Plasticity of GABA(A) receptor-mediated neurotransmission in the nucleus accumbens of alcohol-dependent rats.
Chronic alcohol exposure-induced changes in reinforcement mechanisms and motivational state are thought to contribute to the development of cravings and relapse during protracted withdrawal. The nucleus accumbens (NAcc) is a key structure of the mesolimbic dopaminergic reward system and plays an important role in mediating alcohol-seeking behaviors. Here we describe the long-lasting alterations of γ-aminobutyric acid type A receptors (GABA(A)Rs) of medium spiny neurons (MSNs) in the NAcc after chronic intermittent ethanol (CIE) treatment, a rat model of alcohol dependence. CIE treatment and withdrawal (>40 days) produced decreases in the ethanol and Ro15-4513 potentiation of extrasynaptic GABA(A)Rs, which mediate the picrotoxin-sensitive tonic current (I(tonic)), while potentiation of synaptic receptors, which give rise to miniature inhibitory postsynaptic currents (mIPSCs), was increased. Diazepam sensitivity of both I(tonic) and mIPSCs was decreased by CIE treatment. The average magnitude of I(tonic) was unchanged, but mIPSC amplitude and frequency decreased and mIPSC rise time increased after CIE treatment. Rise-time histograms revealed decreased frequency of fast-rising mIPSCs after CIE treatment, consistent with possible decreases in somatic GABAergic synapses in MSNs from CIE rats. However, unbiased stereological analysis of NeuN-stained NAcc neurons did not detect any decreases in NAcc volume, neuronal numbers, or neuronal cell body volume. Western blot analysis of surface subunit levels revealed selective decreases in α1 and δ and increases in α4, α5, and γ2 GABA(A)R subunits after CIE treatment and withdrawal. Similar, but reversible, alterations occurred after a single ethanol dose (5 g/kg). These data reveal CIE-induced long-lasting neuroadaptations in the NAcc GABAergic neurotransmission.
Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, California; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California;
Jing
J
Liang
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California;
A Kerstin
AK
Lindemeyer
Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, California;
Asha
A
Suryanarayanan
Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, California;
Edward M
EM
Meyer
Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, California;
Vincent N
VN
Marty
Doisy College of Health Sciences, Saint Louis University, St. Louis, Missouri; and.
S Omar
SO
Ahmad
Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, California.
Xuesi Max
XM
Shao
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California;
Richard W
RW
Olsen
Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, California; igor@ucla.edu.
Igor
I
Spigelman
D000437:Alcoholism / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D059330:GABAergic Neurons / Q000378:metabolism / Q000502:physiology; D053444:Inhibitory Postsynaptic Potentials; D008297:Male; D055369:Miniature Postsynaptic Potentials; D009473:Neuronal Plasticity; D009714:Nucleus Accumbens / Q000166:cytology / Q000378:metabolism* / Q000503:physiopathology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*
D021122:Protein Subunits; D011963:Receptors, GABA-A
ethanol; neuroadaptation; tonic current; ventral striatum; withdrawal