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Protracted time-dependent increases in cocaine-seeking behavior during cocaine withdrawal in female relative to male rats

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Abstract

Rationale

Female rats display higher sensitivity to cocaine relative to males under a variety of conditions. Time-dependent increases in cocaine-seeking behavior (as measured by nonreinforced operant responses) during cocaine withdrawal have been reported in male, but not female, rats.

Objectives

The present study determines sex and estrous cycle influences on time-dependent changes in cocaine-seeking behavior.

Materials and methods

Male and female Sprague-Dawley rats were reinforced for “active lever” responses by a cocaine infusion (0.50 mg/kg/infusion, i.v., fixed ratio schedule of reinforcement, FR1) followed by a 20-s time-out when reinforcement was not delivered. Infusions were paired with a light + tone conditioned stimulus. Next, rats underwent cocaine withdrawal for 1, 14, 60, or 180 days before testing cocaine-seeking behavior. Each rat was tested for extinction of operant responding, conditioned-cued reinstatement, and cocaine-primed (10 mg/kg, i.p.) reinstatement.

Results

Both males and females displayed a time-dependent increase in cocaine-seeking behavior (active lever presses) under extinction of operant responding and conditioned-cued reinstatement conditions after 60 days of cocaine withdrawal. Moreover, cocaine-seeking behavior during extinction of operant responding in females, but not males, remained elevated at 180 days of cocaine withdrawal. Furthermore, females tested during estrus exhibited higher cocaine-seeking behavior under both extinction of operant responding and cocaine-primed reinstatement conditions relative to other rats independent of the duration of cocaine withdrawal.

Conclusions

The effects of reproductive cycle and withdrawal duration on cocaine-seeking behavior are additive and time-dependent increases in cocaine-seeking behavior are more enduring in females than in male rats.

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References

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Becker JB, Hu M (2008) Sex differences in drug abuse. Front Neuroendocrinol 29:36–47

    Google Scholar 

  • Bossert JM, Ghitza UE, Lu L, Epstein DH, Shaham Y (2005) Neurobiology of relapse to heroin and cocaine seeking: an update and clinical implications. Eur J Pharmacol 526:36–50

    Article  PubMed  CAS  Google Scholar 

  • Bowman BP, Vaughan SR, Walker QD, Davis SL, Little PJ, Scheffler NM, Thomas BF, Kuhn CM (1999) Effects of sex and gonadectomy on cocaine metabolism in the rat. Brain Res Bull 68:310–314

    Google Scholar 

  • Brady KT, Randall CL (1999) Gender differences in substance use disorders. Psychiatr Clin North Am 22:241–252

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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 161:304–313

    Article  PubMed  CAS  Google Scholar 

  • Chin J, Sternin O, Wu HB, Fletcher H, Perrotti LI, Jenab S, Quiñones-Jenab V (2001) Sex differences in cocaine-induced behavioral sensitization. Cell Mol Biol (Noisy-le-grand) 47(6):1089–1095

    CAS  Google Scholar 

  • Chin J, Sternin O, Wu HB, Burrell S, Lu D, Jenab S, Perrotti LI, Quinones-Jenab V (2002) Endogenous gonadal hormones modulate behavioral and neurochemical responses to acute and chronic cocaine administration. Brain Res 945:123–30

    Article  PubMed  CAS  Google Scholar 

  • Craft RM, Stratmann JA (1996) Discriminative stimulus effects of cocaine in female versus male rats. Drug Alcohol Depend 42:27–37

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Evans SM, Foltin RW (2006) Exogenous progesterone attenuates the subjective effects of smoked cocaine in women, but not in men. Neuropsychopharmacology 31(3):659–74

    Article  PubMed  CAS  Google Scholar 

  • 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 159(4):397–406

    Article  PubMed  CAS  Google Scholar 

  • Feder HH (1981) Estrous cyclicity in mammals. In: Alder NT (ed) Neuroendocrinology of reproduction. Physiology and behavior. Plenum, New York, NY, pp 280–290

    Google Scholar 

  • Feltenstein MW, See RE (2007a) Plasma progesterone levels and cocaine-seeking in freely cycling female rats across the estrous cycle. Drug Alcohol Depend 89:183–189

    Article  PubMed  CAS  Google Scholar 

  • Feltenstein MW, See RE (2007b) Progesterone pretreatment attenuates reinstatement of cocaine-seeking in freely cycling female rats. College on Problems of Drug Dependence Abstracts

  • Feltenstein MW, Henderson AR, See RE (2007) Progesterone pretreatment attenuates reinstatement of cocaine-seeking in freely cycling female rats. Program No. 271.12 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience

  • Festa ED, Russo SJ, Gazi FM, Niyomchai T, Kemen LM, Lin SN, Foltz R, Jenab S, Quinones-Jenab V (2004) Sex differences in cocaine-induced behavioral responses, pharmacokinetics, and monoamine levels. Neuropharmacology 46:672–687

    Article  PubMed  CAS  Google Scholar 

  • Fiorentine R, Anglin MD, Gil-Rivas V, Taylor E (1997) Drug treatment: explaining the gender paradox. Subst Use Misuse 32:653–678

    Article  PubMed  CAS  Google Scholar 

  • Freeman WM, Patel KM, Brucklacher RM, Lull ME, Erwin M, Morgan D, Roberts DCS, Vrana KE (2007) Persistent alterations in mesolimbic gene expression with abstinence from cocaine self-administration. Neuropsychopharmacology, (in press). DOI 10.1038/sj.npp.1301577

  • Fuchs RA, See RE (2002) Basolateral amygdala inactivation abolishes conditioned stimulus- and heroin-induced reinstatement of extinguished heroin-seeking behavior in rats. Psychopharmacology (Berl) 160:425–433

    Article  CAS  Google Scholar 

  • Fuchs RA, Allison-Evans K, 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 17:662–672

    Article  CAS  Google Scholar 

  • Glick SD, Hinds PA (1984) Sex differences in sensitization to cocaine-induced rotation. Eur J Pharmacol 99:119–121

    Article  PubMed  CAS  Google Scholar 

  • Griffin ML, Weiss RD, Mirin SM, Lange U (1989) A comparison of male and female cocaine abusers. Arch Gen Psychiatry 46:122–126

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Grimm JW, Hope BT, Wise RA, Shaham Y (2001) Neuroadaptation. Incubation of cocaine craving after withdrawal. Nature 412:141–142

    Article  PubMed  CAS  Google Scholar 

  • Grimm JW, Shaham Y, Hope BT (2002) Effect of cocaine and sucrose withdrawal period on extinction behavior, cue-induced reinstatement, and protein levels of the dopamine transporter and tyrosine hydroxylase in limbic and cortical areas in rats. Behav Pharmacol 13:379–388

    PubMed  CAS  Google Scholar 

  • Hecht GS, Spear NE, Spear LP (1999) Changes in progressive ratio responding for intravenous cocaine throughout the reproductive process in female rats. Dev Psychobiol 35:136–145

    Article  PubMed  CAS  Google Scholar 

  • Hu M, Becker JB (2003) Effects of sex and estrogen on behavioral sensitization to cocaine in rats. J Neurosci 23:693–699

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Jackson LR, Robinson TE, Becker JB (2006) Sex differences and hormonal influences on acquisition of cocaine self-administration in rats. Neuropsychopharmacology 31:129–138

    PubMed  CAS  Google Scholar 

  • Kantak KM, Goodrich CM, Uribe V (2007) Influence of sex, estrous cycle, and drug-onset age on cocaine self-administration in rats (Rattus norvegicus). Exp Clin Psychopharmacol 15:37–47

    Article  PubMed  CAS  Google Scholar 

  • Kippin TE, Fuchs RA, Mehta RH, Case JM, Parker MP, Bimonte-Nelson HA, See RE (2005) Potentiation of cocaine-primed reinstatement of drug seeking in female rats during estrus. Psychopharmacology 182:245–252

    Article  PubMed  CAS  Google Scholar 

  • Kosten TA, Gawin FH, Kosten TR, Rounsaville BJ (1993) Gender differences in cocaine use and treatment response. J Subst Abuse Treat 10:63–66

    Article  PubMed  CAS  Google Scholar 

  • 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 151:137–149

    Article  PubMed  CAS  Google Scholar 

  • Kouri EM, Lundahl LH, Borden KN, McNeil JF, Lukas SE (2002) Effects of oral contraceptives on acute cocaine response in female volunteers. Pharmacol Biochem Behav 74(1):173–180

    Article  PubMed  CAS  Google Scholar 

  • Larson EB, Carroll ME (2007) Estrogen receptor beta, but not alpha, mediates estrogen’s effect on cocaine-induced reinstatement of extinguished cocaine-seeking behavior in ovariectomized female rats. Neuropsychopharmacology 32:1334–1245

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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(5):461–47, Oct

    Article  PubMed  CAS  Google Scholar 

  • Lu L, Grimm JW, Dempsey J, Shaham Y (2004a) Cocaine seeking over extended withdrawal periods in rats: different time courses of responding induced by cocaine cues versus cocaine priming over the first 6 months. Psychopharmacology 176:101–108

    Article  PubMed  CAS  Google Scholar 

  • Lu L, Grimm JW, Hope BT, Shaham Y (2004b) Incubation of cocaine craving after withdrawal: a review of preclinical data. Neuropharmacology 47(Suppl 1):214–226

    Article  PubMed  CAS  Google Scholar 

  • Lukas SE, Sholar M, Lundahl LH, Lamas X, Kouri E, Wines JD, Kragie L, Mendelson JH (1996) Sex differences in plasma cocaine levels and subjective effects after acute cocaine administration in human volunteers. Psychopharmacology 125(4):346–354

    Article  PubMed  CAS  Google Scholar 

  • Lynch WJ, Carroll ME (1999) Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats. Psychopharmacology (Berl) 144:77–82

    Article  CAS  Google Scholar 

  • Lynch WJ, Carroll ME (2000) Reinstatement of cocaine self-administration in rats: sex differences. Psychopharmacology (Berl) 148:196–200

    Article  CAS  Google Scholar 

  • Lynch WJ, Taylor JR (2004) Sex differences in the behavioral effects of 24-h/day access to cocaine under a discrete trial procedure. Neuropsychopharmacology 29:943–951

    Article  PubMed  CAS  Google Scholar 

  • Lynch WJ, Taylor JR (2005) Decreased motivation following cocaine self-administration under extended access conditions: effects of sex and ovarian hormones. Neuropsychopharmacology 30:927–935

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Lynch WJ, Mangini LD, Taylor JR (2005) Neonatal isolation stress potentiates cocaine seeking behavior in adult male and female rats. Neuropsychopharmacology 30:322–329

    Article  PubMed  CAS  Google Scholar 

  • McCance-Katz EF, Carroll KM, Rounsaville BJ (1999) Gender differences in treatment-seeking cocaine abusers—implications for treatment and prognosis. Am J Addict 8:300–311

    Article  PubMed  CAS  Google Scholar 

  • McKay JR, Rutherford MJ, Cacciola JS, Kabasakalian-McKay R, Alterman AI (1996) Gender differences in the relapse experiences of cocaine patients. J Nerv Ment Dis 184:616–622

    Article  PubMed  CAS  Google Scholar 

  • National Research Council (2003) Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research. National Academies Press. Washington DC

  • Niyomchai T, Akhavan A, Festa ED, Lin SN, Lamm L, Foltz R, Quiñones-Jenab V (2006) Estrogen and progesterone affect cocaine pharmacokinetics in female rats. J Pharmacol Exp Ther 290:1316–1323

    Google Scholar 

  • Peris J, Decambre N, Coleman-Hardee ML, Simpkins JW (1991) Estradiol enhances behavioral sensitization to cocaine and amphetamine-stimulated striatal [3H]dopamine release. Brain Res 566:255–264

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • Robinson TE, Browman KE, Crombag HS, Badiani A (1998) Modulation of the induction or expression of psychostimulant sensitization by the circumstances surrounding drug administration. Neurosci Biobehav Rev 22:347–354

    Article  PubMed  CAS  Google Scholar 

  • Roth ME, Carroll ME (2004) Sex differences in the escalation of intravenous cocaine intake following long- or short-access to cocaine self-administration. Pharmacol Biochem Behav 78:199–207

    Article  PubMed  CAS  Google Scholar 

  • Russo SJ, Jenab S, Fabian SJ, Festa ED, Kemen LM, Quinones-Jenab V (2003) Sex differences in the conditioned rewarding effects of cocaine. Brain Res 970:214–220

    Article  PubMed  CAS  Google Scholar 

  • Schuelke GS, Konkol RJ, Terry LC, Madden JA (1996) Effect of cocaine metabolites on behavior: possible neuroendocrine mechanisms. Brain Res Bull 39:43–48

    Article  PubMed  CAS  Google Scholar 

  • Sell SL, Thomas ML, Cunningham KA (2002) Influence of estrous cycle and estradiol on behavioral sensitization to cocaine in female rats. Drug Alcohol Depend 67:281–290

    Article  PubMed  CAS  Google Scholar 

  • Sofuoglu M, Dudish-Poulsen S, Nelson D, Pentel PR, Hatsukani DK (1999) Sex and menstrual cycle differences in the subjective effects from smoked cocaine in humans. Exp Clin Psychopharmacol 7(3):274–283

    Article  PubMed  CAS  Google Scholar 

  • Sofuoglu M, Babb DA, Hatsukami DK (2002) Effects of progesterone treatment on smoked cocaine response in women. Pharmacol Biochem Behav 72(1-2):431–435

    Article  PubMed  CAS  Google Scholar 

  • Sofuoglu M, Mitchell E, Kosten TR (2004) Effects of progesterone treatment on cocaine responses in male and female cocaine users. Pharmacol Biochem Behav 78(4):699–705

    Article  PubMed  CAS  Google Scholar 

  • Terner JM, de Wit H (2006) Menstrual cycle phase and responses to drugs of abuse in humans. Drug Alcohol Depend 84(1):1–13

    Article  PubMed  CAS  Google Scholar 

  • Sorge RE, Stewart J (2005) The contribution of drug history and time since termination of drug taking to footshock stress-induced cocaine seeking in rats. Psychopharmacology 183:210–217

    Article  PubMed  CAS  Google Scholar 

  • Tran-Nguyen LT, Fuchs RA, Coffey GP, Baker DA, O’Dell LE, Neisewander JL (1998) Time-dependent changes in cocaine-seeking behavior and extracellular dopamine levels in the amygdala during cocaine withdrawal. Neuropsychopharmacology 19:48–59

    Article  PubMed  CAS  Google Scholar 

  • van Haaren F, Meyer ME (1991) Sex differences in locomotor activity after acute and chronic cocaine administration. Pharmacol Biochem Behav 39:923–927

    Article  PubMed  Google Scholar 

  • van Harren F, Garcea M, Anderson KG, Tebbett IR (1997) Cocaine and benzoylecgonine in serum microsamples of intact and gonadectomized male and female Wistar rats. Pharmacol Biochem Behav 58:421–424

    Article  PubMed  Google Scholar 

  • Vanderschuren LJ, Kalivas PW (2000) Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology 151:99–120

    Article  PubMed  CAS  Google Scholar 

  • Westermeyer J, Boedicker AE (2000) Course, severity, and treatment of substance abuse among women versus men. Am J Drug Alcohol Abuse 26:523–535

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Zhou W, Cunningham KA, Thomas ML (2002) Estrogen regulation of gene expression in the brain: a possible mechanism altering the response to psychostimulants in female rats. Brain Res Mol Brain Res 100:75–83

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Psychology, University of California, Santa Barbara, CA, 93106-9660, USA

    Kerry A. Kerstetter, Valerie R. Aguilar, Aaron B. Parrish & Tod E. Kippin

  2. The Neuroscience Research Institute, University of California, Santa Barbara, CA, 93106, USA

    Tod E. Kippin

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  1. Kerry A. Kerstetter
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  2. Valerie R. Aguilar
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Correspondence to Tod E. Kippin.

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Kerstetter, K.A., Aguilar, V.R., Parrish, A.B. et al. Protracted time-dependent increases in cocaine-seeking behavior during cocaine withdrawal in female relative to male rats. Psychopharmacology 198, 63–75 (2008). https://doi.org/10.1007/s00213-008-1089-8

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  • DOI: https://doi.org/10.1007/s00213-008-1089-8

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