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Exposure to ethanol during development triggers neuronal cell death and this is thought to play a central role in the pathophysiology of fetal alcohol spectrum disorder (FASD). Studies suggest that ethanol-induced neurodegeneration during the period of synaptogenesis results from widespread potentiation of GABA(A) receptors and inhibition of NMDA receptors throughout the brain, with neocortical layer II being particularly sensitive. Here, we tested whether ethanol modulates the function of these receptors during this developmental period using patch-clamp electrophysiological and Ca(2+) imaging techniques in acute slices from postnatal day 7-9 rats. We focused on pyramidal neurons in layer II of the parietal cortex (with layer III as a control). Ethanol (70mM) increased spontaneous action potential-dependent GABA release in layer II (but not layer III) neurons without affecting postsynaptic GABA(A) receptors. Protein and mRNA expression for both the Cl(-) importer, NKCC1, and the Cl(-) exporter, KCC2, were detected in layer II/III neurons. Perforated-patch experiments demonstrated that E(Cl)((-)) is shifted to the right of E(m); activation of GABA(A) receptors with muscimol depolarized E(m), decreased action potential firing, and minimally increased [Ca(2+)](i). However, the ethanol-induced increase of GABAergic transmission did not affect neuronal excitability. Ethanol had no effect on currents exogenously evoked by NMDA or AMPA receptor-mediated spontaneous excitatory postsynaptic currents. Acute application of ethanol in the absence of receptor antagonists minimally increased [Ca(2+)](i). These findings are inconsistent with the excessive inhibition model of ethanol-induced neurodegeneration, supporting the view that ethanol damages developing neurons via more complex mechanisms that vary among specific neuronal populations.

Abstract The duration of ethanol-induced loss of righting reflex was significantly prolonged in mice pretreated with the dopamine-β-hydroxylase inhibitor FLA 63. The disappearance of ethanol from blood, brain, liver and kidneys from FLA 63-treated mice was significantly delayed as compared to control mice. In vitro , FLA 63 inhibited the activity of mouse liver alcohol dehydrogenase. These results demonstrate that FLA 63 can alter the disposition of ethanol. Consequently, its pharmacological activity is altered. The interpretation of results from experiments in which FLA 63 is employed with other drugs should not be based solely on its inhibitory action on dopamine-β-hydroxylase.

Groups of water-deprived rats were exposed to acetaldehyde, ethanol or vehicle control. On the conditioning day, the animals were first presented with a solution of saccharin after which the animals that were exposed to acetaldehyde received ethanol and those exposed to ethanol received acetaldehyde. Saccharin was again presented on three more occasions (testing days) without injection of drug. Using the percentage change in saccharin consumed from the first presentation as a measure of aversion, it was found that exposure to acetaldehyde blocked the taste aversion conditioned by ethanol. Animals exposed to ethanol showed no aversion to the saccharin which was paired with a small dose of acetaldehyde, indicating a symmetrical relationship between ethanol and acetaldehyde at this dose. However, exposure with ethanol did not block the aversion produced by conditioning with larger doses of acetaldehyde. These results suggest that the mechanism underlying the smaller dose of the taste aversion conditioned with acetaldehyde may be central while the mechanism underlying the larger dose is probably peripheral.

Activation of the kappa opioid receptor (KOR) system mediates negative emotional states and considerable evidence suggests that KOR and their natural ligand, dynorphin, are involved in ethanol dependence and reward. The central amygdala (CeA) plays a major role in alcohol dependence and reinforcement. Dynorphin peptide and gene expression are activated in the amygdala during acute and chronic administration of alcohol, but the effects of activation or blockade of KOR on inhibitory transmission and ethanol effects have not been studied. We used the slice preparation to investigate the physiological role of KOR and interaction with ethanol on GABA(A) receptor-mediated synaptic transmission. Superfusion of dynorphin or U69593 onto CeA neurons decreased evoked inhibitory postsynaptic potentials (IPSPs) in a concentration-dependent manner, an effect prevented by the KOR antagonist norbinaltorphimine (norBNI). Applied alone, norBNI increased GABAergic transmission, revealing a tonic endogenous activity at KOR. Paired-pulse analysis suggested a presynaptic KOR mechanism. Superfusion of ethanol increased IPSPs and pretreatment with KOR agonists diminished the ethanol effect. Surprisingly, the ethanol-induced augmentation of IPSPs was completely obliterated by KOR blockade. Our results reveal an important role of the dynorphin/KOR system in the regulation of inhibitory transmission and mediation of ethanol effects in the CeA.

Ethanol's aversive property may limit it's use, but the underlying mechanisms are no well-understood. Emerging evidence suggests a critical role for the lateral habenula (LHb) in the aversive response to various drugs, including ethanol. We previously showed that ethanol enhances glutamatergic transmission and stimulates LHb neurons. GABAergic transmission, a major target of ethanol in many brain regions, also tightly regulates LHb activity. This study assessed the action of ethanol on LHb GABAergic transmission in rat brain slices. Application of ethanol accelerated spontaneous action potential firing of LHb neurons, and LHb activity was increased by the GABAA receptor antagonist gabazine, and ethanol-induced acceleration of LHb firing was further increased by gabazine. Additionally, ethanol potentiated GABAergic transmission (inhibitory postsynaptic currents, IPSCs) with an EC50 of 1.5 mM. Ethanol-induced potentiation of IPSCs was increased by a GABAB receptor antagonist; it was mimicked by dopamine, dopamine receptor agonists, and dopamine reuptake blocker, and was completely prevented by reserpine, which depletes store of catecholamine. Moreover, ethanol-induced potentiation of IPSCs involved cAMP signaling. Finally, ethanol enhanced simultaneously glutamatergic and GABAergic transmissions to the majority of LHb neurons: the potentiation of the former being greater than that of the latter, the net effect was increased firing. Since LHb excitation may contribute to aversion, ethanol-induced potentiation of GABAergic inhibition tends to reduce aversion.

This study examined the possible involvement of central mechanisms in the mediation of cannabis-induced conditioned taste aversion. Δ9-Tetrahydrocannabinol, morphine and ethanol were infused into the dorsal hippocampus. The first two compounds were also infused into the caudate nucleus. Additional groups received intraperitoneal injections of these three compounds. At the doses employed in this study, it was found that only Δ9-tetrahydrocannabinol was capable of inducing a conditioned taste aversion, and only when infused into the hippocampus. All intraperitoneal drug injections produced a conditioned taste aversion. The data are discussed in terms of a possible specific interaction between Δ9-tetrahydrocannabinol and the dorsal hippocampus in the central induction of a conditioned taste aversion.

CYP2B6 and CYP2E1 are enzymes responsible for the metabolism of many centrally acting drugs, toxins and endogenous compounds. Human smokers and alcoholics have elevated levels of CYP2B6 and CYP2E1 in certain brain regions, which may contribute to altered drug efficacy, neurotoxicity and metabolic tolerance. The objective of this study was to determine the effects of ethanol self-administration and nicotine treatment, alone and in combination, on brain CYP2B6 and CYP2E1 levels in monkeys. Monkeys were randomized into four groups (N = 10/group): an ethanol-only group, a nicotine-only group, an ethanol + nicotine group and a control (no drug) group. Ethanol (10% alcohol in sucrose solution) was voluntarily self-administered by the monkeys and nicotine was given as subcutaneous injections (0.5 mg/kg bid). Immunocytochemistry revealed induction of both CYP2B6 and CYP2E1 protein in certain brain regions and cells within monkey brain as a result of ethanol self-administration, nicotine treatment and combined exposure to both drugs. Immunoblotting analyses demonstrated CYP2B6 induction by ethanol in the caudate, putamen and cerebellum (1.5-3.2 fold, P < 0.05), and CYP2E1 induction by nicotine in the frontal cortex and putamen (1.6-2.0 fold, P < 0.05). Combined ethanol and nicotine exposure induced CYP2B6 in the caudate, putamen, thalamus and cerebellum (1.4-2.4 fold, P < 0.05), and CYP2E1 in the frontal cortex and putamen (1.5-1.8, P < 0.05). CYP2B6 and CYP2E1 mRNA levels were unaffected by ethanol or nicotine exposure. In summary, ethanol and nicotine can induce CYP2B6 and CYP2E1 protein in the primate brain, which could potentially result in altered sensitivity to centrally acting drugs and toxins.

Phorbol esters have been shown to enhance the release of transmitters and to potentiate the effect of local anaesthetics in olfactory cortex of the rat. This work examined the interaction between phorbol dibutyrate and a range of substances, which act on axonal conduction and synaptic transmission. Synaptically-evoked field responses were elicited by stimulation of the lateral olfactory tract of slices of olfactory cortex, maintained in vitro. Ketamine (0.2-1.0 mM), benzocaine (0.2-1 mM), atropine (0.1-2 mM) and tetrodotoxin (20-200 nM) depressed synaptic transmission and, in the presence of phorbol dibutyrate (1 microM), these substances were more potent by 3.7 +/- 0.5, 1.5 +/- 4, 2.6 +/- 0.6 and 5.5 +/- 1.8 fold, respectively. Pentobarbitone (0.1-2.0 mM) with or without bicuculline, urethane (10-200 mM), halothane (0.5-5.0 mM) (with bicuculline) and ethanol (50-500 mM) also depressed synaptic transmission but their effectiveness was not potentiated by phorbol dibutyrate. It is thought that the increased potency, produced by phorbol ester, was associated with a presynaptic action of those substances.

Abstract This paper is an attempt to characterize the nature of ethanol preference acquired by male albino rats after 30 daily sessions of hypothalamic stimulation. It was observed that rats that acquired ethanol preference following hypothalamic stimulation continued to ingest significant amounts of ethanol even after it was adulterated with 0.05% quinine hydrochloride. None of the ethanol-preferring rats exhibited any signs of withdrawal when ethanol presentations were terminated following 73 days of ethanol ingestion. The ethanol preferring rats were extremely accurate in regulating the amount of absolute ethanol ingested when the concentration of solutions presented to them were systematically varied. The data is discussed in terms of the specificity of the phenomenon and possible shifts in preference-aversion taste function.