Enhancing Effects Of Ethanol Research Articles

Ethanol enhances GABAB‐mediated inhibitory postsynaptic transmission on rat midbrain dopaminergic neurons by facilitating GIRK currents

It is largely accepted that an activation of the dopaminergic system underlies the recreational and convivial effects of ethanol. However, the mechanisms of action of this drug on the dopaminergic neurons are not fully understood yet. In the present study, we have used intracellular electrophysiological techniques (current and single-electrode voltage-clamp) to investigate the actions of ethanol on the gamma-aminobutyric acid (GABA)(B)-mediated inhibitory postsynaptic potentials (IPSPs) in rat midbrain dopaminergic neurons. Ethanol (10-200 mM) augmented, in a concentration-dependent and reversible manner, the amplitude of the GABA(B)-IPSP. In addition, the GABA(B) agonist baclofen generated G-protein-gated inward rectifying K(+) channels (GIRK)-related membrane hyperpolarizations/outward currents that were potentiated by ethanol. The potentiating effect of ethanol persisted in tetrodotoxin (TTX)-treated neurons, suggesting a postsynaptic site of action. These effects of ethanol were not changed by manipulating adenyl cyclase, protein kinases and phospholipase C activity, or by chelating intracellular Ca(2+) with EGTA. Interestingly, the outward current caused by the intracytoplasmatic diffusion of the irreversible G-protein activator GTPgammaS was transiently enhanced by ethanol. Our observations suggest that the action of ethanol occurs on activated GIRK channels downstream of the GABA(B) receptors. These enhancing effects of ethanol on GABA(B)-induced synaptic responses could modulate alcohol intake and the altered mental and motor performance of individuals in an acute intoxicative phase.

클렌부테롤의 피부투과에 미치는 경피흡수촉진제의 영향

Albuterol, a selective -adrenergic receptor stimulant, has been introduced as a potent bronchodilator for patients with bronchial asthma, chronic obstructive bronchial disease, chronic bronchitis and pulmonary emphysema. The percutaneous permeation of albuterol sulfate was investigated in hairless mouse skin in vitro with and without pretreatment with enhancers. The enhancing effects of ethanol and various penetration enhancers such as terpenes, non-ionic surfactants, pyrrolidones, and fatty acids on the permeation of albuterol sulfate were evaluated using Franz diffusion cells. Among terpenes studied, 1,8-cineole was the most effective enhancer, which increased the permeability of albuterol sulfate approximately 33-fold compared with the control without enhancer pretrement, followed by d-limonene with enhancement ratio of 21.79. 2-Pyrrolidone-5-carboxylic acid increased the permeability of albuterol sulfate approximately 5.5-fold compared with the control. Other pyrrolidones tested showed only slight permeability enhancing effect with enhancement ratio less than 2.8. Nonionic surfactants showed moderate enhancing effects. Lauric acid increased the permeability of albuterol sulfate approximately 30-fold with decreasing the lag time from 2.85 to 0.64 hr. Oleic acid and linoleic acid showed enhancement ratio of 24.55 and 22.91, respectively. These findings would allow a more rational approach for designing formulations for the transdermal delivery of albuterol sulfate and similar drugs.

Ethanol enhances medial amygdaloid induced inhibition of predatory attack behaviour in the cat: role of GABAA receptors in the lateral hypothalamus.

The present study tested the hypothesis that the suppressive effects of ethanol upon predatory attack behaviour in the cat involve a pathway from the medial amygdala to the lateral hypothalamus, and that these suppressive effects are mediated by gamma-aminobutyric acid (GABAA) receptors located in the lateral hypothalamus. Cannula electrodes were implanted into the lateral hypothalamus for elicitation of predatory attack behaviour and for microinjections of the GABAA receptor antagonist, bicuculline. Monopolar stimulating electrodes were implanted into the medial amygdala from which subseizure levels of electrical stimulation suppressed predatory attack behaviour. In the first phase of the study, we compared response latencies for predatory attack behaviour following single stimulation of the lateral hypothalamus alone with those following paired trials of dual stimulation of the medial amygdala plus lateral hypothalamus. Dual stimulation significantly suppressed predatory attack. In the second phase of the study, peripheral ethanol administration (in doses of 0.01, 0.5 and 1.0 g/kg, i.p.) enhanced the suppressive effects of medial amygdaloid stimulation in a dose- and time-dependent manner in which peak effects were obtained 60 min post-injection. In the third phase of the study, bicuculline (0.15 nmol) was microinjected into the lateral hypothalamus both prior to and following paired trials of dual stimulation. Drug infusion blocked the suppressive effects of medial amygdaloid stimulation upon predatory attack behaviour elicited from the lateral hypothalamus, indicating the importance of GABAA receptors in mediating this suppression. In the fourth phase of the study, bicuculline, microinjected into the lateral hypothalamus at the time when ethanol's effects were maximal (i.e. 60-80 min post-ethanol administration), totally blocked the suppressive effects of medial amygdaloid stimulation as well as the enhancing effects of ethanol upon medial amygdaloid suppression of this form of aggressive behaviour. In the last phase of the study, bicuculline (0.15 nmol) infusion into the lateral hypothalamus significantly reduced the suppressive effects of ethanol (1.0 g/kg, i.p.) upon predatory attack behaviour elicited from the lateral hypothalamus. These results support the hypothesis that ethanol's suppressive effects upon predatory attack behaviour in the cat are mediated, at least in part, by GABAA receptors in the lateral hypothalamus. The present and recent findings in our laboratory support the view that GABAA receptors in the lateral hypothalamus are activated, in turn, by a GABAergic pathway which arises from the medial hypothalamus whose neurons receive inputs from the medial amygdala.

ENHANCING EFFECT OF ETHANOL ON AFLATOXIN B1-INDUCED DNA-DAMAGE IN GLUTATHIONE-DEPLETED RAT HEPATOCYTES

The effect of reduced glutathione (GSH) and ethanol on aflatoxin B1 (AFB1)-induced DNA single strand breaks was studied in primary cultured hepatocytes. Buthionine sulfoximine (BSO) which decreased intracellular GSH to 13% of those of the control levels increased DNA fragmentation of AFB1-treated hepatocytes by over 17% of those without BSO. Thus, a decrease in hepatocyte GSH levels increased AFB1-induced DNA damage. Although ethanol in itself did not induce DNA damage, a combination of BSO and ethanol increased the percentage by over 23% of that with BSO only. Ethanol did not affect the amount of GSH, total cytochrome P-450 (P450), glutathione S-transferase (GST) and epoxide hydrolase (EHase) in cultured hepatocytes. However, GSH-depleted rat hepatocytes exposed to ethanol significantly increased the level of P450IIIA, which activates AFB1. The enhancing effects of ethanol in the presence of BSO are probably due to the induction of this isozyme in rat hepatocytes. The GSH-depleted hepatocytes are more susceptible to chemical carcinogens in the presence of ethanol.

Ethanol‐Induced Enhancement of Cocaine Bioactivation and Irreversible Protein Binding: Evidence Against a Role of Cytochrome P‐450IIE1

Chronic ethanol consumption potentiates cocaine-induced liver injury in rodents. Since cocaine has to be bioactivated by a cytochrome P-450-dependent N-oxidative pathway to exert its hepatotoxic effects, we studied the role of the ethanol-inducible P-450IIE1 for cocaine metabolism. Male Sprague-Dawley rats were pretreated with either a liquid diet containing ethanol (30% of calories) for 4 weeks or injected with pyrazole (200 mg/kg/day, ip, for 3 days). Both agents induced microsomal p-nitrophenol hydroxylation which is a probe for the catalytic activity of P-450IIE1. However, only ethanol, but not pyrazole, increased both microsomal cocaine N-demethylase activity (by 47%) and the extent of irreversible binding of [3H]-cocaine to microsomal proteins (by 100%), which was taken as a quantitative endpoint for the formation of a reactive metabolite. Cocaine N-demethylation and irreversible protein binding of cocaine were not inhibited by P-450IIE1 isozyme-selective substrates, nor was the rate of cocaine metabolism and binding decreased by functionally active polyclonal anti-rat P-450IIE1 antibodies. Furthermore, pyrazole pretreatment sensitized cultured hepatocytes to the glutathione-dependent cytotoxic effects of nontoxic concentrations of cocaine. These results indicate that (a) cocaine is not a major substrate for the ethanol-inducible P-450IIE1, (b) the enhancing effects of ethanol on cocaine bioactivation may be due to induction of other P-450 isoforms, and (c) induction of P-450IIE1 may potentiate cocaine-induced hepatocellular toxicity in vitro independently of cocaine metabolism, e.g., by P-450IIE1-dependent oxidative stress.

Ethanol and the benzodiazepine-GABA receptor-ionophore complex

Ethanol has a pharmacological profile similar to that of classes of drugs like benzodiazepines and barbiturates, which enhance GABAergic transmission in the mammalian CNS. Several lines of behavioral, electrophysiological and biochemical studies suggest that ethanol may bring about most of its effects by enhancing GABAergic transmission. Recently, ethanol at relevant pharmacological concentrations has been shown to enhance GABA-induced 36Cl-fluxes in cultured spinal cord neurons, synaptoneurosomes and microsacs. These enhancing effects of ethanol were blocked by GABA antagonists. Ro15-4513, an azido analogue of classical BZ antagonist Ro15-1788, reversed most of the behavioral effects of ethanol and other effects involving 36Cl-flux studies. The studies summarized below indicate that most of the pharmacological effects of ethanol can be related to its effects on GABAergic transmission.