GABA transmission in the nucleus accumbens is altered after withdrawal from repeated cocaine.
Repeated cocaine causes enduring changes in dopamine and glutamate transmission in the nucleus accumbens, and dopamine and glutamate terminals synapse on GABAergic accumbens neurons. The present study demonstrates that there are changes in GABA transmission in the accumbens at 3 weeks after discontinuing daily cocaine injections. No-net flux microdialysis revealed a significant increase in the basal levels of extracellular GABA in the accumbens of cocaine-treated rats. The elevated extracellular GABA was normalized by blocking voltage-dependent Na+ channels and provided increased tone on GABA(B) presynaptic autoreceptors and heteroreceptors because blocking GABA(B) receptors produced a greater elevation in extracellular GABA, dopamine, and glutamate in cocaine-treated compared with control subjects. For many G-protein-coupled receptors, increased agonist can cause receptor desensitization. Consistent with GABA(B) receptor desensitization, baclofen-stimulated GTPgammaS binding was reduced, and the reduction in G-protein coupling was accompanied by reduced Ser phosphorylation of the GABA(B2) receptor subunit. No effect by repeated cocaine was found in the levels of total GABA(B1) or GABA(B2) protein. Together, these data demonstrate that withdrawal from repeated cocaine treatment produces an increase in the basal levels of extracellular GABA in the accumbens that depends on neuronal activity. The increase may be mediated in part by functional desensitization of GABA(B) receptors, likely the result of diminished Ser phosphorylation of the GABA(B2) receptor.
Xi
Zheng-Xiong
ZX
Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Ramamoorthy
Sammanda
S
Shen
Hui
H
Lake
Russell
R
Samuvel
Devadoss J
DJ
Kalivas
Peter W
PW
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002908:Chronic Disease; D003042:Cocaine / Q000009:adverse effects; D019970:Cocaine-Related Disorders / Q000503:physiopathology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000032:analysis / Q000378:metabolism; D004334:Drug Administration Schedule; D005110:Extracellular Space / Q000737:chemistry / Q000378:metabolism; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D018698:Glutamic Acid / Q000032:analysis / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D008297:Male; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000503:physiopathology*; D010766:Phosphorylation / Q000187:drug effects; D021122:Protein Subunits / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000032:analysis / Q000378:metabolism*
D018755:GABA Agonists; D018756:GABA Antagonists; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D021122:Protein Subunits; D018080:Receptors, GABA-B; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D003042:Cocaine; D004298:Dopamine