects from smoked cocaine in humans. Exp Clin Psychopharmacol 7: 274–283.
Substance Abuse and Mental Health Services Administration (2001). Summary of Findings from the 2000 National Household Survey on Drug Abuse. Office of Applied Studies, NHSDA Series H-13, DHHS Publication No. (SMA) 01-3549, Rockville, MD.
Tornatzky W, Miczek KA (2000). Cocaine self-administration ‘binges’: transition from behavioral and autonomic regulation toward homeostatic dysregulation in rats. Psychopharmacology 148: 289–291.
Van Etten ML, Neumark YD, Anthony JC (1999). Male-female differences in the earliest stages of drug involvement. Addiction 94: 1413–1419.
Walker QD, Cabassa J, Kaplan KA, Li ST, Haroon J, Spohr HA et al (2001). Sex differences in cocaine-stimulated motor behavior: disparate effects of gonadectomy. Neuropsychopharmacology 25: 118–130.
Acknowledgements
We are grateful to Victoria Stewart for her technical assistance, and to Drs Marilyn Carroll, Yavin Shaham, Theresa Lee, and Barry Everitt for their critical comments on a previous version of this paper. We acknowledge the Yale Interdisciplinary Women's Health Research Scholar Program on Women and Drug Abuse, NIH Office of Research on Women's Health. This work was supported by NIDA grants DA11717 and DA016556 (JRT) and DA114038 (WJL).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lynch, W., Taylor, J. Sex Differences in the Behavioral Effects of 24-h/day Access to Cocaine under a Discrete Trial Procedure. Neuropsychopharmacol 29, 943–951 (2004). https://doi.org/10.1038/sj.npp.1300389
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.npp.1300389
Keywords
This article is cited by
-
Cocaine self-administration induces sex-dependent protein expression in the nucleus accumbens
Communications Biology (2021)
-
A buprenorphine-validated rat model of opioid use disorder optimized to study sex differences in vulnerability to relapse
Psychopharmacology (2021)
-
MDPV self-administration in female rats: influence of reinforcement history
Psychopharmacology (2021)
-
Females develop features of an addiction-like phenotype sooner during withdrawal than males
Psychopharmacology (2021)
-
Intermittent access cocaine self-administration produces psychomotor sensitization: effects of withdrawal, sex and cross-sensitization
Psychopharmacology (2020)
