title: Long-lasting potentiation of GABAergic synapses in dopamine neurons after a single in vivo ethanol exposure.
abstract: The mesolimbic dopamine (DA) system originating in the ventral tegmental area (VTA) is involved in many drug-related behaviors, including ethanol self-administration. In particular, VTA activity regulating ethanol consummatory behavior appears to be modulated through GABA(A) receptors. Previous exposure to ethanol enhances ethanol self-administration, but the mechanisms underlying this phenomenon are not well understood. In this study, we examined changes occurring at GABA synapses onto VTA DA neurons after a single in vivo exposure to ethanol. We observed that evoked GABA(A) IPSCs in DA neurons of ethanol-treated animals exhibited paired-pulse depression (PPD) compared with saline-treated animals, which exhibited paired-pulse facilitation (PPF). Furthermore, PPD was still present 1 week after the single exposure to ethanol. An increase in frequency of spontaneous miniature GABA(A) IPSCs (mIPSCs) was also observed in the ethanol-treated animals. Additionally, the GABA(B) receptor antagonist (3-aminopropyl)(diethoxymethyl) phosphinic acid shifted PPD to PPF, indicating that presynaptic GABA(B) receptor activation, likely attributable to GABA spillover, might play a role in mediating PPD in the ethanol-treated mice. The activation of adenylyl cyclase by forskolin increased the amplitude of GABA(A) IPSCs and the frequency of mIPSCs in the saline- but not in the ethanol-treated animals. Conversely, the protein kinase A (PKA) inhibitor N-[z-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide significantly decreased both the frequency of spontaneous mIPSCs and the amplitude of GABA(A) IPSCs in the ethanol-treated mice but not in the saline controls. The present results indicate that potentiation of GABAergic synapses, via a PKA-dependent mechanism, occurs in the VTA after a single in vivo exposure to ethanol, and such potentiation might be a key synaptic modification underlying increased ethanol intake.
authors.affiliation: Ernest Gallo Clinic and Research Center, Department of Neurology, University of California, San Francisco, California 94110, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Melis
authors.forename: Rosana
authors.initials: R
authors.lastname: Camarini
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ungless
authors.forename: Antonello
authors.initials: A
authors.lastname: Bonci
mesh_terms: D000284:Administration, Oral; D000437:Alcoholism / Q000209:etiology; D000818:Animals; D002755:Choice Behavior / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004558:Electric Stimulation; D000431:Ethanol / Q000008:administration & dosage* / Q000097:blood; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011963:Receptors, GABA-A / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D018755:GABA Agonists; D018756:GABA Antagonists; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D011963:Receptors, GABA-A; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D017868:Cyclic AMP-Dependent Protein Kinases; D004298:Dopamine