Differential GABAB Receptor Modulation of Ethanol Effects on GABAA Synaptic Activity in Hippocampal CA1 Neurons

Abstract

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.