Estrogen regulates responses of dopamine neurons in the ventral tegmental area to cocaine.
BACKGROUND
Sex differences in cocaine abuse have been well documented. However, the underlying mechanism remains unclear.


OBJECTIVE
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.


CONCLUSIONS
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.
State Key Laboratory of Drug Research, Department of Neuropharmacology, Shanghai Institute of Material Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai, China.
Die
D
Zhang
Shen
S
Yang
Chunhao
C
Yang
Guozhang
G
Jin
Xuechu
X
Zhen
D000818:Animals; D002452:Cell Count; D003042:Cocaine / Q000494:pharmacology*; D003627:Data Interpretation, Statistical; D004298:Dopamine / Q000502:physiology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology / Q000502:physiology*; D030762:Estrous Cycle / Q000502:physiology*; D005260:Female; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D010052:Ovariectomy; D020891:Raclopride / Q000494:pharmacology; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects*
D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D004965:Estrogen Antagonists; D004967:Estrogens; D020891:Raclopride; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D003042:Cocaine; D004298:Dopamine