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Sex differences in dopamine release regulation in the striatum


The mesolimbic dopamine system—which originates in the ventral tegmental area and projects to the striatum—has been shown to be involved in the expression of sex-specific behavior and is thought to be a critical mediator of many psychiatric diseases. While substantial work has focused on sex differences in the anatomy of dopamine neurons and relative dopamine levels between males and females, an important characteristic of dopamine release from axon terminals in the striatum is that it is rapidly modulated by local regulatory mechanisms independent of somatic activity. These processes can occur via homosynaptic mechanisms—such as presynaptic dopamine autoreceptors and dopamine transporters—as well as heterosynaptic mechanisms, such as retrograde signaling from postsynaptic cholinergic and GABAergic systems, among others. These regulators serve as potential targets for the expression of sex differences in dopamine regulation in both ovarian hormone-dependent and independent fashions. This review describes how sex differences in microcircuit regulatory mechanisms can alter dopamine dynamics between males and females. We then describe what is known about the hormonal mechanisms controlling/regulating these processes. Finally, we highlight the missing gaps in our knowledge of these systems in females. Together, a more comprehensive and mechanistic understanding of how sex differences in dopamine function manifest will be particularly important in developing evidence-based therapeutics that target this system and show efficacy in both sexes.

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Fig. 1: Homosynaptic and heterosynaptic regulation of striatal dopamine release from axon terminals.
Fig. 2: Sex differences in regulation of dopamine release at dopamine terminals in the striatum.


  1. 1.

    Piccinelli M, Wilkinson G. Gender differences in depression: critical review. Br J Psychiatry. 2000;177:486–92.

    CAS  PubMed  Google Scholar 

  2. 2.

    Becker JB, McClellan ML, Reed BG. Sex differences, gender and addiction. J Neurosci Res. 2017;95:136–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Rubinow DR, Schmidt PJ. Sex differences and the neurobiology of affective disorders. Neuropsychopharmacology. 2019;44:111–28.

    PubMed  Google Scholar 

  4. 4.

    Petersen N, London ED. Addiction and dopamine: sex differences and insights from studies of smoking. Curr Opin Behav Sci. 2018;23:150–9.

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Dewing P, Chiang CWK, Sinchak K, Sim H, Fernagut P-O, Kelly S, et al. Direct regulation of adult brain function by the male-specific factor SRY. Curr Biol. 2006;16:415–20.

    CAS  PubMed  Google Scholar 

  6. 6.

    McArthur S, McHale E, Gillies GE. The size and distribution of midbrain dopaminergic populations are permanently altered by perinatal glucocorticoid exposure in a sex- region- and time-specific manner. Neuropsychopharmacology. 2007;32:1462–76.

    CAS  PubMed  Google Scholar 

  7. 7.

    Kritzer MF, Creutz LM. Region and sex differences in constituent dopamine neurons and immunoreactivity for intracellular estrogen and androgen receptors in mesocortical projections in rats. J Neurosci. 2008;28:9525–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Cummings JA, Jagannathan L, Jackson LR, Becker JB. Sex differences in the effects of estradiol in the nucleus accumbens and striatum on the response to cocaine: neurochemistry and behavior. Drug Alcohol Depend. 2014;135:22–28.

    CAS  PubMed  Google Scholar 

  9. 9.

    Becker JB. Gender differences in dopaminergic function in striatum and nucleus accumbens. Pharm Biochem Behav. 1999;64:803–12.

    CAS  Google Scholar 

  10. 10.

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

    CAS  PubMed  Google Scholar 

  11. 11.

    Becker JB, Perry AN, Westenbroek C. Sex differences in the neural mechanisms mediating addiction: a new synthesis and hypothesis. Biol Sex Differ. 2012;3:14.

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Castner SA, Xiao L, Becker JB. Sex differences in striatal dopamine: in vivo microdialysis and behavioral studies. Brain Res. 1993;610:127–34.

    CAS  PubMed  Google Scholar 

  13. 13.

    Walker QD, Rooney MB, Wightman RM, Kuhn CM. Dopamine release and uptake are greater in female than male rat striatum as measured by fast cyclic voltammetry. Neuroscience. 2000;95:1061–70.

    CAS  PubMed  Google Scholar 

  14. 14.

    Gillies G, McArthur S, McHale E. Sex dimorphisms in the 3D cytoarchitecture of the adult VTA and permanent alterations by glucocorticoid exposure in late gestation. Front Neuroendocrinol. 2006;27:95–6.

    Google Scholar 

  15. 15.

    Yoest KE, Quigley JA, Becker JB. Rapid effects of ovarian hormones in dorsal striatum and nucleus accumbens. Horm Behav. 2018;104:119–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Nolan SO, Zachry JE, Johnson AR, Brady LJ, Siciliano CA, Calipari ES. Direct dopamine terminal regulation by local striatal microcircuitry. J Neurochem. 2020;155:475–93.

  17. 17.

    Richardson BD, Saha K, Krout D, Cabrera E, Felts B, Henry LK, et al. Membrane potential shapes regulation of dopamine transporter trafficking at the plasma membrane. Nat Commun. 2016;7:1–12.

    Google Scholar 

  18. 18.

    Benoit‐Marand M, Ballion B, Borrelli E, Boraud T, Gonon F. Inhibition of dopamine uptake by D2 antagonists: an in vivo study. J Neurochem. 2011;116:449–58.

    PubMed  Google Scholar 

  19. 19.

    Benoit-Marand M, Borrelli E, Gonon F. Inhibition of dopamine release via presynaptic D2 receptors: time course and functional characteristics in vivo. J Neurosci. 2001;21:9134–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Zhang H, Sulzer D. Regulation of striatal dopamine release by presynaptic auto- and heteroreceptors. Basal Ganglia. 2012;2:5–13.

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Brimblecombe KR, Gracie CJ, Platt NJ, Cragg SJ. Gating of dopamine transmission by calcium and axonal N-, Q-, T- and L-type voltage-gated calcium channels differs between striatal domains. J Physiol. 2015;593:929–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Martel P, Leo D, Fulton S, Bérard M, Trudeau L-E. Role of Kv1 potassium channels in regulating dopamine release and presynaptic D2 receptor function. Plos One. 2011;6:e20402.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Becker JB, Chartoff E. Sex differences in neural mechanisms mediating reward and addiction. Neuropsychopharmacology. 2019;44:166–83.

    CAS  PubMed  Google Scholar 

  24. 24.

    Pereira DB, Schmitz Y, Mészáros J, Merchant P, Hu G, Li S, et al. Fluorescent false neurotransmitter reveals functionally silent dopamine vesicle clusters in the striatum. Nat Neurosci. 2016;19:578–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Arnold AP, Chen X. What does the “four core genotypes” mouse model tell us about sex differences in the brain and other tissues? Front Neuroendocrinol. 2009;30:1–9.

    PubMed  Google Scholar 

  26. 26.

    Carruth LL, Reisert I, Arnold AP. Sex chromosome genes directly affect brain sexual differentiation. Nat Neurosci. 2002;5:933–4.

    CAS  PubMed  Google Scholar 

  27. 27.

    McCarthy MM, Arnold AP. Reframing sexual differentiation of the brain. Nat Neurosci. 2011;14:677–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Xiao L, Becker JB. Quantitative microdialysis determination of extracellular striatal dopamine concentration in male and female rats: effects of estrous cycle and gonadectomy. Neurosci Lett. 1994;180:155–8.

    CAS  PubMed  Google Scholar 

  29. 29.

    Yoest KE, Cummings JA, Becker JB. Oestradiol influences on dopamine release from the nucleus accumbens shell: sex differences and the role of selective oestradiol receptor subtypes. Br J Pharm. 2019;176:4136–48.

    CAS  Google Scholar 

  30. 30.

    Calipari ES, Juarez B, Morel C, Walker DM, Cahill ME, Ribeiro E, et al. Dopaminergic dynamics underlying sex-specific cocaine reward. Nat Commun. 2017;8:13877.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Zhang Y, Chen Y-H, Bangaru SD, He L, Abele K, Tanabe S, et al. Origin of the voltage dependence of G-protein regulation of P/Q-type Ca2+ channels. J Neurosci Off. J Soc Neurosci. 2008;28:14176–88.

    CAS  Google Scholar 

  32. 32.

    Schmitz Y, Benoit‐Marand M, Gonon F, Sulzer D. Presynaptic regulation of dopaminergic neurotransmission. J Neurochem. 2003;87:273–89.

    CAS  PubMed  Google Scholar 

  33. 33.

    Becker JB, Beer ME, Robinson TE. Striatal dopamine release stimulated by amphetamine or potassium: influence of ovarian hormones and the light-dark cycle. Brain Res. 1984;311:157–60.

    CAS  PubMed  Google Scholar 

  34. 34.

    Becker JB, Ramirez VD. Sex differences in the amphetamine stimulated release of catecholamines from rat striatal tissue in vitro. Brain Res. 1981;204:361–72.

    CAS  PubMed  Google Scholar 

  35. 35.

    Song Z, Yang H, Peckham EM, Becker JB. Estradiol-Induced potentiation of dopamine release in dorsal striatum following amphetamine administration requires estradiol receptors and mGlu5. ENeuro. 2019;6:ENEURO.0446-18.2019.

  36. 36.

    Becker JB. Direct effect of 17 beta-estradiol on striatum: sex differences in dopamine release. Synapse. 1990;5:157–64.

    CAS  PubMed  Google Scholar 

  37. 37.

    Almey A, Milner TA, Brake WG. Estrogen receptors in the central nervous system and their implication for dopamine-dependent cognition in females. Horm Behav. 2015;74:125–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Creutz LM, Kritzer MF. Mesostriatal and mesolimbic projections of midbrain neurons immunoreactive for estrogen receptor beta or androgen receptors in rats. J Comp Neurol. 2004;476:348–62.

    CAS  PubMed  Google Scholar 

  39. 39.

    Creutz LM, Kritzer MF. Estrogen receptor-β immunoreactivity in the midbrain of adult rats: Regional, subregional, and cellular localization in the A10, A9, and A8 dopamine cell groups. J Comp Neurol. 2002;446:288–300.

    CAS  PubMed  Google Scholar 

  40. 40.

    Almey A, Milner TA, Brake WG. Estrogen receptor α and G-protein coupled estrogen receptor 1 are localized to GABAergic neurons in the dorsal striatum. Neurosci Lett. 2016;622:118–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Almey A, Filardo EJ, Milner TA, Brake WG. Estrogen receptors are found in glia and at extranuclear neuronal sites in the dorsal striatum of female rats: evidence for cholinergic but not dopaminergic colocalization. Endocrinology. 2012;153:5373–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Falardeau P, Di, Paolo T. Regional effect of estradiol on rat caudate-putamen dopamine receptors: lateral-medial differences. Neurosci Lett. 1987;74:43–48.

    CAS  PubMed  Google Scholar 

  43. 43.

    Di Paolo T, Rouillard C, Bédard P. 17β-estradiol at a physiological dose acutely increases dopamine turnover in rat brain. Eur J Pharm. 1985;117:197–203.

    Google Scholar 

  44. 44.

    Pogun S. Sex differences in brain and behavior: emphasis on nicotine, nitric oxide and place learning. Int J Psychophysiol. 2001;42:195–208.

    CAS  PubMed  Google Scholar 

  45. 45.

    Ohtani H, Nomoto M, Douchi T. Chronic estrogen treatment replaces striatal dopaminergic function in ovariectomized rats. Brain Res. 2001;900:163–8.

    CAS  PubMed  Google Scholar 

  46. 46.

    Thompson TL, Moss RL. Estrogen regulation of dopamine release in the nucleus accumbens: genomic-and nongenomic-mediated effects. J Neurochem. 1994;62:1750–6.

    CAS  PubMed  Google Scholar 

  47. 47.

    Dluzen DE, McDermott JL. Sex DIfferences in Dopamine- and Vesicular Monoamine-transporter Functions. Ann N. Y Acad Sci. 2008;1139:140–50.

    CAS  PubMed  Google Scholar 

  48. 48.

    Ford CP. The role of D2-autoreceptors in regulating dopamine neuron activity and transmission. Neuroscience. 2014;282:13–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Palij P, Bull DR, Sheehan MJ, Millar J, Stamford J, Kruk ZL, et al. Presynaptic regulation of dopamine release in corpus striatum monitored in vitro in real time by fast cyclic voltammetry. Brain Res. 1990;509:172–4.

    CAS  PubMed  Google Scholar 

  50. 50.

    Kennedy RT, Jones SR, Wightman RM. Dynamic observation of dopamine autoreceptor effects in rat striatal slices. J Neurochem. 1992;59:449–55.

    CAS  PubMed  Google Scholar 

  51. 51.

    Phillips PEM, Hancock PJ, Stamford JA. Time window of autoreceptor-mediated inhibition of limbic and striatal dopamine release. Synapse. 2002;44:15–22.

    CAS  PubMed  Google Scholar 

  52. 52.

    Rougé-Pont F, Usiello A, Benoit-Marand M, Gonon F, Piazza PV, Borrelli E. Changes in extracellular dopamine induced by morphine and cocaine: crucial control by D2 receptors. J Neurosci. 2002;22:3293–301.

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Anzalone A, Lizardi-Ortiz JE, Ramos M, De Mei C, Hopf FW, Iaccarino C, et al. Dual control of dopamine synthesis and release by presynaptic and postsynaptic dopamine D2 receptors. J Neurosci. 2012;32:9023–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Schmitz Y, Schmauss C, Sulzer D. Altered dopamine release and uptake kinetics in mice lacking D2 receptors. J Neurosci. 2002;22:8002–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Walker QD, Ray R, Kuhn CM. Sex differences in neurochemical effects of dopaminergic drugs in rat striatum. Neuropsychopharmacol Publ Am Coll Neuropsychopharmacol. 2006;31:1193–202.

    CAS  Google Scholar 

  56. 56.

    Vandegrift BJ, You C, Satta R, Brodie MS, Lasek AW. Estradiol increases the sensitivity of ventral tegmental area dopamine neurons to dopamine and ethanol. PloS One. 2017;12:e0187698.

    PubMed  PubMed Central  Google Scholar 

  57. 57.

    Jaber M, Jones S, Giros B, Caron MG. The dopamine transporter: a crucial component regulating dopamine transmission. Mov Disord. 1997;12:629–33.

    CAS  PubMed  Google Scholar 

  58. 58.

    Ciliax BJ, Heilman C, Demchyshyn LL, Pristupa ZB, Ince E, Hersch SM, et al. The dopamine transporter: immunochemical characterization and localization in brain. J Neurosci. 1995;15:1714–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Freed C, Revay R, Vaughan RA, Kriek E, Grant S, Uhl GR, et al. Dopamine transporter immunoreactivity in rat brain. J Comp Neurol. 1995;359:340–9.

    CAS  PubMed  Google Scholar 

  60. 60.

    Jones SR, Gainetdinov RR, Jaber M, Giros B, Wightman RM, Caron MG. Profound neuronal plasticity in response to inactivation of the dopamine transporter. Proc Natl Acad Sci USA. 1998;95:4029–34.

    CAS  PubMed  Google Scholar 

  61. 61.

    Chen N, Reith ME. Structure and function of the dopamine transporter. Eur J Pharm. 2000;405:329–39.

    CAS  Google Scholar 

  62. 62.

    Giros B, Jaber M, Jones SR, Wightman RM, Caron MG. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 1996;379:606–12.

    CAS  PubMed  Google Scholar 

  63. 63.

    Condon MD, Platt NJ, Zhang Y-F, Roberts BM, Clements MA, Vietti-Michelina S, et al. Plasticity in striatal dopamine release is governed by release-independent depression and the dopamine transporter. Nat Commun. 2019;10:4263.

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Morissette M, Biron D, Di Paolo T. Effect of estradiol and progesterone on rat striatal dopamine uptake sites. Brain Res Bull. 1990;25:419–22.

    CAS  PubMed  Google Scholar 

  65. 65.

    Foster JD, Yang J-W, Moritz AE, ChallaSivaKanaka S, Smith MA, Holy M, et al. Dopamine transporter phosphorylation site threonine 53 regulates substrate reuptake and amphetamine-stimulated efflux. J Biol Chem. 2012;287:29702–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Vaughan RA, Foster JD. Mechanisms of dopamine transporter regulation in normal and disease states. Trends Pharm Sci. 2013;34:489–96.

    CAS  PubMed  Google Scholar 

  67. 67.

    Becker JB, Molenda H, Hummer DL. Gender differences in the behavioral responses to cocaine and amphetamine. Ann N. Y Acad Sci. 2001;937:172–87.

    CAS  PubMed  Google Scholar 

  68. 68.

    Cui M, Aras R, Christian WV, Rappold PM, Hatwar M, Panza J, et al. The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway. Proc Natl Acad Sci USA. 2009;106:8043–8.

    CAS  PubMed  Google Scholar 

  69. 69.

    Ji J, Dluzen DE. Sex differences in striatal dopaminergic function within heterozygous mutant dopamine transporter knock-out mice. J Neural Transm. 2008;115:809–17.

    CAS  PubMed  Google Scholar 

  70. 70.

    Erickson JD, Eiden LE, Hoffman BJ. Expression cloning of a reserpine-sensitive vesicular monoamine transporter. Proc Natl Acad Sci. 1992;89:10993–7.

    CAS  PubMed  Google Scholar 

  71. 71.

    Liu Y, Peter D, Roghani A, Schuldiner S, Prive GG, Eisenberg D, et al. A cDNA that suppresses MPP+ toxicity encodes a vesicular amine transporter. Cell 1992;70:539–51.

    CAS  PubMed  Google Scholar 

  72. 72.

    Vastagh C, Liposits Z. Impact of proestrus on gene expression in the medial preoptic area of mice. Front Cell Neurosci. 2017;11:183.

  73. 73.

    Rehavi M, Goldin M, Roz N, Weizman A. Regulation of rat brain vesicular monoamine transporter by chronic treatment with ovarian hormones. Mol Brain Res. 1998;57:31–7.

    CAS  PubMed  Google Scholar 

  74. 74.

    Exley R, Clements MA, Hartung H, McIntosh JM, Cragg SJ. α 6-containing nicotinic acetylcholine receptors dominate the nicotine control of dopamine neurotransmission in nucleus accumbens. Neuropsychopharmacology. 2008;33:2158–66.

    CAS  PubMed  Google Scholar 

  75. 75.

    Brodnik ZD, Batra A, Oleson EB, España RA. Local GABAA receptor-mediated suppression of dopamine release within the nucleus accumbens. ACS Chem Neurosci. 2019;10:1978–85.

    CAS  PubMed  Google Scholar 

  76. 76.

    Huang Y, Thathiah A. Regulation of neuronal communication by G protein-coupled receptors. FEBS Lett. 2015;589:1607–19.

    CAS  PubMed  Google Scholar 

  77. 77.

    Chesselet M-F. Presynaptic regulation of neurotransmitter release in the brain: facts and hypothesis. Neuroscience. 1984;12:347–75.

    CAS  PubMed  Google Scholar 

  78. 78.

    Svingos AL, Chavkin C, Colago EEO, Pickel VM. Major coexpression of κ-opioid receptors and the dopamine transporter in nucleus accumbens axonal profiles. Synapse. 2001;42:185–92.

    CAS  PubMed  Google Scholar 

  79. 79.

    Ronken E, Mulder AH, Schoffelmeer AN. Interacting presynaptic kappa-opioid and GABAA receptors modulate dopamine release from rat striatal synaptosomes. J Neurochem. 1993;61:1634–9.

    CAS  PubMed  Google Scholar 

  80. 80.

    Lopes EF, Roberts BM, Siddorn RE, Clements MA, Cragg SJ. Inhibition of nigrostriatal dopamine release by striatal GABAA and GABAB receptors. J Neurosci. 2019;39:1058–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Kuwajima M, Dehoff MH, Furuichi T, Worley PF, Hall RA, Smith Y. Localization and expression of group I metabotropic glutamate receptors in the mouse striatum, globus pallidus, and subthalamic nucleus: regulatory effects of MPTP treatment and constitutive homer deletion. J Neurosci. 2007;27:6249–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Manzoni O, Michel J-M, Bockaert J. Metabotropic glutamate receptors in the rat nucleus accumbens. Eur J Neurosci. 1997;9:1514–23.

    CAS  PubMed  Google Scholar 

  83. 83.

    Shin JH, Adrover MF, Wess J, Alvarez VA. Muscarinic regulation of dopamine and glutamate transmission in the nucleus accumbens. Proc Natl Acad Sci. 2015;112:8124–9.

    CAS  PubMed  Google Scholar 

  84. 84.

    Zhang W, Yamada M, Gomeza J, Basile AS, Wess J. Multiple muscarinic acetylcholine receptor subtypes modulate striatal dopamine release, as studied with M1–M5 muscarinic receptor knock-out mice. J Neurosci. 2002;22:6347–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Meitzen J, Meisel RL, Mermelstein PG. Sex differences and the effects of estradiol on striatal function. Curr Opin. Behav Sci. 2018;23:42–8.

    Google Scholar 

  86. 86.

    Pitman KA, Puil E, Borgland SL. GABA(B) modulation of dopamine release in the nucleus accumbens core. Eur J Neurosci. 2014;40:3472–80.

    PubMed  Google Scholar 

  87. 87.

    Brog JS, Salyapongse A, Deutch AY, Zahm DS. The patterns of afferent innervation of the core and shell in the “Accumbens” part of the rat ventral striatum: immunohistochemical detection of retrogradely transported fluoro-gold. J Comp Neurol. 1993;338:255–78.

    CAS  PubMed  Google Scholar 

  88. 88.

    Pennartz CM, Groenewegen HJ, Lopes, da Silva FH. The nucleus accumbens as a complex of functionally distinct neuronal ensembles: an integration of behavioural, electrophysiological and anatomical data. Prog Neurobiol. 1994;42:719–61.

    CAS  PubMed  Google Scholar 

  89. 89.

    Thibeault KC, Kutlu MG, Sanders C, Calipari ES. Cell-type and projection-specific dopaminergic encoding of aversive stimuli in addiction. Brain Res. 2019;1713:1–15.

    CAS  PubMed  Google Scholar 

  90. 90.

    Hruska RE, Pitman KT. Distribution and localization of estrogen-sensitive dopamine receptors in the rat brain. J Neurochem. 1982;39:1418–23.

    CAS  PubMed  Google Scholar 

  91. 91.

    Miller JC. Sex differences in dopaminergic and cholinergic activity and function in the nigro-striatal system of the rat. Psychoneuroendocrinology. 1983;8:225–36.

    CAS  PubMed  Google Scholar 

  92. 92.

    Lévesque D, Gagnon S, Di Paolo T. Striatal D1 dopamine receptor density fluctuates during the rat estrous cycle. Neurosci Lett. 1989;98:345–50.

    PubMed  Google Scholar 

  93. 93.

    Planert H, Berger TK, Silberberg G. Membrane properties of striatal direct and indirect pathway neurons in mouse and rat slices and their modulation by dopamine. PLos One. 2013;8:e57054.

  94. 94.

    Cao J, Willett JA, Dorris DM, Meitzen J Sex Differences in Medium Spiny Neuron Excitability and Glutamatergic Synaptic Input: Heterogeneity Across Striatal Regions and Evidence for Estradiol-Dependent Sexual Differentiation. Front Endocrinol. 2018;9.

  95. 95.

    Mermelstein PG, Becker JB, Surmeier DJ. Estradiol reduces calcium currents in rat neostriatal neurons via a membrane receptor. J Neurosci. 1996;16:595–604.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Schultz KN, Esenwein SA, von, Hu M, Bennett AL, Kennedy RT, Musatov S, et al. Viral vector-mediated overexpression of estrogen receptor-α in striatum enhances the estradiol-induced motor activity in female rats and estradiol-modulated GABA release. J Neurosci. 2009;29:1897–903.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Hu M, Watson CJ, Kennedy RT, Becker JB. Estradiol attenuates the K+-induced increase in extracellular GABA in rat striatum. Synapse. 2006;59:122–4.

    CAS  PubMed  Google Scholar 

  98. 98.

    Xiao L, Becker JB. Effects of estrogen agonists on amphetamine-stimulated striatal dopamine release. Synapse. 1998;29:379–91.

    CAS  PubMed  Google Scholar 

  99. 99.

    Meitzen J, Mermelstein PG. Estrogen receptors stimulate brain region specific metabotropic glutamate receptors to rapidly initiate signal transduction pathways. J Chem Neuroanat. 2011;42:236–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Zhang H, Sulzer D. Glutamate spillover in the striatum depresses dopaminergic transmission by activating group I metabotropic glutamate receptors. J Neurosci. 2003;23:10585–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Liss B, Roeper J. Ion channels and regulation of dopamine neuron activity. (Oxford University Press, 2009).

  102. 102.

    Rice ME, Cragg SJ. Nicotine amplifies reward-related dopamine signals in striatum. Nat Neurosci. 2004;7:583–4.

    CAS  PubMed  Google Scholar 

  103. 103.

    Zhang H, Sulzer D. Frequency-dependent modulation of dopamine release by nicotine. Nat Neurosci. 2004;7:581–2.

    CAS  PubMed  Google Scholar 

  104. 104.

    Jin X, Steinbach JH. A portable site: a binding element for 17β-estradiol can be placed on any subunit of a nicotinic α4β2 receptor. J Neurosci. 2011;31:5045–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Exley R, Cragg SJ. Presynaptic nicotinic receptors: a dynamic and diverse cholinergic filter of striatal dopamine neurotransmission. Br J Pharm. 2008;153:S283–S297.

    CAS  Google Scholar 

  106. 106.

    Gibbs R. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Yee J, Famous KR, Hopkins TJ, McMullen MC, Pierce RC, Schmidt HD. Muscarinic acetylcholine receptors in the nucleus accumbens core and shell contribute to cocaine priming-induced reinstatement of drug seeking. Eur J Pharm. 2011;650:596–604.

    CAS  Google Scholar 

  108. 108.

    Mateo Y, Johnson KA, Covey DP, Atwood BK, Wang H-L, Zhang S, et al. Endocannabinoid actions on cortical terminals orchestrate local modulation of dopamine release in the nucleus accumbens. Neuron. 2017;96:1112–26.e5.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Adrover MF, Shin JH, Quiroz C, Ferré S, Lemos JC, Alvarez VA. Prefrontal cortex-driven dopamine signals in the striatum show unique spatial and pharmacological properties. J Neurosci. 2020;40:7510–22.

    CAS  PubMed  Google Scholar 

  110. 110.

    Kosillo P, Zhang Y-F, Threlfell S, Cragg SJ. Cortical control of striatal dopamine transmission via striatal cholinergic interneurons. Cereb Cortex N. Y NY. 2016;26:4160–9.

    Google Scholar 

  111. 111.

    Lemos JC, Shin JH, Alvarez VA. Striatal cholinergic interneurons are a novel target of corticotropin releasing factor. J Neurosci. 2019;39:5647–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Bruijnzeel AW. Kappa-opioid receptor signaling and brain reward function. Brain Res Rev. 2009;62:127–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Russell SE, Rachlin AB, Smith KL, Muschamp J, Berry L, Zhao Z, et al. Sex differences in sensitivity to the depressive-like effects of the kappa opioid receptor agonist U-50488 in rats. Biol Psychiatry. 2014;76:213–22.

    CAS  PubMed  Google Scholar 

  114. 114.

    Chartoff EH, Mavrikaki M. Sex differences in kappa opioid receptor function and their potential impact on addiction. Front Neurosci. 2015;9:466.

  115. 115.

    Conway SM, Puttick D, Russell S, Potter D, Roitman MF, Chartoff EH. Females are less sensitive than males to the motivational- and dopamine-suppressing effects of kappa opioid receptor activation. Neuropharmacology. 2019;146:231–41.

    CAS  PubMed  Google Scholar 

  116. 116.

    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.

    CAS  PubMed  Google Scholar 

  117. 117.

    Lynch WJ, Roth ME, Carroll ME. Biological basis of sex differences in drug abuse: preclinical and clinical studies. Psychopharmacology. 2002;164:121–37.

    CAS  PubMed  Google Scholar 

  118. 118.

    Carroll ME, Smethells JR. Sex differences in behavioral dyscontrol: role in drug addiction and novel treatments. Front Psychiatry. 2016;6:175.

  119. 119.

    Ovtscharoff W, Eusterschulte B, Zienecker R, Reisert I, Pilgrim C. Sex differences in densities of dopaminergic fibers and GABAergic neurons in the prenatal rat striatum. J Comp Neurol. 1992;323:299–304.

    CAS  PubMed  Google Scholar 

  120. 120.

    Collins AL, Aitken TJ, Greenfield VY, Ostlund SB, Wassum KM. Nucleus accumbens acetylcholine receptors modulate dopamine and motivation. Neuropsychopharmacology. 2016;41:2830–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Kutlu MG, Zachry JE, Brady LJ, Melugin PR, Kelly SJ, Sanders C, et al. A novel multidimensional reinforcement task in mice elucidates sex-specific behavioral strategies. Neuropsychopharmacology. 2020;45:1463–72.

    PubMed  Google Scholar 

  122. 122.

    Nestler EJ, Carlezon WA. The mesolimbic dopamine reward circuit in depression. Biol Psychiatry. 2006;59:1151–9.

    CAS  PubMed  Google Scholar 

  123. 123.

    Koob GF. Dopamine, addiction and reward. Semin Neurosci. 1992;4:139–48.

    Google Scholar 

  124. 124.

    Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology. 2010;35:217–38.

    PubMed  Google Scholar 

  125. 125.

    Zachry JE, Johnson AR, Calipari ES. Sex differences in value-based decision making underlie substance use disorders in females. Alcohol Alcohol. 2019;54:339–41.

    PubMed  PubMed Central  Google Scholar 

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ESC, JEZ, SON, and CAS conceptualized, wrote, and edited the manuscript. LJB and SJK wrote and edited the manuscript. ESC, JEZ, and SON made the figures.

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Correspondence to Erin S. Calipari.

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Zachry, J.E., Nolan, S.O., Brady, L.J. et al. Sex differences in dopamine release regulation in the striatum. Neuropsychopharmacol. 46, 491–499 (2021).

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