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NEUROPHARMACOLOGY

Differential GABA_B Receptor Modulation of Ethanol Effects on GABA_A Synaptic Activity in Hippocampal CA1 Neurons

VA Eastern Colorado Health Care System, Medical Research Service, Denver, Colorado (P.H.W., W.R.P.); Department of Psychiatry, University of Colorado Health Sciences Center, Denver, Colorado (P.H.W., W.R.P.); and the Institut fur Neurophysiologie, Heinrich-Heine-Universitat, Dusseldorf, Germany (W.P.)

We tested the hypothesis that differential sensitivity to ethanol of synaptic GABA_A somatic and dendritic inhibitory postsynaptic currents (IPSCs) in hippocampal CA1 pyramidal neurons could be due to differences in the extent of GABA_B receptor activity at GABAergic synapses in these two hippocampal subfields. Our present results show that dendritic (distally evoked) GABA IPSCs contain a larger GABA_B IPSC component of the total GABA IPSC than the somatic (proximally evoked) subfield. The inhibition of GABA_B receptors by pretreatment of hippocampal slices with CGP-52432 [3[[(3,4-dichlorophenyl)methyl]amino]propyl](diethoxymethyl) phosphinic acid], a selective GABA_B receptor antagonist, changes the basal ethanol-insensitive, distally evoked GABA_A IPSCs to become more sensitive to ethanol. In addition, paired-pulse stimulation of the proximal and distal subfields of hippocampal pyramidal neurons shows that ethanol alone increases the probability of GABA release at proximal but not distal regions. Changes by ethanol on the probability of GABA release are only seen at distal locations during GABA_B blockade. Finally, when the modulation of presynaptic GABA_B receptors is minimized by the local application of 10 mM GABA directly onto somatic or dendritic GABAergic synaptic regions, postsynaptic GABA_B receptors seem to exert significant negative (inhibiting) influence on the effects of ethanol on GABA_A IPSCs in the distal subfields of CA1 pyramidal neurons. Together, our data suggest that differences in both presynaptic and postsynaptic GABA_B receptor activity at these GABAergic synapses may modulate the differential ethanol sensitivity of proximal and distal GABA IPSCs_A in hippocampal CA1 pyramidal neurons.

Address correspondence to: Dr. William R. Proctor, Dept. of Psychiatry (C-261), University of Colorado Health Sciences Center, 4200 E. 9th Avenue, Denver, CO 80262. E-mail: bill.proctor{at}uchsc.edu

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