Sex differences in the dopaminergic response to psychostimulants could have implications for drug abuse risk and other psychopathology involving the dopamine system, but human data are limited and mixed.
Here, we sought to investigate sex differences in dopamine release after oral d-amphetamine administration.
We used [18F]fallypride positron emission tomography (PET) to measure the change in dopamine D2/3 receptor availability (%ΔBPND, an index of dopamine release) between placebo and d-amphetamine sessions in two independent datasets containing a total of 39 females (on either hormonal birth control n = 18, postmenopausal n = 10, or studied in the first 10 days of their menstrual cycle n = 11) and 37 males.
Using both a priori anatomical regions of interest based on previous findings and voxelwise analyses, we failed to consistently detect broad sex differences in d-amphetamine-induced dopamine release. Nevertheless, there was limited evidence for greater right ventral striatal dopamine release in young adult males relative to similarly aged females, but this was not consistently observed across samples. Plasma estradiol did not correlate with dopamine release and this measure did not differ in females on and off hormonal birth control.
While our finding in young adults from one dataset of greater %ΔBPND in males is partially consistent with a previously published study on sex differences in d-amphetamine-induced dopamine release, our data do not support the presence of consistent widespread sex differences in this measure of dopamine release.
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Alyea RA, Watson CS (2009) Nongenomic mechanisms of physiological estrogen-mediated dopamine efflux. BMC Neurosci 10:59
Alyea RA, Laurence SE, Kim SH, Katzenellenbogen BS, Katzenellenbogen JA, Watson CS (2008) The roles of membrane estrogen receptor subtypes in modulating dopamine transporters in PC-12 cells. J Neurochem 106:1525–1533
Becker JB (1990) Estrogen rapidly potentiates amphetamine-induced striatal dopamine release and rotational behavior during microdialysis. Neurosci Lett 118:169–171
Becker JB (1999) Gender differences in dopaminergic function in striatum and nucleus accumbens. Pharmacol Biochem Behav 64:803–812
Becker JB, Hu M (2008) Sex differences in drug abuse. Front Neuroendocrinol 29:36–47
Buckholtz JW, Treadway MT, Cowan RL, Woodward ND, Li R, Ansari MS, Baldwin RM, Schwartzman AN, Shelby ES, Smith CE, Kessler RM, Zald DH (2010) Dopaminergic network differences in human impulsivity. Science 329:532
Calipari ES, Juarez B, Morel C, Walker DM, Cahill ME, Ribeiro E, Roman-Ortiz C, Ramakrishnan C, Deisseroth K, Han MH, Nestler EJ (2017) Dopaminergic dynamics underlying sex-specific cocaine reward. Nat Commun 8:13877
Camp DM, Robinson TE (1988) Susceptibility to sensitization. I. Sex differences in the enduring effects of chronic d-amphetamine treatment on locomotion, stereotyped behavior and brain monoamines. Behav Brain Res 30:55–68
Cummings JA, Jagannathan L, Jackson LR, Becker JB (2014) Sex differences in the effects of estradiol in the nucleus accumbens and striatum on the response to cocaine: neurochemistry and behavior. Drug Alcohol Depend 135:22–28
Czoty PW, Riddick NV, Gage HD, Sandridge M, Nader SH, Garg S, Bounds M, Garg PK, Nader MA (2009) Effect of menstrual cycle phase on dopamine D2 receptor availability in female cynomolgus monkeys. Neuropsychopharmacology 34:548–554
de la Fuente-Fernandez R, Ruth TJ, Sossi V, Schulzer M, Calne DB, Stoessl AJ (2001) Expectation and dopamine release: mechanism of the placebo effect in Parkinson's disease. Science 293:1164–1166
Dohrenwend BP, Dohrenwend BS (1976) Sex differences and psychiatric disorders. AJS 81:1447–1454
Earls F (1987) Sex differences in psychiatric disorders: origins and developmental influences. Psychiatr Dev 5:1–23
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 159:397–406
First MB, Spitzer RL, Gibbon M, Williams JBW (2002) Structured clinical interview for DSM-IV-TR axis I disorders, research version, non-patient edition. (SCID-I/NP). Biometrics Research, New York State Psychiatric Institute, New York
Friston KJ, Holmes AP, Worsley KJ, Poline J-P, Frith CD, Frackowiak RSJ (1995) Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 2:189–210
Gardiner SA, Morrison MF, Mozley PD, Mozley LH, Brensinger C, Bilker W, Newberg A, Battistini M (2004) Pilot study on the effect of estrogen replacement therapy on brain dopamine transporter availability in healthy, postmenopausal women. Am J Geriatr Psychiatry 12:621–630
Griffin ML, Weiss RD, Mirin SM, Lange U (1989) A comparison of male and female cocaine abusers. Arch Gen Psychiatry 46:122–126
Gunn RN, Lammertsma AA, Hume SP, Cunningham VJ (1997) Parametric imaging of ligand-receptor binding in PET using a simplified reference region model. NeuroImage 6:279–287
Ivanova T, Beyer C (2003) Estrogen regulates tyrosine hydroxylase expression in the neonate mouse midbrain. J Neurobiol 54:638–647
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 145:67–75
Kosten TA, Gawin FH, Kosten TR, Rounsaville BJ (1993) Gender differences in cocaine use and treatment response. J Subst Abus Treat 10:63–66
Laakso A, Vilkman H, Bergman J, Haaparanta M, Solin O, Syvalahti E, Salokangas RK, Hietala J (2002) Sex differences in striatal presynaptic dopamine synthesis capacity in healthy subjects. Biol Psychiatry 52:759–763
Lammertsma AA, Hume SP (1996) Simplified reference tissue model for PET receptor studies. NeuroImage 4:153–158
Lee JJ, Ham JH, Lee PH, Sohn YH (2015) Gender differences in age-related striatal dopamine depletion in Parkinson’s disease. J Mov Disord 8:130–135
Lidstone SC, Schulzer M, Dinelle K, Mak E, Sossi V, Ruth TJ, de la Fuente-Fernandez R, Phillips AG, Stoessl AJ (2010) Effects of expectation on placebo-induced dopamine release in Parkinson disease. Arch Gen Psychiatry 67:857–865
Lynch WJ (2008) Acquisition and maintenance of cocaine self-administration in adolescent rats: effects of sex and gonadal hormones. Psychopharmacology 197:237–246
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, 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, 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
Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH (2003) An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. NeuroImage 19:1233–1239
Mawlawi O, Martinez D, Slifstein M, Broft A, Chatterjee R, Hwang DR, Huang Y, Simpson N, Ngo K, Van Heertum R, Laruelle M (2001) Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D(2) receptor parameter measurements in ventral striatum. J Cereb Blood Flow Metab 21:1034–1057
Morean ME, de Wit H, King AC, Sofuoglu M, Rueger SY, O'Malley SS (2013) The drug effects questionnaire: psychometric support across three drug types. Psychopharmacology 227:177–192
Morris ED, Yoder KK (2007) Positron emission tomography displacement sensitivity: predicting binding potential change for positron emission tomography tracers based on their kinetic characteristics. J Cereb Blood Flow Metab 27:606–617
Mozley LH, Gur RC, Mozley PD, Gur RE (2001) Striatal dopamine transporters and cognitive functioning in healthy men and women. Am J Psychiatry 158:1492–1499
Munro CA, McCaul ME, Wong DF, Oswald LM, Zhou Y, Brasic J, Kuwabara H, Kumar A, Alexander M, Ye W, Wand GS (2006) Sex differences in striatal dopamine release in healthy adults. Biol Psychiatry 59:966–974
Nordstrom AL, Olsson H, Halldin C (1998) A PET study of D2 dopamine receptor density at different phases of the menstrual cycle. Psychiatry Res 83:1–6
Osterlund MK, Keller E, Hurd YL (2000) The human forebrain has discrete estrogen receptor alpha messenger RNA expression: high levels in the amygdaloid complex. Neuroscience 95:333–342
Pasqualini C, Olivier V, Guibert B, Frain O, Leviel V (1995) Acute stimulatory effect of estradiol on striatal dopamine synthesis. J Neurochem 65:1651–1657
Riccardi P, Zald D, Li R, Park S, Ansari MS, Dawant B, Anderson S, Woodward N, Schmidt D, Baldwin R, Kessler R (2006) Sex differences in amphetamine-induced displacement of [(18)F]fallypride in striatal and extrastriatal regions: a PET study. Am J Psychiatry 163:1639–1641
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 DC, Bennett SA, Vickers GJ (1989) The estrous cycle affects cocaine self-administration on a progressive ratio schedule in rats. Psychopharmacology 98:408–411
Samanez-Larkin GR, Buckholtz JW, Cowan RL, Woodward ND, Li R, Ansari MS, Arrington CM, Baldwin RM, Smith CE, Treadway MT, Kessler RM, Zald DH (2013) A thalamocorticostriatal dopamine network for psychostimulant-enhanced human cognitive flexibility. Biol Psychiatry 74:99–105
Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK (2008) Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch Gen Psychiatry 65:220–231
Seeman MV (1997) Psychopathology in women and men: focus on female hormones. Am J Psychiatry 154:1641–1647
Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H, Bannister PR, De Luca M, Drobnjak I, Flitney DE, Niazy RK, Saunders J, Vickers J, Zhang Y, De Stefano N, Brady JM, Matthews PM (2004) Advances in functional and structural MR image analysis and implementation as FSL. NeuroImage 23(Suppl 1):S208–S219
Smith CT, Dang LC, Cowan RL, Kessler RM, Zald DH (2016a) Variability in paralimbic dopamine signaling correlates with subjective responses to d-amphetamine. Neuropharmacology 108:394–402
Smith CT, Weafer J, Cowan RL, Kessler RM, Palmer AA, de Wit H, Zald DH (2016b) Individual differences in timing of peak positive subjective responses to d-amphetamine: relationship to pharmacokinetics and physiology. J Psychopharmacol 30:330–343
Smith CT, Dang LC, Buckholtz JW, Tetreault AM, Cowan RL, Kessler RM, Zald DH (2017) The impact of common dopamine D2 receptor gene polymorphisms on D2/3 receptor availability: C957T as a key determinant in putamen and ventral striatum. Transl Psychiatry 7:e1091
Treadway MT, Buckholtz JW, Cowan RL, Woodward ND, Li R, Ansari MS, Baldwin RM, Schwartzman AN, Kessler RM, Zald DH (2012) Dopaminergic mechanisms of individual differences in human effort-based decision-making. J Neurosci 32:6170–6176
Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, Mazoyer B, Joliot M (2002) Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. NeuroImage 15:273–289
Vernaleken I, Peters L, Raptis M, Lin R, Buchholz HG, Zhou Y, Winz O, Rosch F, Bartenstein P, Wong DF, Schafer WM, Grunder G (2011) The applicability of SRTM in [(18)F]fallypride PET investigations: impact of scan durations. J Cereb Blood Flow Metab 31:1958–1966
Walker QD, Rooney MB, Wightman RM, Kuhn CM (2000) Dopamine release and uptake are greater in female than male rat striatum as measured by fast cyclic voltammetry. Neuroscience 95:1061–1070
Watson CS, Alyea RA, Hawkins BE, Thomas ML, Cunningham KA, Jakubas AA (2006) Estradiol effects on the dopamine transporter - protein levels, subcellular location, and function. J Mol Signal 1:5
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
This work was supported by AG043458 (DHZ & GRS-L) and AG042596 (GRS-L) from the National Institute on Aging and DA019670 (DHZ), DA041157 (CTS), and DA036979 (LCD) from the National Institute on Drug Abuse.
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The authors declare that there is no conflict of interest.
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Smith, C.T., Dang, L.C., Burgess, L.L. et al. Lack of consistent sex differences in d-amphetamine-induced dopamine release measured with [18F]fallypride PET. Psychopharmacology 236, 581–590 (2019). https://doi.org/10.1007/s00213-018-5083-5
- (up to 10): Sex differences
- D2/3 receptor availability
- Dopamine release