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Ethanol facilitates glutamatergic transmission to dopamine neurons in the ventral tegmental area.
Neuropsychopharmacology 2009; 34(2):307-18N

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+Show Affiliations

Department of Anesthesiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18596684

Citation

Xiao, Cheng, et al. "Ethanol Facilitates Glutamatergic Transmission to Dopamine Neurons in the Ventral Tegmental Area." Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, vol. 34, no. 2, 2009, pp. 307-18.
Xiao C, Shao XM, Olive MF, et al. Ethanol facilitates glutamatergic transmission to dopamine neurons in the ventral tegmental area. Neuropsychopharmacology. 2009;34(2):307-18.
Xiao, C., Shao, X. M., Olive, M. F., Griffin, W. C., Li, K. Y., Krnjević, K., ... Ye, J. H. (2009). Ethanol facilitates glutamatergic transmission to dopamine neurons in the ventral tegmental area. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 34(2), pp. 307-18. doi:10.1038/npp.2008.99.
Xiao C, et al. Ethanol Facilitates Glutamatergic Transmission to Dopamine Neurons in the Ventral Tegmental Area. Neuropsychopharmacology. 2009;34(2):307-18. PubMed PMID: 18596684.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ethanol facilitates glutamatergic transmission to dopamine neurons in the ventral tegmental area. AU - Xiao,Cheng, AU - Shao,Xuesi Max, AU - Olive,M Foster, AU - Griffin,William C,3rd AU - Li,Ke-Yong, AU - Krnjević,Kresimir, AU - Zhou,Chunyi, AU - Ye,Jiang-Hong, Y1 - 2008/07/02/ PY - 2008/7/4/pubmed PY - 2009/2/24/medline PY - 2008/7/4/entrez SP - 307 EP - 18 JF - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology JO - Neuropsychopharmacology VL - 34 IS - 2 N2 - 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. SN - 1740-634X UR - https://www.unboundmedicine.com/medline/citation/18596684/Ethanol_facilitates_glutamatergic_transmission_to_dopamine_neurons_in_the_ventral_tegmental_area_ L2 - http://dx.doi.org/10.1038/npp.2008.99 DB - PRIME DP - Unbound Medicine ER -