Dopamine Receptor D2 and Associated microRNAs Are Involved in Stress Susceptibility and Resistance to Escitalopram Treatment.
BACKGROUND
Early life stress has been demonstrated to increase the risk of developing depression in adulthood. However, the roles and associated molecular mechanisms of stresses in the onset and relapse of depression have yet to be fully elucidated.


METHODS
Depression-like behaviors were induced in rats by maternal deprivation and chronic unpredictable stress. Depression- and anxiety-like behaviors of rats, dopamine receptor D2 level, and microRNAs expression in rats' brain tissues were measured.


RESULTS
Chronic unpredictable stress alone induced depression-like behaviors in rats, but maternal deprivation enhanced the effect of chronic unpredictable stress. Escitalopram significantly decreased depression-like behaviors in chronic unpredictable stress rats but was less effective in maternal deprivation with chronic unpredictable stress rats. Maternal deprivation increased dopamine receptor D2 messenger RNA expression and decreased microRNA-9 expression in the striatum. Chronic unpredictable stress increased dopamine receptor D2 mRNA and protein levels and decreased microRNA-9 expression in the nucleus accumbens. Furthermore, maternal deprivation enhanced the effect of chronic unpredictable stress on dopamine receptor D2 gene and microRNA-9 expression. Chronic unpredictable stress increased the expression of microRNA-326 in the nucleus accumbens but decreased it in the striatum, whereas maternal deprivation elevated microRNA-326 expression in the striatum. Escitalopram normalized microRNA-326 expression but had no effect on the expression of microRNA-9, dopamine receptor D2 mRNA, and dopamine receptor D2 protein in both the nucleus accumbens and striatum. The in vitro study showed that only microRNA-9 directly targeted the 3' untranslated region of dopamine receptor D2 mRNA and inhibited dopamine receptor D2 protein expression.


CONCLUSIONS
Early life stress enhanced the susceptibility to late life stress and resistance to escitalopram treatment through decreasing microRNA-9 expression and subsequently upregulating dopamine receptor D2 expression in the nucleus accumbens. microRNA-326 may be a novel target of escitalopram.
Medical Psychological Institute, Second Xiangya Hospital, Central South University,Changsha, PR China (Drs Y. Zhang, Y. Wang, L. Wang, Bai, and Zhu); Department of Radiation Oncology, University of Maryland, Baltimore, MD (Drs Y. Zhang and X. Zhang); National Technology Institute of Psychiatry, Central South University, Changsha, PR China (Drs Y. Wang and L. Wang); Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South University, Changsha, PR China (Drs Bai and Zhu).
Yi
Y
Zhang
Medical Psychological Institute, Second Xiangya Hospital, Central South University,Changsha, PR China (Drs Y. Zhang, Y. Wang, L. Wang, Bai, and Zhu); Department of Radiation Oncology, University of Maryland, Baltimore, MD (Drs Y. Zhang and X. Zhang); National Technology Institute of Psychiatry, Central South University, Changsha, PR China (Drs Y. Wang and L. Wang); Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South University, Changsha, PR China (Drs Bai and Zhu).
Yuting
Y
Wang
Medical Psychological Institute, Second Xiangya Hospital, Central South University,Changsha, PR China (Drs Y. Zhang, Y. Wang, L. Wang, Bai, and Zhu); Department of Radiation Oncology, University of Maryland, Baltimore, MD (Drs Y. Zhang and X. Zhang); National Technology Institute of Psychiatry, Central South University, Changsha, PR China (Drs Y. Wang and L. Wang); Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South University, Changsha, PR China (Drs Bai and Zhu).
Lei
L
Wang
Medical Psychological Institute, Second Xiangya Hospital, Central South University,Changsha, PR China (Drs Y. Zhang, Y. Wang, L. Wang, Bai, and Zhu); Department of Radiation Oncology, University of Maryland, Baltimore, MD (Drs Y. Zhang and X. Zhang); National Technology Institute of Psychiatry, Central South University, Changsha, PR China (Drs Y. Wang and L. Wang); Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South University, Changsha, PR China (Drs Bai and Zhu).
Mei
M
Bai
Medical Psychological Institute, Second Xiangya Hospital, Central South University,Changsha, PR China (Drs Y. Zhang, Y. Wang, L. Wang, Bai, and Zhu); Department of Radiation Oncology, University of Maryland, Baltimore, MD (Drs Y. Zhang and X. Zhang); National Technology Institute of Psychiatry, Central South University, Changsha, PR China (Drs Y. Wang and L. Wang); Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South University, Changsha, PR China (Drs Bai and Zhu).
Xiuwu
X
Zhang
Medical Psychological Institute, Second Xiangya Hospital, Central South University,Changsha, PR China (Drs Y. Zhang, Y. Wang, L. Wang, Bai, and Zhu); Department of Radiation Oncology, University of Maryland, Baltimore, MD (Drs Y. Zhang and X. Zhang); National Technology Institute of Psychiatry, Central South University, Changsha, PR China (Drs Y. Wang and L. Wang); Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South University, Changsha, PR China (Drs Bai and Zhu). xiongzhaozhu@163.com.
Xiongzhao
X
Zhu
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D002908:Chronic Disease; D015283:Citalopram / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism*; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000502:physiology; D008297:Male; D008426:Maternal Deprivation; D035683:MicroRNAs / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013315:Stress, Psychological / Q000188:drug therapy / Q000378:metabolism; D035501:Uncertainty
D018687:Antidepressive Agents, Second-Generation; C000605119:MIRN326 microRNA, rat; C582333:MIRN9 microRNA, rat; D035683:MicroRNAs; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D015283:Citalopram
depression; dopamine receptor D2; microRNAs; stress