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

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 ER alpha antagonist Y134 largely attenuated the cocaine-inhibited DA neuron firing. We also found that cocaine-induced locomotor activity was estrous cycle dependant; 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.