, Volume 235, Issue 1, pp 135–143 | Cite as

Sex-specific attenuation of impulsive action by progesterone in a go/no-go task for cocaine in rats

  • Natashia Swalve
  • John R. Smethells
  • Rebecca Younk
  • Jared Mitchell
  • Ben Dougen
  • Marilyn E. Carroll
Original Investigation



Previous work indicated that progesterone (PRO) reduced impulsive choice for cocaine in female but not male rats (Smethells et al. Psychopharmacology 233:2999–3008, 2016). Impulsive action, typically measured by responding for a reinforcer during a signaled period of nonavailability of natural reinforcers, predicts initiation and escalation of drug use in animals and humans. The present study examined impulsive action for cocaine using PRO in male and female rats trained on a go/no-go task.


Rats were trained on a go/no-go task to respond for cocaine infusions (0.4 mg/kg/inf). During the “go” component, responding was reinforced on a VI 30-s schedule, whereas during the “no-go” component, withholding a response was reinforced on a differential reinforcement of other behavior (DRO) 30-s schedule. A response during the no-go component resets the DRO timer and served as a measure of impulsive action. After baseline responding was established, rats were pretreated with vehicle (VEH) or PRO (0.5 mg/kg), and DRO resets and responding during the go component for cocaine were compared in males vs. females.


DRO resets were significantly lower following PRO treatment compared to VEH in female, but not male, rats. Response rates and overall infusions during the go component were not significantly altered by PRO in either females or males.


Treatment with PRO resulted in a sex-specific reduction in impulsive action for cocaine, while not affecting cocaine self-administration.


Drug addiction Go/no-go Impulsive action Progesterone Rats Sex differences 


Funding information

This study was supported by NIH/NIDA P50 DA033942 (MEC) and NIDA training grant T32 DA007097 (JRS: Thomas Molitor, PI).


  1. Anker JJ, Carroll ME (2011) Females are more vulnerable to drug abuse than males: evidence from preclinical studies and role of ovarian hormones. In: Neill JC, Kulkarni J (eds) Biological Basis of Sex Differences in Psychopharmacology: Current Topics in Behavioral Neurosciences. Springer, London, pp 73–96Google Scholar
  2. 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 15:472–480CrossRefPubMedGoogle Scholar
  3. Anker JJ, Gliddon LA, Carroll ME (2008) Impulsivity on a Go/No-go task for intravenous cocaine and food in male and female rats selectively bred for high and low saccharin intake. Behav Pharmacol 19:615–629CrossRefPubMedGoogle Scholar
  4. Anker JJ, Zlebnik NE, Gliddon LA, Carroll ME (2009) Performance under a Go/No-go task in rats selected for high and low impulsivity with a delay-discounting procedure. Behav Pharmacol 20:406–414CrossRefPubMedGoogle Scholar
  5. Anker JJ, Zlebnik NE, Navin SE, Carroll ME (2011) Responding during signaled availability and nonavailability of iv cocaine and food in rats: age and sex differences. Psychopharmacology 215:785–799CrossRefPubMedPubMedCentralGoogle Scholar
  6. Anker JJ, Holtz NA, Carroll ME (2012) Effects of progesterone on escalation of IV cocaine self-administration in rats selectively bred for high (HiS) or low (LoS) saccharin intake. Behav Pharmacol 23:205–2010 22327022CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bayless DW, Darling JS, Stout WJ, Daniel JM (2012) Sex differences in attentional processes in adult rats as measured by performance on the 5-choice serial reaction time task. Behav Brain Res 235(1):48–54Google Scholar
  8. Becker JB, Koob GF (2016) Sex differences in animal models: focus on addiction. Pharmacol Rev 68:242–263CrossRefPubMedPubMedCentralGoogle Scholar
  9. Bickel WK, Odum AL, Madden GJ (1999) Impulsivity and cigarette smoking: delay discounting in current, never, and ex-smokers. Psychopharmacology 146:447–454CrossRefPubMedGoogle Scholar
  10. Bickel WK, Miller ML, Yi R et al (2007) Behavioral and neuroeconomics of drug addiction: competing neural systems and temporal discounting processes. Drug Alcohol Depend 90:85–91CrossRefGoogle Scholar
  11. Burton CL, Fletcher PJ (2012) Age and sex differences in impulsive action in rats: the role of dopamine and glutamate. Behav Brain Res 230:21–33CrossRefPubMedGoogle Scholar
  12. 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(5):929–942CrossRefPubMedGoogle Scholar
  13. 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):61–69CrossRefPubMedGoogle Scholar
  14. Carroll ME, Anker JJ (2010) Sex differences and ovarian steroid hormones in animal models of drug dependence. Horm Behav 58:44–56CrossRefPubMedGoogle Scholar
  15. Carroll ME, Lynch WJ (2016) How to study sex differences using animal models. Addic Biol 21(5):1007–1029. CrossRefGoogle Scholar
  16. Carroll ME, Smethells JR (2016) Sex differences in behavioral dyscontrol: role in drug addiction and novel treatments. Front Psych 6:175Google Scholar
  17. 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(3):304–313CrossRefPubMedGoogle Scholar
  18. Colzato LS, Ruiz MJ, van den Wildenberg WP, Bajo MT, Hommel B (2010) Estrogen modulates inhibitory control in healthy human females: evidence from the stop-signal paradigm. Neuroscience 167:709–715CrossRefPubMedGoogle Scholar
  19. Cosgrove KP, Hunter R, Carroll ME (2002) Wheel-running attenuates intravenous cocaine self-administration in rats: sex differences. Pharmacol Biochem Behav 73:663–671CrossRefPubMedGoogle Scholar
  20. Crosbie J, Arnold P, Paterson A, Swanson J, Dupuis A, Li X, Shan J, Goodale T, Tam C, Strug LJ, Schachar RJ (2013) Response inhibition and ADHD traits: correlates and heritability in a sommunity sample. J Abnorm Child Psychol 41:497–507CrossRefPubMedPubMedCentralGoogle Scholar
  21. 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 2:3CrossRefPubMedPubMedCentralGoogle Scholar
  22. Czoty PW, Stoops WW, Rush CR (2016) Evaluation of the “pipeline” for development of medications for cocaine use disorder: a review of translational preclinical, human laboratory, and clinical trial research. Pharmacol Rev 68:533–562CrossRefPubMedPubMedCentralGoogle Scholar
  23. DeVito EE, Herman AI, Andrew JW, Valentine GW, Sofuoglu M (2014) Subjective, physiological, and cognitive responses to intravenous nicotine: effects of sex and menstrual cycle phase. Neuropsychopharmacology 39:1413–1410CrossRefGoogle Scholar
  24. Evans SM, Foltin RW (2006) Exogenous progesterone attenuates the subjective effects of smoked cocaine in women, but not in men. Neuropsychopharmacology 31:659–674CrossRefPubMedGoogle Scholar
  25. Evans SM, Foltin RW (2010) Does the response to cocaine differ as a function of sex or hormonal status in human and non-human primates? Horm Behav 58:13–21CrossRefPubMedGoogle Scholar
  26. Fattore L, Melis M (2016) Sex differences in impulsive and compulsive behaviors: a focus on drug addiction. Addict Biol 21:1043–1051CrossRefPubMedGoogle Scholar
  27. Fattore L, Altea S, Fratta W (2008) Sex differences in drug addiction: a review of animal and human studies. Womens Health (Lond) 4:51–65CrossRefGoogle Scholar
  28. Fernie G, Cole JC, Goudie AJ, Field M (2010) Risk-taking but not response inhibition or delay discounting predict alcohol consumption in social drinkers. Drug Alcohol Depend 112:54–61CrossRefPubMedGoogle Scholar
  29. Fields S, Collins C, Leraas K, Reynolds B (2009) Dimensions of impulsive behavior in adolescent smokers and nonsmokers. Exp Clin Psychopharmacol 17:301–311CrossRefGoogle Scholar
  30. Fox HC, Sofuoglu M, Morgan PT et al (2013) The effects of exogenous progesterone on drug craving and stress arousal in cocaine dependence: impact of gender and cue type. Psychoneuroendocrinology 38:1532–1544CrossRefPubMedPubMedCentralGoogle Scholar
  31. 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 179(3):662–672CrossRefPubMedGoogle Scholar
  32. Giordano LA, Bickel WK, Loewenstein G et al (2002) Mild opioid deprivation increases the degree that opioid-dependent outpatients discount delayed heroin and money. Psychopharmacology 163:174–182CrossRefPubMedGoogle Scholar
  33. Grant JE, Chamberlain SR (2014) Impulsive action and impulsive choice across substance and behavioral addictions: cause or consequence? Addict Behav 39:1632–1639CrossRefPubMedGoogle Scholar
  34. Hsu WH, Bellin SI, Dellmann HD, Hanson CE (1986) Xylazine-ketamine-induced anesthesia in rats and its antagonism by yohimbine. J Am Vet Med Assoc 189:1040–1043PubMedGoogle Scholar
  35. Jackson LR, Robinson TE, Becker JB (2006) Sex differences and hormonal influences on acquisition of cocaine self-administration in rats. Neuropsychopharmacology 31:129–138CrossRefPubMedGoogle Scholar
  36. Jentsch JD, Taylor JR (2003) Sex-related differences in spatial divided attention and motor impulsivity in rats. Behav Neurosci 117:76–83CrossRefPubMedGoogle Scholar
  37. Jentsch JD, Ashenhurst JR, Cervantes M, James AS, Groman SM, Pennington ZT (2014) Dissecting impulsivity and its relationships to drug addictions. Ann N Y Acad Sci 1327:1–26PubMedPubMedCentralGoogle Scholar
  38. Kosten TA, Zhang XY (2008) Sex differences in non-reinforced responding for cocaine. Am J Drug Alcohol Abuse 34:473–488CrossRefPubMedGoogle Scholar
  39. Kosten TA, Gawin FH, Kosten TR, Rounsaville BJ (1993) Gender differences in cocaine use and treatment response. J Subst Abus Treat 10:63–66CrossRefGoogle Scholar
  40. Krishnan-Sarin S, Reynolds B, Duhig AM, Smith A, Liss T, McFetridge A, Cavallo DA, Carroll KM, Potenza MN (2007) Behavioral impulsivity predicts treatment outcome in a smoking cessation program for adolescent smokers. Dr Alc Dep 88:79–82CrossRefGoogle Scholar
  41. 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 15:461–471CrossRefPubMedGoogle Scholar
  42. Liu T, Xiao T, Shi J (2013) Response inhibition preattentive processing, and sex difference in young children: an event-related potential study. Neuroreport 24:126–130CrossRefPubMedGoogle Scholar
  43. Lynch WJ (2009) Sex differences in vulnerability to drug self-administration. Exp Clin Psychopharmacol 14:34–41CrossRefGoogle Scholar
  44. Lynch WJ, Carroll ME (1999) Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats. Psychopharmacology 144:77–82CrossRefPubMedGoogle Scholar
  45. Lynch WJ, Arizzi MN, Carroll ME (2000) Effects of sex and the estrous cycle on regulation of intravenously self-administered cocaine in rats. Psychopharmacology 152:132–139CrossRefPubMedGoogle Scholar
  46. Madden GJ, Petry NM, Badger GJ, Bickel WK (1997) Impulsive and self-control choices in opioid-dependent patients and non-drug-using control patients: drug and monetary rewards. Exp Clin Psychopharmacol 5:256CrossRefPubMedGoogle Scholar
  47. McCance-Katz EF, Carroll KM, Rounsaville BJ (1999) Gender differences in treatment-seeking cocaine abusers—implications for treatment and prognosis. Am J Addict 8:300–311CrossRefPubMedGoogle Scholar
  48. Millivojevic V, Fox HC, Sofuoglu M, Covault J, Sinha R (2016) Effects of progesterone stimulated allopregnanolone on craving and stress response in cocaine dependent men and women. Psychoneuroendocrinology 65:44–53CrossRefGoogle Scholar
  49. Morgan JE, Gray NS, Snowden RJ (2011) The relationship between psychopathy and impulsivity: a multi-impulsivity measurement approach. Personal Individ Differ 51:429–434CrossRefGoogle Scholar
  50. National Research Council (2011) Guidelines for the Care and Use of Laboratory Animals, 8th edn. The National Academic Press, Washington, DCGoogle Scholar
  51. Paine TA, Olmstead MC (2004) Cocaine disrupts both behavioural inhibition and conditional discrimination in rats. Psychopharmacology 175:443–450PubMedGoogle Scholar
  52. Papaleo F, Erickson L, Liu G, Chen J, Weinberger DR (2012) COMT genetic reduction produces sexually divergent effects on cortical analomy and working memory in mice and humans. Creeb Cortex 25:2529–2541Google Scholar
  53. Perry JL, Carroll ME (2008) The role of impulsive behavior in drug abuse. Psychopharmacology 200:1026CrossRefGoogle Scholar
  54. Perry JL, Larson EB, German JP, Madden GJ, Carroll ME (2005) Impulsivity (delay discounting) as a predictor of acquisition of i.v. cocaine self-administration in female rats. Psychopharmacology 178:193–201CrossRefPubMedGoogle Scholar
  55. Perry AN, Westenbroek C, Becker JB (2013) The development of a preference for cocaine over food identifies individual rats with addiction-like behaviors. PLoS One 8(11):946–945CrossRefGoogle Scholar
  56. Peterson AB, Aivick DP, Lynch WJ (2014) Dose-dependent effectiveness of wheel running to attenuate cocaine-seeking: impact of sex and estrous cycle in rats. Psychopharmacology 231:2661–2670CrossRefPubMedGoogle Scholar
  57. Petry NM (2001) Delay discounting of money and alcohol in actively using alcoholics, currently abstinent alcoholics, and controls. Psychopharmacology 154:243–250CrossRefPubMedGoogle Scholar
  58. Quinones-Jenab V, Jenab S (2012) Influence of sex differences and gonadal hormones on cocaine addiction. ILAR J 53:14–22CrossRefPubMedGoogle Scholar
  59. Reynolds B, Richards JB, Horn K, Karraker K (2004) Delay discounting and probability discounting as related to cigarette smoking status in adults. Behav Process 65:35–42CrossRefGoogle Scholar
  60. Roberts DC, Bennett SA, Vickers GJ (1989) The estrous cycle affects cocaine self-administration on a progressive ratio schedule in rats. Psychopharmacology 98:408–411CrossRefPubMedGoogle Scholar
  61. 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 172(4):443–449CrossRefPubMedGoogle Scholar
  62. Saladin ME, McClure EA, Baker MS, Carpenter MJ, Viswanathan R, Hartwell GK (2015) Increasing progesterone levels are associated with smoking abstinence among free-cycling women smokers who receive brief pharmacotherapy. Nic Tobacco Res 17:398–406CrossRefGoogle Scholar
  63. Saunders B, Farag N, Vincent AS, Collins FL Jr, Sorocco KH, Lovallo WR (2008) Impulsive errors on a Go-NoGo reaction time task. Alcohol Clin Exp Res 32:888–894CrossRefPubMedPubMedCentralGoogle Scholar
  64. Smethells JR, Carroll ME (2015) Discrepant effects of acute cocaine on impulsive choice (delay discounting) in female rats during an increasing-and adjusting-delay procedure. Psychopharmacology 232:2455–2462ECrossRefPubMedPubMedCentralGoogle Scholar
  65. Smethells JR, Swalve NL, Eberly LE, Carroll ME (2016) Sex differences in the reduction of impulsive choice (delay discounting) for cocaine in rats with atomoxetine and progesterone. Psychopharmacology 233:2999–3008CrossRefPubMedPubMedCentralGoogle Scholar
  66. Solinas M, Thiriet C, Jaber M (2010) Prevention and treatment of drug addiction by environmental enrichment. Neurobiology 96:572–592Google Scholar
  67. Somoza EC, Winship D, Gorodetzky CW, Lewis D, Ciraulo DA, Galloway GP et al (2013) A multisite, double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of vigabatrin for treating cocaine dependence. JAMA Psychiatry 70:630–637CrossRefPubMedGoogle Scholar
  68. Substance Abuse and Mental Health Services Administration (SAMHSA) (2015) Results from the 2014 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-50, HHS Publication No. (SMA) 15-4927. NSDUH Series H-50). Retrieved from
  69. Swalve N, Smethells JR, Zlebnik NE, Carroll ME (2016a) Sex differences in reinstatement of cocaine-seeking behavior with combination treatments of progesterone and atomoxetine. Pharmacol Biochem Behav 145:17–23CrossRefPubMedPubMedCentralGoogle Scholar
  70. Swalve N, Smethells JR, Carroll ME (2016b) Progesterone attenuates impulsive action for sucrose in a Go/No-go task for sucrose pellets in female and male rats. Horm Behav 85:43–47CrossRefPubMedPubMedCentralGoogle Scholar
  71. Swalve N, Smethells JR, Carroll ME (2016c) Sex differences in attenuation of nicotine reinstatement after individual and combined treatments of progesterone and varenicline. Behav Brain Res 308:46–52CrossRefPubMedPubMedCentralGoogle Scholar
  72. Swalve N, Smethells JR, Carroll ME (2016d) Sex differences in the acquisition and maintenance of cocaine and nicotine self-administration in rats. Psychopharmacology 233:1005–1013CrossRefPubMedGoogle Scholar
  73. Townshend JM, Duka T (2005) Binge drinking, cognitive performance and mood in a population of young social drinkers. Alcohol Clin Exp Res 29:317–325CrossRefPubMedGoogle Scholar
  74. Weafer J, de Wit H (2014) Sex differences in impulsive action and impulsive choice. Addict Behav 39:1573–1579CrossRefPubMedGoogle Scholar
  75. Wetherill RR, Franklin TR, Allen SS (2016) Ovarian hormones, menstrual cycle phase, and smoking: a review with recommendations for future studies. Curr Addict Rep 3:1–8CrossRefPubMedPubMedCentralGoogle Scholar
  76. Zlebnik NE, Saykao AT, Carroll ME (2014) Effects of combined exercise and progesterone treatments on cocaine seeking in male and female rats. Psychopharmacology 231:3787–3798CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Natashia Swalve
    • 1
  • John R. Smethells
    • 2
  • Rebecca Younk
    • 3
  • Jared Mitchell
    • 3
  • Ben Dougen
    • 3
  • Marilyn E. Carroll
    • 3
  1. 1.Department of PsychologyAlma CollegeAlmaUSA
  2. 2.Department of MedicineMinneapolis Medical Research FoundationMinneapolisUSA
  3. 3.Department of PsychiatryUniversity of MinnesotaMinneapolisUSA

Personalised recommendations