Morphine-induced synaptic plasticity in the VTA is reversed by HDAC inhibition.
Dopamine (DA) dysfunction originating from the ventral tegmental area (VTA) occurs as a result of synaptic abnormalities following consumption of drugs of abuse and underlies behavioral plasticity associated with drug abuse. Drugs of abuse can cause changes in gene expression through epigenetic mechanisms in the brain that underlie some of the lasting neuroplasticity and behavior associated with addiction. Here we investigated the function of histone acetylation and histone deacetylase (HDAC)2 in the VTA in recovery of morphine-induced synaptic modifications following a single in vivo exposure to morphine. Using a combination of immunohistochemistry, Western blot, and whole cell patch-clamp recording in rat midbrain slices, we show that morphine increased HDAC2 activity in VTA DA neurons and reduced histone H3 acetylation at lysine 9 (Ac-H3K9) in the VTA 24 h after the injection. Morphine-induced synaptic changes at glutamatergic synapses involved endocannabinoid signaling to reduce GABAergic synaptic strength onto VTA DA neurons. Both plasticities were recovered by in vitro incubation of midbrain slices with a class I-specific HDAC inhibitor (HDACi), CI-994, through an increase in acetylation of histone H3K9. Interestingly, HDACi incubation also increased levels of Ac-H3K9 and triggered GABAergic and glutamatergic plasticities in DA neurons of saline-treated rats. Our results suggest that acute morphine-induced changes in VTA DA activity and synaptic transmission engage HDAC2 activity locally in the VTA to maintain synaptic modifications through histone hypoacetylation.
Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Michael E
ME
Authement
Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Ludovic D
LD
Langlois
Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Haifa
H
Kassis
Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Shawn
S
Gouty
Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Matthieu
M
Dacher
Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Ryan D
RD
Shepard
Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Brian M
BM
Cox
Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland fereshteh.nugent@usuhs.edu.
Fereshteh S
FS
Nugent
D000818:Animals; D000831:Animals, Newborn; D048588:Benzoxazines / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D009020:Morphine / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D009473:Neuronal Plasticity / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects*
D048588:Benzoxazines; D002121:Calcium Channel Blockers; D018690:Excitatory Amino Acid Agonists; D056572:Histone Deacetylase Inhibitors; D009025:Morpholines; D009281:Naphthalenes; D009294:Narcotics; D008734:Methoxyhydroxyphenylglycol; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D009020:Morphine; D014446:Tyrosine 3-Monooxygenase; D056464:Histone Deacetylase 2; C010117:3,4-dihydroxyphenylglycol
electrophysiology; histone deacetylase; synaptic plasticity; synaptic transmission; ventral tegmental area