Oestradiol influences on dopamine release from the nucleus accumbens shell: sex differences and the role of selective oestradiol receptor subtypes

Br J Pharmacol. 2019 Nov;176(21):4136-4148. doi: 10.1111/bph.14531. Epub 2018 Dec 18.


Background and purpose: Females are more sensitive than males to both the acute and prolonged effects of psychomotor stimulants. In females, this is regulated by oestradiol, which enhances dopamine release in the dorsal striatum. In this study, we tested the acute effect of oestradiol on dopamine release in the nucleus accumbens (NAc) shell after cocaine administration and investigated which oestradiol receptors (ERs) contribute to sex differences in the response to cocaine.

Experimental approach: The ability of oestradiol benzoate (EB) to acutely modulate the effect of cocaine on phasic dopamine release in the NAc shell was measured by fast-scan cyclic voltammetry in anaesthetized male and female rats. The roles of ER subtypes, ERα and ERβ, was determined with selective agonists.

Key results: EB acutely enhanced the effect of cocaine on stimulated dopamine release from the NAc shell in females but not in male rats only at levels of stimulation expected to optimally saturate dopamine transporters. Enhanced dopamine release after cocaine administration was also observed in females after selective activation of ERβ but not ERα. EB attenuated the effect of cocaine on NAc shell dopamine reuptake in males but not in females.

Conclusions and implications: Oestradiol acutely and rapidly regulates dopamine release in females and dopamine reuptake in males. In females, oestradiol rapidly enhances the effect of cocaine on dopamine release, likely via activation of ERβ. The effect of oestradiol in males is not seen with selective receptor subtype activation, a topic deserving of further study.

Linked articles: This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cocaine / pharmacology*
  • Dopamine / metabolism*
  • Dopamine Uptake Inhibitors / pharmacology*
  • Estradiol / metabolism*
  • Estrogens / metabolism*
  • Female
  • Male
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism*
  • Rats, Sprague-Dawley
  • Receptors, Estrogen / metabolism
  • Sex Characteristics*


  • Dopamine Uptake Inhibitors
  • Estrogens
  • Receptors, Estrogen
  • Estradiol
  • Cocaine
  • Dopamine