Inhibition by ethanol of excitatory amino acid receptors and nicotinic acetylcholine receptors at rat locus coeruleus neurons

Abstract

The frequency of spontaneous action potentials of locus coeruleus (LC) neurons was recorded extracellularly in pontine slices of the rat brain. Ethanol (1-100 mM) elevated the firing rate in most neurons; this effect was concentration-dependent. (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA; 0.03-1 microM), kainate (0.1-3 microM), N-methyl-D-aspartate (NMDA; 1-30 microM), substance P (0.01-1 microM), nicotine (0.1-10 microM) and alpha,beta-methylene ATP (alpha,beta-meATP; 0.3-30 microM), all increased the firing. Application of ethanol (10-100 mM) to the superfusion medium for 10 min, reproducibly and concentration-dependently inhibited the facilitatory effect of NMDA (10 microM). However, the inhibitory effect of ethanol (100 mM) decreased during a 30-min superfusion period and after the wash-out of ethanol the sensitivity of LC neurons to NMDA (10 microM) tended to overshoot above their initial level. Although NMDA was more potent in the absence than in the presence of external Mg2+, ethanol (100 mM) continued to depress the facilitatory effect of a low concentration of NMDA (3 microM) in a Mg(2+)-free medium. By contrast, in a medium containing normal Mg2+, ethanol (100 mM) failed to significantly interfere with the increase in firing rate induced by a high concentration of NMDA (30 microM). The effects of kainate (0.5 microM), AMPA (0.3 microM) and nicotine (1 microM) were also depressed by ethanol (100 mM), while the effects of substance P (0.03 microM) and alpha,beta-meATP (30 microM) were not changed.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition by ethanol of excitatory amino acid receptors in rat locus coeruleus neurons in vitro

“…These data are in partial contradiction with previous extracellular experiments, where ethanol (100 mM) increased the firing rate (Fröhlich et al 1994). Although the reason for this discrepancy is unknown, it has to be considered that extracellular, in contrast to intracellular microelectrodes may activate previously silent neurons by mechanical irritation.…”

“…Previous extracellular experiments documented a concentration-dependent inhibition by ethanol (10, 100 mM) of the NMDA-induced increase in the firing rate of LC neurons (Fröhlich et al 1994). The two compounds were suggested to interact in a truly antagonistic manner, since their effect on co-application was less than the sum of their individual effects.…”

“…An in vivo study documented that although both NMDA and kainate increased the firing rate of LC neurons, only the effect of NMDA was attenuated by ethanol (Engberg and Hajos 1992). By contrast, under in vitro conditions ethanol interacted with NMDA, AMPA and kainate with comparable potencies (Fröhlich et al 1994). However, ethanol did not attenuate the facilitatory effects of the NK 1 and P2 receptor agonists, substance P and α,β-methylene ATP (α,β-meATP).…”

Nicotinic Acetylcholine Receptors in the Ventral Tegmental Area are Important Targets for Nicotine and Ethanol Co-dependence

“…Some have argued that EtOH is simply a co-agonist and requires NIC to elicit a cholinergic response [85]. However, EtOH is not only a co-agonist in the presence of a ligand binding to cholinergic receptors, but also operates directly on some types of nAChRs in vitro [83,86] and in vivo [87][88][89]. The sensitivity and effects elicited by EtOH binding to nAChRs are dependent upon subunit composition [90].…”

AMPA Receptor Potentiation can Prevent Ethanol-Induced Intoxication

“…Historically, it was thought the most likely mechanism for this modulation was the inhibitory action of ethanol at the NMDA subtype of the glutamate receptor. Preclinical studies have shown acute exposure to ethanol dosedependently attenuates NMDA-evoked currents in hippocampal (Lovinger et al, 1990) and locus coeruleus neurons (Frölich et al, 1994), blocks extracellular striatal increases in glutamate caused by focal application of NMDA (Carboni et al, 1993), and protects against NMDA-induced convulsions (Kulkarni et al, 1990) in rats. Furthermore, the NMDA antagonists ketamine, MK-801, and phencyclidine substitute for ethanol in animal drug discrimination studies (Grant et al, 1991;Colombo and Grant, 1992;Schecter et al, 1993), and ketamine has ethanol-like effects in healthy subjects (Krystal et al, 1994) and recently detoxified alcoholics (Krystal et al, 1998).…”