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

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Abstract

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-β-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 ERα antagonist Y134 largely attenuated the cocaine-inhibited DA neuron firing. We also found that cocaine-induced locomotor activity was estrous cycle dependant; 17-β-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.

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Acknowledgments

This work was supported by the National Basic Research plan of the Ministry of Science and Technology (2007AA02z163; 2007CB935804), a Pujiang-plan grant from the Shanghai Commission of Science and Technology (07pj14104), and a grant Natural Science Foundation of China (30770662).

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  1. State Key Laboratory of Drug Research, Department of Neuropharmacology, Shanghai Institute of Material Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Pudong, Rm# 2-315, Shanghai, 201203, China

    Die Zhang, Shen Yang, Chunhao Yang, Guozhang Jin & Xuechu Zhen

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  1. Die Zhang
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  2. Shen Yang
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  3. Chunhao Yang
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  4. Guozhang Jin
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Correspondence to Xuechu Zhen.

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Zhang, D., Yang, S., Yang, C. et al. Estrogen regulates responses of dopamine neurons in the ventral tegmental area to cocaine. Psychopharmacology 199, 625–635 (2008). https://doi.org/10.1007/s00213-008-1188-6

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  • DOI: https://doi.org/10.1007/s00213-008-1188-6

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