Estrogen regulates responses of dopamine neurons in the ventral tegmental area to cocaine

Psychopharmacology (Berl). 2008 Sep;199(4):625-35. doi: 10.1007/s00213-008-1188-6. Epub 2008 Jun 1.


Rationale: Sex differences in cocaine abuse have been well documented. However, the underlying mechanism remains unclear.

Objectives: To explore the potential role of ovarian hormones in the regulation of dopamine (DA) neuron firing activity in ventral tegmental area (VTA) induced by acute cocaine in intact female or ovariectomized (OVX) rats.

Results: The basal firing activity of VTA DA neurons was changed in a manner phase-locked to the estrous cycle: being highest in estrus and lowest in proestrus. Acute cocaine produced greater inhibition (P < 0.05) on the firing of VTA DA neurons during proestrus than during estrus. The inhibitory effect was completely blocked by OVX and restored by replacement of 17-beta-estradiol or, to a less extent, by replacement of progesterone. In addition, we also detected female hormone-associated changes in slow oscillation in VTA DA neurons. The results indicate that ovarian hormones, particularly estrogen, not only synergize with the inhibitory effect of cocaine on VTA DA neuron activity but also play an essential role in maintaining the sensitivity of DA neurons to cocaine-mediated inhibition on firing. Moreover, pretreatment of estrogen receptor (ER) antagonist raloxifene or a selective ERalpha antagonist Y134 largely attenuated the cocaine-inhibited DA neuron firing. We also found that cocaine-induced locomotor activity was estrous cycle dependent; 17-beta-estradiol but not progesterone replacement restored the cocaine-induced locomotor activity in OVX rats.

Conclusion: The present results demonstrated that ovarian hormones, particularly estrogen, produce profound effect on VTA DA neuron activity, which, in turn, may contribute to the sex differences in response to psychostimulants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Count
  • Cocaine / pharmacology*
  • Data Interpretation, Statistical
  • Dopamine / physiology*
  • Dopamine Antagonists / pharmacology
  • Dopamine Uptake Inhibitors / pharmacology*
  • Estradiol / pharmacology
  • Estrogen Antagonists / pharmacology
  • Estrogens / pharmacology
  • Estrogens / physiology*
  • Estrous Cycle / physiology*
  • Female
  • Motor Activity / drug effects
  • Neurons / drug effects*
  • Ovariectomy
  • Raclopride / pharmacology
  • Raloxifene Hydrochloride / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Ventral Tegmental Area / cytology
  • Ventral Tegmental Area / drug effects*


  • Dopamine Antagonists
  • Dopamine Uptake Inhibitors
  • Estrogen Antagonists
  • Estrogens
  • Raclopride
  • Raloxifene Hydrochloride
  • Estradiol
  • Cocaine
  • Dopamine