Epigenetic upregulation of PSD-95 contributes to the rewarding behavior by morphine conditioning.
Abuse of opiates, including morphine, induced remarkable synaptic adaptation in several brain regions including ventral tegmental area (VTA), which underlay the induction and maintenance of opioid dependence and addiction. Scaffolding protein postsynaptic density protein 95 (PSD-95) is critically involved in the glutamatergic synaptic maturation and plasticity in the central neurons. The present study revealed a significantly increased mRNA and protein expression of PSD-95 in the VTA of the rats conditioned with morphine. The further chromatin immunoprecipitation study found an increased histone H3 acetylation in the promoter region of Dlg4. An upregulation of expression of phosphorylated cAMP response element-binding protein (pCREB) and the occupancy of pCREB in the Dlg4 promoter region were shown in the VTA of the morphine-conditioned rats. Inhibition of pCREB activity significantly decreased the histone H3 acetylation in Dlg4 promoter region, PSD-95 upregulation, enhancement of glutamatergic strength and the preference to morphine-paired chamber in the rats with morphine conditioning. These results suggested that CREB-mediated epigenetic upregulation of PSD-95 critically contributed to the enhanced glutamatergic transmission and rewarding behavior induced by morphine conditioning.
Department of Preventive Medicine, Third Military Medical University, Chongqing 400038, China; Department of Neurobiology, Third Military Medical University, Chongqing 400038, China.
Ziwen
Z
Wang
Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Pingao
P
Yan
Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Tianli
T
Hui
Department of Neurobiology, Third Military Medical University, Chongqing 400038, China. Electronic address: jqzhang01@163.com.
Jiqiang
J
Zhang
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects*; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors; D000076122:Disks Large Homolog 4 Protein; D044127:Epigenesis, Genetic / Q000187:drug effects*; D018698:Glutamic Acid / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D009020:Morphine / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward; D015854:Up-Regulation / Q000187:drug effects
D017362:Cyclic AMP Response Element-Binding Protein; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009294:Narcotics; D018698:Glutamic Acid; D009020:Morphine
Glutamatergic transmission; Histone acetylation; Morphine; Postsynaptic density protein 95; cAMP response element-binding protein