Psychiatric diseases characterized by dysregulated risky decision making are differentially represented in males and females. The factors that govern such sex differences, however, remain poorly understood. Using a task in which rats make discrete trial choices between a small, “safe” food reward and a large food reward accompanied by varying probabilities of footshock punishment, we recently showed that females are more risk averse than males. The objective of the current experiments was to test the extent to which these sex differences in risky decision making are mediated by gonadal hormones. Male and female rats were trained in the risky decision-making task, followed by ovariectomy (OVX), orchiectomy (ORX), or sham surgery. Rats were then retested in the task, under both baseline conditions and following administration of estradiol and/or testosterone. OVX increased choice of the large, risky reward (increased risky choice), an effect that was attenuated by estradiol administration. In contrast, ORX decreased risky choice, but testosterone administration was without effect in either ORX or sham males. Estradiol, however, decreased risky choice in both groups of males. Importantly, none of the effects of hormonal manipulation on risky choice were due to altered shock sensitivity or food motivation. These data show that gonadal hormones are required for maintaining sex-typical profiles of risk-taking behavior in both males and females, and that estradiol is sufficient to promote risk aversion in both sexes. The findings provide novel information about the mechanisms supporting sex differences in risk taking and may prove useful in understanding sex differences in the prevalence of psychiatric diseases associated with altered risk taking.
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Bechara A, Dolan S, Denburg N, Hindes A, Anderson SW, Nathan PE. Decision-making deficits, linked to a dysfunctional ventromedial prefrontal cortex, revealed in alcohol and stimulant abusers. Neuropsychologia. 2001;39:376–89.
Gowin JL, Mackey S, Paulus MP. Altered risk-related processing in substance users: Imbalance of pain and gain. Drug alcohol Depend. 2013;132:13–21.
Bornovalova MA, Daughters SB, Hernandez GD, Richards JB, Lejuez CW. Differences in impulsivity and risk-taking propensity between primary users of crack cocaine and primary users of heroin in a residential substance-use program. Exp Clin Psychopharmacol. 2005;13:311–18.
Cahill L. Why sex matters for neuroscience. Nat Rev Neurosci. 2006;7:477–84.
Carroll ME, Lynch WJ, Roth ME, Morgan AD, Cosgrove KP. Sex and estrogen influence drug abuse. Trends Pharmacol Sci. 2004;25:273–9.
Becker JB, Hu M. Sex differences in drug abuse. Front Neuroendocrinol. 2008;29:36–47.
Orsini CA, Setlow B. Sex differences in animal models of decision making. J Neurosci Res. 2017;95:260–69.
van den Bos R, Jolles J, van der Knaap L, Baars A, de Visser L. Male and female Wistar rats differ in decision-making performance in a rodent version of the Iowa Gambling Task. Behav Brain Res. 2012;234:375–9.
Georgiou P, Zanos P, Bhat S, Tracy JK, Merchenthaler IJ, McCarthy MM, et al. Dopamine and stress system modulation of sex differences in decision making. Neuropsychopharmacology. 2017.
Orsini CA, Willis ML, Gilbert RJ, Bizon JL, Setlow B. Sex differences in a rat model of risky decision making. Behav Neurosci. 2016;130:50–61.
Liley AE, Gabriel DBK, Sable HJ, Simon NW. Sex differences and effects of predictive cues on delayed punishment discounting. eNeuro. 2019;6.
Chowdhury TG, Wallin-Miller KG, Rear AA, Park J, Diaz V, Simon NW, et al. Sex differences in reward- and punishment-guided actions. Cogn Affect Behav Neurosci. 2019;19:1404–17.
Pellman BA, Schuessler BP, Tellakat M, Kim JJ. Sexually dimorphic risk mitigation strategies in rats. eNeuro. 2017;4.
Cooper SE, Goings SP, Kim JY, Wood RI. Testosterone enhances risk tolerance without altering motor impulsivity in male rats. Psychoneuroendocrinology. 2014;40:201–12.
Wallin KG, Alves JM, Wood RI. Anabolic-androgenic steroids and decision making: probability and effort discounting in male rats. Psychoneuroendocrinology. 2015;57:84–92.
Wood RI, Armstrong A, Fridkin V, Shah V, Najafi A, Jakowec M. ‘Roid rage in rats? Testosterone effects on aggressive motivation, impulsivity and tyrosine hydroxylase. Physiol Behav. 2013;110-111:6–12.
Uban KA, Rummel J, Floresco SB, Galea LA. Estradiol modulates effort-based decision making in female rats. Neuropsychopharmacology. 2012;37:390–401.
Kerstetter KA, Ballis MA, Duffin-Lutgen S, Carr AE, Behrens AM, Kippin TE. Sex differences in selecting between food and cocaine reinforcement are mediated by estrogen. Neuropsychopharmacology. 2012;37:2605–14.
Bagley JR, Adams J, Bozadjian RV, Bubalo L, Ploense KL, Kippin TE. Estradiol increases choice of cocaine over food in male rats. Physiol Behav. 2017.
Orsini CA, Blaes SL, Setlow B, Simon NW. Recent updates in modeling risky decision making in rodents. Methods Mol Biol. 2019;2011:79–92.
Simon NW, Gilbert RJ, Mayse JD, Bizon JL, Setlow B. Balancing risk and reward: a rat model of risky decision making. Neuropsychopharmacology. 2009;34:2208–17.
Cross CP, Copping LT, Campbell A. Sex differences in impulsivity: a meta-analysis. Psychol Bull. 2011;137:97–130.
Grissom NM, Reyes TM. Let’s call the whole thing off: evaluating gender and sex differences in executive function. Neuropsychopharmacology. 2019;44:86–96.
van den Bos R, Homberg J, de Visser L. A critical review of sex differences in decision-making tasks: focus on the Iowa Gambling Task. Behav Brain Res 2013;238:95–108.
Crocker AD, Russell RW. The up-and-down method for the determination of nociceptive thresholds in rats. Pharmacol, Biochem, Behav. 1984;21:133–36.
Orsini CA, Hernandez CM, Singhal S, Kelly KB, Frazier CJ, Bizon JL, et al. Optogenetic inhibition reveals distinct roles for basolateral amygdala activity at discrete time points during risky decision making. J Neurosci. 2017;37:11537–48.
Gibbs RB. Fluctuations in relative levels of choline acetyltransferase mRNA in different regions of the rat basal forebrain across the estrous cycle: effects of estrogen and progesterone. J Neurosci. 1996;16:1049–55.
Benmansour S, Piotrowski JP, Altamirano AV, Frazer A. Impact of ovarian hormones on the modulation of the serotonin transporter by fluvoxamine. Neuropsychopharmacology. 2009;34:555–64.
Larson EB, Roth ME, Anker JJ, Carroll ME. Effect of short- vs. long-term estrogen on reinstatement of cocaine-seeking behavior in female rats. Pharmacol, Biochem, Behav. 2005;82:98–108.
Daniel JM, Bohacek J. The critical period hypothesis of estrogen effects on cognition: Insights from basic research. Biochim Biophys Acta. 2010;1800:1068–76.
Gibbs RB. Testosterone and estradiol produce different effects on cognitive performance in male rats. Hormones Behav. 2005;48:268–77.
de Bruijn M, Broekman M, van der Schoot P. Sexual interactions between estrous female rats and castrated male rats treated with testosterone propionate or estradiol benzoate. Physiol Behav. 1987;43:35–39.
Spritzer MD, Daviau ED, Coneeny MK, Engelman SM, Prince WT, Rodriguez-Wisdom KN. Effects of testosterone on spatial learning and memory in adult male rats. Hormones Behav. 2011;59:484–96.
Wagner BA, Braddick VC, Batson CG, Cullen BH, Miller LE, Spritzer MD. Effects of testosterone dose on spatial memory among castrated adult male rats. Psychoneuroendocrinology. 2018;89:120–30.
Wilson MJ, McMillin JM, Seal US, Ahmed K. Circadian variation of serum testosterone in the adult male rat with a late morning acrophase. Experientia. 1976;32:944–5.
Roth ME, Casimir AG, Carroll ME. Influence of estrogen in the acquisition of intravenously self-administered heroin in female rats. Pharmacol Biochem Behav. 2002;72:313–8.
Koss WA, Haertel JM, Philippi SM, Frick KM. Sex differences in the rapid cell signaling mechanisms underlying the memory-enhancing effects of 17beta-estradiol. eNeuro. 2018;5.
Jacome LF, Barateli K, Buitrago D, Lema F, Frankfurt M, Luine VN. Gonadal hormones rapidly enhance spatial memory and increase hippocampal spine density in male rats. Endocrinology. 2016;157:1357–62.
Luine V, Rodriguez M. Effects of estradiol on radial arm maze performance of young and aged rats. Behav Neural Biol. 1994;62:230–6.
Locklear MN, Kritzer MF. Assessment of the effects of sex and sex hormones on spatial cognition in adult rats using the Barnes maze. Hormones Behav. 2014;66:298–308.
Killgore WD, Grugle NL, Killgore DB, Balkin TJ. Sex differences in self-reported risk-taking propensity on the Evaluation of Risks scale. Psychol Rep. 2010;106:693–700.
Rosenblitt JC, Soler H, Johnson SE, Quadagno DM. Sensation seeking and hormones in men and women: exploring the link. Hormones Behav. 2001;40:396–402.
St Onge JR, Abhari H, Floresco SB. Dissociable contributions by prefrontal D1 and D2 receptors to risk-based decision making. J Neurosci. 2011;31:8625–33.
Op de Macks ZA, Bunge SA, Bell ON, Wilbrecht L, Kriegsfeld LJ, Kayser AS, et al. Risky decision-making in adolescent girls: the role of pubertal hormones and reward circuitry. Psychoneuroendocrinology. 2016;74:77–91.
Wallin-Miller KG, Chesley J, Castrillon J, Wood RI. Sex differences and hormonal modulation of ethanol-enhanced risk taking in rats. Drug Alcohol Depend. 2017;174:137–44.
Simon NW, Montgomery KS, Beas BS, Mitchell MR, LaSarge CL, Mendez IA, et al. Dopaminergic modulation of risky decision-making. J Neurosci. 2011;31:17460–70.
St Onge JR, Floresco SB. Dopaminergic modulation of risk-based decision making. Neuropsychopharmacology. 2009;34:681–97.
Orsini CA, Moorman DE, Young JW, Setlow B, Floresco SB. Neural mechanisms regulating different forms of risk-related decision-making: Insights from animal models. Neurosci Biobehav Rev. 2015.
Smethells JR, Swalve NL, Eberly LE, Carroll ME. Sex differences in the reduction of impulsive choice (delay discounting) for cocaine in rats with atomoxetine and progesterone. Psychopharmacology. 2016;233:2999–3008.
Swalve N, Smethells JR, Carroll ME. Progesterone attenuates impulsive action in a Go/No-Go task for sucrose pellets in female and male rats. Hormones Behav. 2016;85:43–7.
Swalve N, Smethells JR, Younk R, Mitchell J, Dougen B, Carroll ME. Sex-specific attenuation of impulsive action by progesterone in a go/no-go task for cocaine in rats. Psychopharmacology. 2018;235:135–43.
Milivojevic V, Fox HC, Sofuoglu M, Covault J, Sinha R. Effects of progesterone stimulated allopregnanolone on craving and stress response in cocaine dependent men and women. Psychoneuroendocrinology. 2016;65:44–53.
Derntl B, Pintzinger N, Kryspin-Exner I, Schopf V. The impact of sex hormone concentrations on decision-making in females and males. Front Neurosci. 2014;8:352.
Jackson LR, Robinson TE, Becker JB. Sex differences and hormonal influences on acquisition of cocaine self-administration in rats. Neuropsychopharmacology. 2006;31:129–38.
Anker JJ, Larson EB, Gliddon LA, Carroll ME. Effects of progesterone on the reinstatement of cocaine-seeking behavior in female rats. Exp Clin Psychopharmacol. 2007;15:472–80.
Larson EB, Anker JJ, Gliddon LA, Fons KS, Carroll ME. Effects of estrogen and progesterone on the escalation of cocaine self-administration in female rats during extended access. Exp Clin Psychopharmacol. 2007;15:461–71.
Tobiansky DJ, Korol AM, Ma C, Hamden JE, Jalabert C, Tomm RJ, et al. Testosterone and corticosterone in the mesocorticolimbic system of male rats: effects of gonadectomy and caloric restriction. Endocrinology. 2018;159:450–64.
Tobiansky DJ, Wallin-Miller KG, Floresco SB, Wood RI, Soma KK. Androgen regulation of the mesocorticolimbic system and executive function. Front Endocrinol. 2018;9:279.
Celec P, Ostatnikova D, Hodosy J. On the effects of testosterone on brain behavioral functions. Front Neurosci. 2015;9:12.
Frye CA, Edinger KL, Seliga AM, Wawrzycki JM. 5alpha-reduced androgens may have actions in the hippocampus to enhance cognitive performance of male rats. Psychoneuroendocrinology. 2004;29:1019–27.
Edinger KL, Lee B, Frye CA. Mnemonic effects of testosterone and its 5alpha-reduced metabolites in the conditioned fear and inhibitory avoidance tasks. Pharmacol Biochem Behav. 2004;78:559–68.
Dominguez-Ordonez R, Garcia-Juarez M, Lima-Hernandez FJ, Gomora-Arrati P, Blaustein JD, Etgen AM, et al. Estrogen receptor alpha and beta are involved in the activation of lordosis behavior in estradiol-primed rats. Hormones Behav. 2016;86:1–7.
Dominguez-Ordonez R, Garcia-Juarez M, Lima-Hernandez FJ, Gomora-Arrati P, Blaustein JD, Gonzalez-Flores O. Sexual receptivity facilitated by unesterified estradiol: dependence on estrogen and progestin receptors and priming dose of estradiol benzoate. Behav Neurosci. 2015;129:777–88.
Olster DH, Blaustein JD. Progesterone facilitation of lordosis in male and female Sprague-Dawley rats following priming with estradiol pulses. Hormones Behav. 1988;22:294–304.
Mazzucco CA, Walker HA, Pawluski JL, Lieblich SE, Galea LA. ERalpha, but not ERbeta, mediates the expression of sexual behavior in the female rat. Behav Brain Res. 2008;191:111–7.
Beach FA, Orndoff RK. Variation in the responsiveness of female rats to ovarian hormones as a function of preceding hormonal deprivation. Hormones Behav. 1974;5:201–5.
Whalen RE, DeBold JF. Comparative effectiveness of testosterone, androstenedione and dihydrotestosterone in maintaining mating behavior in the castrated male hamster. Endocrinology. 1974;95:1674–9.
Beach FA, Holz-Tucker AM. Effects of different concentrations of androgen upon sexual behavior in castrated male rats. J Comp Physiol Psychol. 1949;42:433–53.
Hu M, Crombag HS, Robinson TE, Becker JB. Biological basis of sex differences in the propensity to self-administer cocaine. Neuropsychopharmacology. 2004;29:81–5.
Perry AN, Westenbroek C, Becker JB. The development of a preference for cocaine over food identifies individual rats with addiction-like behaviors. PloS One. 2013;8:e79465.
Becker JB. Estrogen rapidly potentiates amphetamine-induced striatal dopamine release and rotational behavior during microdialysis. Neurosci Lett. 1990;118:169–71.
Peris J, Decambre N, Coleman-Hardee ML, Simpkins JW. Estradiol enhances behavioral sensitization to cocaine and amphetamine-stimulated striatal [3H]dopamine release. Brain Res. 1991;566:255–64.
Lynch WJ, Carroll ME. Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats. Psychopharmacology. 1999;144:77–82.
Bazzett TJ, Becker JB. Sex differences in the rapid and acute effects of estrogen on striatal D2 dopamine receptor binding. Brain Res. 1994;637:163–72.
Castner SA, Xiao L, Becker JB. Sex differences in striatal dopamine: in vivo microdialysis and behavioral studies. Brain Res. 1993;610:127–34.
Mitchell MR, Weiss VG, Beas BS, Morgan D, Bizon JL, Setlow B. Adolescent risk taking, cocaine self-administration, and striatal dopamine signaling. Neuropsychopharmacology. 2014;39:955–62.
Georgiou P, Zanos P, Bhat S, Tracy JK, Merchenthaler IJ, McCarthy MM, et al. Dopamine and stress system modulation of sex differences in decision making. Neuropsychopharmacology. 2018;43:313–24.
We thank Ms. Bonnie McLaurin for her role in gonadectomy surgeries. We are additionally grateful to Mr Matt Bruner, Ms Shannon Wall, and Ms Vicky Kelley for their assistance with behavioral testing.
The authors declare no competing interests.
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Orsini, C.A., Blaes, S.L., Hernandez, C.M. et al. Regulation of risky decision making by gonadal hormones in males and females. Neuropsychopharmacol. (2020). https://doi.org/10.1038/s41386-020-00827-0