title: Ethanol facilitates glutamatergic transmission to dopamine neurons in the ventral tegmental area.
abstract: The cellular mechanisms underlying alcohol addiction are poorly understood. In several brain areas, ethanol depresses glutamatergic excitatory transmission, but how it affects excitatory synapses on dopamine neurons of the ventral tegmental area (VTA), a crucial site for the development of drug addiction, is not known. We report here that in midbrain slices from rats, clinically relevant concentrations of ethanol (10-80 mM) increase the amplitude of evoked EPSCs and reduce their paired-pulse ratio in dopamine neurons in the VTA. The EPSCs were mediated by glutamate alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. In addition, ethanol increases the frequency but not the amplitude of spontaneous EPSCs. Furthermore, ethanol increases extracellular glutamate levels in the VTA of midbrain slices. The effects of ethanol are mimicked by SKF 38393, a dopamine D(1) receptor agonist, and by GBR 12935, a dopamine reuptake inhibitor, and they are blocked by SKF 83566, a D(1) antagonist, or by reserpine, which depletes dopamine stores. The enhancement of sEPSC frequency reaches a peak with 40 mM ethanol and declines with concentrations >or=80 mM ethanol, which is quite likely a result of D(2) receptor activation as raclopride, a D(2) receptor blocker, significantly enhanced 80 mM ethanol-induced enhancement of sEPSCs. Finally, 6, 7-dinitroquinoxaline-2, 3-dione (DNQX), an AMPA receptor antagonist, attenuates ethanol-induced excitation of VTA DA neurons. We therefore conclude that, acting via presynaptic D(1) receptors, ethanol at low concentrations increases glutamate release in the VTA, thus raising somatodendritic dopamine release, which further activates the presynaptic D(1) receptors. Enhancement of this positive feedback loop may significantly contribute to the development of alcohol addiction.
authors.affiliation: Department of Anesthesiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Xiao
authors.forename: Xuesi Max
authors.initials: XM
authors.lastname: Shao
authors.forename: M Foster
authors.initials: MF
authors.lastname: Olive
authors.forename: William C
authors.initials: WC
authors.lastname: Griffin
authors.forename: Ke-Yong
authors.initials: KY
authors.lastname: Li
authors.forename: Kresimir
authors.initials: K
authors.lastname: Krnjević
authors.forename: Chunyi
authors.initials: C
authors.lastname: Zhou
authors.forename: Jiang-Hong
authors.initials: JH
authors.lastname: Ye
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D065127:Dopamine D2 Receptor Antagonists; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D020891:Raclopride / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000037:antagonists & inhibitors; D012110:Reserpine / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism
chemical_list: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D004298:Dopamine; D065127:Dopamine D2 Receptor Antagonists; D018765:Dopamine Uptake Inhibitors; D000431:Ethanol; D018698:Glutamic Acid; D010879:Piperazines; D011810:Quinoxalines; D020891:Raclopride; D018091:Receptors, AMPA; D017447:Receptors, Dopamine D1; D012110:Reserpine; C056723:FG 9041; C044630:1-(2 (diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine; C044846:SKF83566