Low ethanol concentrations enhance GABAergic inhibitory postsynaptic potentials in hippocampal pyramidal neurons only after block of GABAB receptors.

Abstract

Despite considerable evidence that ethanol can enhance chloride flux through the y-aminobutyric acid type A (GABAA) receptor-channel complex in several central neuron types, the effect ofethanol on hippocampal GABAergic systems is still controversial. Therefore, we have reevaluated this interaction in hippocampal pyramidal neurons subjected to local monosynaptic activation combined with pharmacological isolation of the various components of excitatory and inhibitory synaptic potentials, using intracellular currentand voltage-clamp recording methods in the hippocampal slice. In accord with our previous findings, we found that ethanol had little effect on compound inhibitory postsynaptic potentials/currents (IPSP/Cs) containing both GABAA and GABAB components. However, after selective pharmacological blockade of the GABAB component of the IPSP (GABAB-IPSP/C) by low It is common knowledge that alcohol intoxication and the resulting loss of motor and cognitive control in humans have led to untold trauma and suffering. Despite the likelihood that such problems arise from the action of ethanol on the central nervous system (CNS) and several decades of alcohol research suggesting a general depressant effect of intoxicating doses of ethanol on CNS neurons, until recently little has been known about the mechanisms behind this depression. Studies over the past decade have shown that the most sensitive site for ethanol action is the synapse (1-5), and more recently it has been suggested that ethanol-evoked neuronal depression might arise from either a blunting of excitatory glutamatergic synaptic transmission (see, e.g., refs. 6-8) and/or an enhancement of inhibitory y-aminobutyric acid (GABA)ergic transmission (see refs. 4 and 9).With regard to inhibitory neurotransmission, ethanol has often been reported to enhance GABAA receptor activation, and the resulting Cl-currents or fluxes, in neurons or isolated preparations of several brain regions (4,9 (see refs. 24-26). In addition, the development of local or focal stimulation techniques (27,28), combined with these selective antagonists, now allows study of pharmacologically isolated synaptic components. Therefore, we have repeated earlier studies of ethanol effects on GABAergic monosynaptic IPSPs with two different slice preparation methods, including the one used in previous studies from our laboratory (13), but now with pharmacologically isolated IPSP components. We now report that, under these conditions, low ethanol concentrations reproducibly enhance GABAAergic IPSPs of hippocampal pyramidal neurons (HPNs), but only when GABAB receptors are blocked.MATERIALS AND METHODS Preparation. The two hippocampal slice preparations used were as described (13,29,30). In brief, male Sprague-Dawley Abbreviations: IPSP/C, inhibitory postsynaptic potential/current; IPSC, inhibitory postsynaptic current; HPN, hippocampal pyramidal neuron; GABA, y-aminobutyric acid; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; d-APV, DL-2-amino-5-phosphonovaleric acid; ACSF, artificial cer...

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

“…Carlen et al (1982) reported enhanced inhibitory postsynaptic potentials (IPSPs) from CA1 hippocampal cells by ethanol, an observation later confirmed by a number of laboratories Wan et al, 1996;Weiner et al, 1994aWeiner et al, , b, 1997a. However, Siggins et al (1987b) reported that ethanol most often reduced hippocampal CA1 and CA3 neuronal IPSPs induced by stimulation of the hilar mossy fiber pathway.…”

“…Wan et al (1996) found that IPSCs from CA1 pyramidal cells were only sensitive to ethanol enhancement in the presence of a GABA B antagonist, providing a mechanism for the variability reported (see subsequent section on GABA B receptor influences). In another brain region, investigators (Nie et al, 2004;Roberto et al, 2003) reported that ethanol enhanced IPSCs from amygdaloid neurons.…”

“…In contrast to work on dissociated neurons, several studies demonstrated that evoked release of GABA in a slice preparation was sensitive to ethanol (Carlen et al, 1982;Bloom and Siggins, 1987;Proctor et al, 1992;Roberto et al, 2003;Wan et al, 1996;Weiner et al, 1994aWeiner et al, , b, 1997a. Carlen et al (1982) reported enhanced inhibitory postsynaptic potentials (IPSPs) from CA1 hippocampal cells by ethanol, an observation later confirmed by a number of laboratories Wan et al, 1996;Weiner et al, 1994aWeiner et al, , b, 1997a.…”

“…Subsequently, Roberto et al (2003Roberto et al ( , 2004a provided evidence that ethanol enhanced the effect of stimulusinduced GABA-mediated IPSPs and mIPSCs from neurons in slices from the central nucleus of the amygdala and caused release of GABA into microdialysatesFclear evidence that ethanol could facilitate GABA release. This action of ethanol to release GABA can apparently be modified at presynaptic sites (see designation in Figure 4), by GABA B (Ariwodola and Weiner, 2004;Wan et al, 1996) and corticotrophin releasing factor (CRF; Nie et al, 2004) receptors. Additionally, other neurotransmitter receptors affected by ethanol can influence neural circuits that influence GABA transmission (Carta et al, 2003(Carta et al, , 2004; Figure 3 Effect of ethanol on neural rate from cerebellar Purkinje neurons.…”

“…Several studies demonstrated that GABA B receptor antagonists enhance the ability of ethanol to facilitate GABA transmission in the hippocampus (Ariwodola and Weiner, 2004;Wan et al, 1996;Wu et al, 2004) and nucleus accumbens (Nie et al, 2000). Melis et al (2002) linked the long-lasting potentiation of GABAergic synapses on dopaminergic neurons in the ventral tegmental area by systemic ethanol to an effect on presynaptic GABA B receptors.…”