Abstract
Ethanol alters N-methyl-d-aspartate (NMDA) and γ-aminobutyric acid subtype A (GABAA) receptor-mediated neurotransmission. We have previously demonstrated that GABAB receptor blockade uncovers ethanol enhancement of GABAA responses in the hippocampus. Therefore, we evaluated in vivo and in vitro the role of GABAB receptors in ethanol-induced inhibition of neuronal activity as well as NMDA responses in the hippocampus, ventral tegmental area (VTA), and nucleus accumbens (NAcc), three brain areas with known sensitivity to low doses of ethanol. In vivo, in situ microelectrophoretic application of ethanol enhanced inhibition of VTA GABA neuron firing rate by the GABAB agonist baclofen and reduced inhibition of VTA GABA firing rate by the GABAA agonist muscimol. The GABAB antagonist CGP35348 blocked baclofen- and ethanol-induced, but not muscimol-induced, reduction of NMDA-activated firing of hippocampal hilar mossy cells, hilar interneurons, and VTA GABA neurons, as well as ethanol inhibition of NMDA receptor-sensitive, amygdala-driven NAcc neurons. We performed in vitro studies in NAcc slices to evaluate the mechanism of GABAB receptor-mediated ethanol inhibition of NMDA neurotransmission. In the presence of the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione and the GABAA receptor antagonist bicuculline, superfusion of the GABAB antagonist CGP55845 blocked ethanol (66 mM) inhibition of evoked NMDA receptor-mediated excitatory postsynaptic potentials. However, CGP55845 did not significantly affect ethanol inhibition of NMDA currents produced by pressure application of NMDA or non-NMDA glutamatergic excitatory postsynaptic potentials evoked in the presence of the bicuculline and the NMDA antagonistdl-2-amino-5-phosphonovalerate. Taken together, these findings suggest that the sensitivity of NMDA receptor-mediated neurotransmission to ethanol is regulated by GABABreceptors, possibly at presynaptic sites.
Footnotes
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Send reprint requests to: Scott C. Steffensen, Ph.D., Department of Neuropharmacology (CVN-13), The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037. E-mail:ssteffensen{at}scripps.edu
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↵1 This work was supported by U.S. Public Health Service Grants AA10075 to S.C.S. and AA06420 to G.R.S.
- Abbreviations:
- GABA
- γ-aminobutyric acid
- aCSF
- artificial cerebrospinal fluid
- APV
- dl-2-amino-5-phosphonovalerate
- CNQX
- 6-cyano-7-nitroquinoxaline-2,3-dione
- EPSP
- excitatory postsynaptic potential
- IPSP
- inhibitory postsynaptic potential
- IPSC
- inhibitory postsynaptic current
- NAcc
- nucleus accumbens
- NMDA
- N-methyl-d-aspartate
- TTX
- tetrodotoxin
- VTA
- ventral tegmental area
- Received January 19, 2000.
- Accepted May 2, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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