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.
AU - Li, Ke Yong
AU - Krnjević, Kresimir
AU - Zhou, Chunyi
AU - Ye, Jiang Hong
N1 - Funding Information:
This work was made possible by NIH Grant AA15925, AA016964 (JHY), UMDNJ foundation (JHY), AA013852 (MFO). We thank Dr David Lovinger for his helpful comments on this work.
PY - 2009/1
Y1 - 2009/1
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 α-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 D1 receptor agonist, and by GBR 12935, a dopamine reuptake inhibitor, and they are blocked by SKF 83566, a D1 antagonist, or by reserpine, which depletes dopamine stores. The enhancement of sEPSC frequency reaches a peak with 40 mM ethanol and declines with concentrations ≥80 mM ethanol, which is quite likely a result of D2 receptor activation as raclopride, a D2 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 D1 receptors, ethanol at low concentrations increases glutamate release in the VTA, thus raising somatodendritic dopamine release, which further activates the presynaptic D1 receptors. Enhancement of this positive feedback loop may significantly contribute to the development of alcohol addiction.
AB - 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 α-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 D1 receptor agonist, and by GBR 12935, a dopamine reuptake inhibitor, and they are blocked by SKF 83566, a D1 antagonist, or by reserpine, which depletes dopamine stores. The enhancement of sEPSC frequency reaches a peak with 40 mM ethanol and declines with concentrations ≥80 mM ethanol, which is quite likely a result of D2 receptor activation as raclopride, a D2 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 D1 receptors, ethanol at low concentrations increases glutamate release in the VTA, thus raising somatodendritic dopamine release, which further activates the presynaptic D1 receptors. Enhancement of this positive feedback loop may significantly contribute to the development of alcohol addiction.
KW - Addiction
KW - Alcohol
KW - D and D receptors
KW - Glutamate
KW - Mesolimbic system
KW - Raclopride
UR - http://www.scopus.com/inward/record.url?scp=57849130287&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=57849130287&partnerID=8YFLogxK
U2 - 10.1038/npp.2008.99
DO - 10.1038/npp.2008.99
M3 - Article
C2 - 18596684
AN - SCOPUS:57849130287
SN - 0893-133X
VL - 34
SP - 307
EP - 318
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 2
ER -