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Background: Abundant evidence at the anatomical, electrophysiological, and molecular levels implicates metabotropic glutamate receptor subtype 5 (mGluR5) in addiction. Consistently, the effects of a wide range of doses of different mGluR5 negative allosteric modulators (NAMs) have been tested in various animal models of addiction. Here, these studies were subjected to a systematic review to find out if mGluR5 NAMs have a therapeutic potential that can be translated to the clinic., Methods: Literature on consumption/self-administration and reinstatement of drug seeking as outcomes of interest published up to April 2015 was retrieved via PubMed. The review focused on the effects of systemic (i.p., i.v., s.c.) administration of the mGluR5 NAMs 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP) and 2-Methyl-6-(phenylethynyl)pyridine (MPEP) on paradigms with cocaine, ethanol, nicotine, and food in rats., Results: MTEP and MPEP were found to reduce self-administration of cocaine, ethanol, and nicotine at doses ≥1mg/kg and 2.5mg/kg, respectively. Dose-response relationship resembled a sigmoidal curve, with low doses not reaching statistical significance and high doses reliably inhibiting self-administration of drugs of abuse. Importantly, self-administration of cocaine, ethanol, and nicotine, but not food, was reduced by MTEP and MPEP in the dose range of 1 to 2mg/kg and 2.5 to 3.2mg/kg, respectively. This dose range corresponds to approximately 50% to 80% mGluR5 occupancy. Interestingly, the limited data found in mice and monkeys showed a similar therapeutic window., Conclusion: Altogether, this review suggests a therapeutic window for mGluR5 NAMs that can be translated to the treatment of substance-related and addictive disorders., (© The Author 2016. Published by Oxford University Press on behalf of CINP.)

Aims: Ethanol (EtOH) activates the mesolimbic dopamine system and increases dopamine levels in the nucleus accumbens (nAc), which is believed to underlie the rewarding effects of alcohol. Accumulating evidence now implicates that acetaldehyde, the first metabolite of EtOH, may play an important role in mediating some of the rewarding properties of its parent compound. The objective of this study was to investigate if the increase in accumbal dopamine output observed when administering EtOH locally in the nAc by reversed microdialysis is mediated by acetaldehyde., Methods: Acetaldehyde (1, 10, 100 or 200 µM) or EtOH (300 mM) was administered via reversed microdialysis in the nAc of male Wistar rats. In a separate experiment, animals were administered EtOH (300 mM) in the nAc, following pre-treatment with the acetaldehyde-sequestering agent d-penicillamine (50 mg/kg injected intraperitoneally 60 min before drug challenge). Microdialysates from the nAc were collected every 20 min and dopamine content was quantified using high-performance liquid chromatography., Results: Acetaldehyde administered in the nAc did not influence accumbal dopamine levels at any of the concentrations applied, whereas EtOH induced a significant increase in accumbal dopamine. The dopamine-elevating properties of EtOH were not attenuated by pre-treatment with d-penicillamine., Conclusion: The current results show that EtOH administered in the nAc induces an elevation in accumbal dopamine levels, which is not mimicked by acetaldehyde alone, nor is it influenced by acetaldehyde sequestering. This would suggest that the increase in accumbal dopamine following nAc EtOH administration is not mediated by acetaldehyde., (© The Author 2014. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Study Objectives: Strong clinical and preclinical evidence suggests that acute ethanol promotes sleep. However, very little is known about how and where ethanol acts to promote sleep. We hypothesized that ethanol may induce sleep by increasing extracellular levels of adenosine and inhibiting orexin neurons in the perifornical hypothalamus., Design: Experiments 1 and 2: Within-Subject Design; Experiment 3: Between-Subject Design., Setting: N/A., Patients or Participants: N/A., Interventions: N/A., Measurements and Results: Using adult male Sprague-Dawley rats as our animal model, we performed three experiments to test our hypothesis. Our first experiment examined the effect of A1 receptor blockade in the orexinergic perifornical hypothalamus on sleep- promoting effects of ethanol. Bilateral microinjection of the selective A1 receptor antagonist 1,3-dipropyl-8-phenylxanthine (500 μM; 250 nL/side) into orexinergic perifornical hypothalamus significantly reduced nonrapid eye movement sleep with a concomitant increase in wakefulness, suggesting that blockade of adenosine A1 receptor attenuates ethanol-induced sleep promotion. Our second experiment examined adenosine release in the orexinergic perifornical hypothalamus during local ethanol infusion. Local infusion of pharmacologically relevant doses of ethanol significantly and dose-dependently increased adenosine release. Our final experiment used c-Fos immunohistochemistry to examine the effects of ethanol on the activation of orexin neurons. Acute ethanol exposure significantly reduced the number of orexin neurons containing c-Fos, suggesting an inhibition of orexin neurons after ethanol intake., Conclusions: Based on our results, we believe that ethanol promotes sleep by increasing adenosine in the orexinergic perifornical hypothalamus, resulting in A1 receptor-mediated inhibition of orexin neurons.

The maladaptive drug memory developed between the drug-rewarding effect and environmental cues contributes to difficulty in preventing drug relapse. Established reward memories can be disrupted by pharmacologic interventions following their reactivation. Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) kinase, has been proved to be involved in various memory consolidation. However, it is less well characterized in drug memory reconsolidation. Using a conditioned place preference (CPP) procedure, we examined the effects of systemically administered rapamycin on reconsolidation of drug memory in rats. We found that systemically administered rapamycin (0.1 or 10 mg/kg, i.p.) after re-exposure to drug-paired environment, dose dependently decreased the expression of CPP 1 d later, and the effect lasted for up to 14 d and could not be reversed by a priming injection of morphine. The effect of rapamycin on morphine-associated memory was specific to drug-paired context, and rapamycin had no effect on subsequent CPP expression when rats were exposed to saline-paired context or homecage. These results indicated that systemic administration of rapamycin after memory reactivation can persistently inhibit the drug seeking behaviour via disruption of morphine memory reconsolidation in rats. Additionally, the effect of rapamycin on memory reconsolidation was reproduced in cocaine CPP and alcohol CPP. Furthermore, rapamycin did not induce conditioned place aversion and had no effect on locomotor activity and anxiety behaviour. These findings suggest that rapamycin could erase the acquired drug CPP in rats, and that mTOR activity plays an important role in drug reconsolidation and is required for drug relapse.

Aims: Alcohol toxicity can induce multiple organ dysfunction, including the liver. Gallated catechins (GCs), the components of green tea extract (GTE), have been known to inhibit intestinal lipid absorption. This study was designed to investigate the inhibitory effect of GC on the absorption of the lipid-soluble ethanol in normal mice. In addition, the effectiveness of prolonging the GC-mediated effect was evaluated as a means of preventing alcoholic liver damage., Methods: GTE was administered orally immediately or 90 min before ethanol administration and the blood ethanol and acetaldehyde levels were measured. Binge ethanol administration (by gavage every 6 h for 24 h) was used to induce acute liver injury, and GTE was administered 90 min prior to every ethanol administration., Results: When GTE, but not GC-decreased GTE, was administered immediately before ethanol intake, the blood ethanol and acetaldehyde levels were significantly lower than those in the control. On the other hand, GTE has no effect when GTE was administered 90 min before ethanol intake. When GTE was co-administered with polyethylene glycol (PEG) or poly-γ-glutamate (PGA) 90 min before ethanol intake, the lowering effect of GTE on the blood ethanol and acetaldehyde levels was maintained in contrast to the GTE-alone-treated group. After binge ethanol administration, liver weight decreased, and serum alanine aminotransferase and aspartate aminotransferase levels were elevated. Additionally, histopathological changes, such as macrovesicular steatosis and necrosis, were induced in the liver, together with reactive oxygen species generation. When GTE + PEG or GTE + PGA, but not GTE alone, was administered 90 min before ethanol intake, acute liver injury was ameliorated., Conclusion: These findings support the development of GTE + PEG or GTE + PGA as an inhibitor of intestinal alcohol absorption for the preventative treatment of acute alcohol toxicity.

Epidemiological and animal studies have suggested that chronic alcohol consumption is a major risk factor for osteoporosis. Using bone from cycling female rats infused chronically with ethanol (EtOH) in vivo and osteoblastic cells in vitro, we found that EtOH significantly increased estrogen receptor alpha (ERalpha) and beta (ERbeta) mRNA and ERalpha protein levels. Treatment with 17beta-estradiol (E2) in vivo and in vitro interfered with these effects of EtOH on bone and osteoblastic cells. ERalpha agonist propylpyrazoletriol (PPT) and ERbeta agonist diarylpropionitrile (DPN) attenuated EtOH-induced ERalpha and ERbeta gene overexpression, respectively. Similar to the ER antagonist ICI 182780, EtOH blocked nuclear translocation of ERalpha-ECFP in the presence of E2 in UMR-106 osteoblastic cells. EtOH also downregulated ERE-luc reporter activity. On the other hand, EtOH by itself upregulated some common ERalpha- and ERbeta-mediated genes apparently by an ER-independent pathway. EtOH also transactivated the luciferase activity of the p21 promoter region independent of additional exogenous ERalpha, activated p21 and p53, and stimulated senescence-associated beta-galactosidase activity in rat stromal osteoblasts. E2 treatment attenuated these EtOH actions. We conclude that inhibitory cross-talk between EtOH and E2 in osteoblasts on ERs, p53/p21, and cell senescence provides a pathophysiologic mechanism underlying bone loss and the protective effects of estrogens in alcohol-exposed females.

Objectives: The objective of this work was to investigate the antiulcerogenic and anti-inflammatory activities of the essential oil from Pterodon emarginatus seeds., Methods: The following tests were used: ulcers induced by ethanol, indometacin and HCl/ethanol, and pleurisy induced by carrageenan in Swiss albino rats. The rats were treated by the oral route with essential oil of P. emarginatus seeds., Key Findings: The essential oil at 100, 300 and 500 mg/kg exhibited significant protection against ulcers induced by ethanol, indometacin and HCl/ethanol (P < 0.001). The essential oil caused a marked reduction in the exudate volume and inhibited leucocyte and neutrophil influx (P < 0.05) in carrageenan-induced pleurisy. Moreover, the essential oil significantly decreased nitric oxide (NO) and interleukin-1 (IL-1) levels, without affecting tumour necrosis factor-alpha production., Conclusions: The results demonstrated the marked antiulcerogenic and anti-inflammatory effects of the essential oil from P. emarginatus, which are, at least in part, a consequence of NO and IL-1 modulation. P. emarginatus or its constituents might represent new therapeutic options to treat gastric ulcers and inflammatory diseases.

Aims: We investigated the effects of [N-allyl-Dmt(1)]endomorphin-2 (TL-319), a novel and highly potent micro-opioid receptor antagonist, on ethanol (EtOH)-induced enhancement of GABA(A) receptor-mediated synaptic activity in the hippocampus., Methods: Evoked and spontaneous inhibitory postsynaptic currents (eIPSCs and sIPSCs) were isolated from CA1 pyramidal cells from brain slices of male rats using whole-cell patch-clamp techniques., Results: TL-319 had no effect on the baseline amplitude of eIPSCs or the frequency of sIPSCs. However, it induced a dose-dependent suppression of an ethanol-induced increase of sIPSC frequency with full reversal at concentrations of 500 nM and higher. The non-specific competitive opioid receptor antagonist naltrexone also suppressed EtOH-induced increases in sIPSC frequency but only at a concentration of 60 microM., Conclusion: These data indicate that blockade of micro-opioid receptors by low concentrations of [N-allyl-Dmt(1)]endomorphin-2 can reverse ethanol-induced increases in GABAergic neurotransmission and possibly alter its anxiolytic or sedative effects. This suggests the possibility that high potency opioid antagonists may emerge as possible candidate compounds for the treatment of ethanol addiction.

The purpose of this study was to investigate the role of K+ channels in duodenal dismotility induced by ethanol in vitro. The amplitude of spontaneous contractions was reduced by ethanol in longitudinal and circular muscle, while frequency did not change. Charybdotoxin antagonized ethanol-induced inhibition of the amplitude of spontaneous contractions. Ethanol decreased ACh-induced contractions and this effect was cancelled out by charybdotoxin. Ca2+-activated K+ channels may be involved in duodenal dismotility induced by ethanol.

Aims: This study aimed at comparing the cerebral cytotoxicity of ethanol and its main metabolite acetaldehyde after acute or chronic exposures of rat astrocytes in primary culture., Methods: Cytotoxicity was evaluated on the cell reduction of viability (MTT reduction test) and on the characterization of DNA damage by single cell gel electrophoresis (or comet assay)., Results: Changes in astrocyte survival and in DNA integrity only occurred when the astrocytes were chronically exposed to ethanol (20 mM; 3, 6 or 9 days). On the other hand, viability and DNA integrity were deeply affected by acute exposure to acetaldehyde. Both effects were dependent on the concentration of acetaldehyde. The cytotoxic effect of acetaldehyde was also indirectly evaluated after modifications of the normal ethanol metabolism by the use of different inducers or inhibitors. In presence of ethanol, the concomitant induction of catalase (i.e. by glucose oxidase) and inhibition of aldehyde dehydrogenase (i.e. by methylene blue) led to acetaldehyde accumulation within cells. It was followed by both a reduction in viability and a substantial increase in DNA strand breaks., Conclusions: These data were thus consistent with a possible predominant role of acetaldehyde during brain ethanol metabolism. On the other hand, the effects observed after AMT could also suggest a possible direct ethanol effect and a role for free radical attacks. These data were thus consistent with a possible predominant role of acetaldehyde during brain ethanol metabolism. On the other hand, the effects observed after AMT could also suggest a possible direct ethanol effect and a role for free radical attacks.

We tested the hypothesis that combined administration of IL-1 and TNF antagonists would protect fracture healing from inhibition by chronic ethanol exposure. Adult male rats were fed a liquid diet +/- ethanol (CON and ETOH) by intragastric infusion for three weeks prior to and three weeks after creation of an externally fixated tibial fracture. Beginning the day of fracture, one-half of each dietary group received 2.0 mg/kg/day IL-1ra and 2.0 mg/kg/2-days sTNFR1 (CON + ANTAG and ETOH + ANTAG), while all other animals received vehicle alone (CON + VEH and ETOH + VEH). Scoring of ex vivo radiographs and analysis by pQCT revealed a significantly lower incidence of bridging and reduced total mineral content in the ETOH + VEH group compared to all other groups. These results support, for the first time, the hypothesis that IL-1 and TNF antagonists are capable of protecting fracture healing from the inhibition associated with chronic ethanol consumption.

In female SD rats that were injected with 4 g/kg BW ethanol p.o. followed by a 5 mg/kg BW lipopolysaccharide (LPS) i.v. injection, serum glutamic pyruvic transaminases (GPT) activity increased to about eight times that of normal rats. In this model, rats that had been fed a diet containing 1% Hydrangeae Dulcis Folium (HDF) extracts for fifteen days showed significantly lower serum GPT activity (380.0+/-58.2 IU/l) than the control group (3527.0+/-774.1 IU/l). HDF's efficacy was far superior to milk thistle in this model (2950.0+/-915.9 IU/l). When mouse macrophages were treated with HDF extracts at 50 microg/ml, TNF-alpha production induced by LPS was suppressed to about 10% of the control. Rat serum TNF-alpha levels induced by LPS was decreased to 58.7% of the control by administering 1000 mg/kg BW HDF extract p.o. These results indicate that HDF prevents alcohol-induced liver injury through the inhibition of TNF-alpha production.

Basic inhibitory mechanisms of costunolide and its active component, alpha-methylene-gamma-butyrolactone (alpha-MGBL), on blood-ethanol elevation were investigated in rats. In normal rats, blood-ethanol elevation (30 min later) induced by 20% (v/v) ethanol [5 ml/kg, per os (p.o.)] was strongly inhibited by pretreatment (30 min earlier) with costunolide and alpha-MGBL (50 mg/kg, p.o.). In pylorus-ligated rats given ethanol, blood-ethanol level (30 min) was barely elevated compared with that of normal rats. Neither costunolide nor alpha-MGBL affected the blood-ethanol elevation in pylorus-ligated rats or that induced by intraperitoneal and intraduodenal ethanol administration. Moreover, these compounds given orally induced no irreversible changes in alcohol dehydrogenase activity in rat liver. We continuously investigated the rate of gastric emptying in rats given various test meals. Costunolide and alpha-MGBL suppressed gastric emptying in rats given 20% ethanol and 1% sodium carboxymethyl cellulose. alpha-MGBL (50 mg/kg), but not costunolide, suppressed gastric emptying in 20% glucose-loaded rats. In an in vitro experiment, alpha-MGBL contracted the pylorus strip at a high concentration (20 mM), which was the estimated concentration in the stomach when the substance was given orally in vivo. These findings suggested that alpha-MGBL constricted the pylorus and caused delay of gastric emptying. Moreover, both compounds increased gastric fluid secretion with pepsin and mucus. In conclusion, the inhibitory effects of costunolide and alpha-MGBL on blood-ethanol elevation were based on inhibition of gastric emptying and dilution of the ethanol concentration by the increased gastric fluid.

The role of endogenous nitric oxide and sulphydryls in gastric protection afforded by sodium cromoglycate against ethanol-induced gastric lesions was studied in rats. Drugs were administered either intraperitoneally (i.p.) or subcutaneously (s.c.) 30, 45 or 60 min before oral administration of ethanol. Administration of cromoglycate before ethanol dose-dependently inhibited ethanol-induced gastric lesions. Pretreatment with NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide biosynthesis, dose-dependently aggravated gastric lesions and reduced cromoglycate-induced gastric protection. The attenuating effect of L-NAME on gastric protection elicited by cromoglycate was reversible by pretreatment with L-arginine but not by D-arginine. On the other hand, ethanol-induced gastric lesions were found to be associated with a reduction of nonprotein sulphydryl content of glandular stomachs. Pretreatment with cromoglycate prevented non protein sulphydryl depletion and afforded protection. Pretreatment with N-ethylmaleimide, a sulphydryl blocker, caused dose-dependent enhancement of ethanol-induced gastric lesions and further depletion of non protein-sulphydryl. Treatment with N-ethylmaleimide before cromoglycate reduced the gastric protection that was associated with depletion of nonprotein sulphydryls. Furthermore, combined N-ethylmaleimide and L-NAME pretreatment caused a greater aggravation of ethanol-induced gastric lesions and significantly produced a higher reduction of the protective effects of cromoglycate. However, pretreatment with L-arginine only partially restored the protective effects of cromoglycate. These results suggest that the protective effects of cromoglycate may be dependent on the maintenance of a critical level of both endogenous nitric oxide and nonprotein sulphydryls in the gastric mucosa.

The central pharmacological effects of ethanol are well known and resemble those of the benzodiazepines (BZD). In addition BZD may interact with ethanol, resulting in enhanced cerebral depression. Ro 15-4513, BZD inverse agonist, potentially antagonizes a lot of effects of ethanol but not all. In our study, another BZD inverse agonist, CGS 8216, reverses the hypnotic effect of ethanol and hypoactivity in mice and rats. CGS 8216 increased also ethanol's locomotor stimulation in mice. This supports the hypothesis that some effects of ethanol are mediated by the GABA-BZD-chloride channel receptor complex. Our behavioural experiments described in this report suggest that CGS 8216, like Ro 15-4513, may act on the alpha-6 subunit of this receptor complex.

The effects of metadoxine (pyrrolidone-carboxylic acid; PCA) and pyridoxine on the locomotor responses to ethanol in mice were compared. Metadoxine (200 and 400 mg/kg i.p.) and PCA (86 and 172 mg/kg) prevented, in a dose-related manner, the locomotor stimulant effect of a low dose of ethanol (1.5 g/kg i.p.), whereas pyridoxine (228 mg/kg i.p.) was completely ineffective. Neither compound modified the sedative effect of a high ethanol dose (2.5 g/kg i.p.). The results indicate that the antagonistic effect of metadoxine on ethanol stimulant response is due to the PCA component of the molecule.

This study shows inhibition of the increase in locomotor activity induced by ethanol (2 g/kg i.p.) in mice by a low dose (0.1 mg/kg i.p.) of the non-opioid beta-endorphin fragment ORG 5878 (des-enkephalin-gamma-endorphin). ORG 5878 (0.1 mg/kg i.p.) also significantly antagonised the large increase in electroshock seizure threshold produced by ethanol (1.5 g/kg i.p.). In contrast, the hypothermia induced by ethanol (2 g/kg i.p.) was not altered by ORG 5878 (0.1 mg/kg i.p.). The effects of ORG 5878 showed an abnormal dose-response relationship, in that a high dose (1 mg/kg i.p.) did not significantly suppress any of the behavioural effects of ethanol examined although there was some indication that it attenuated the stimulant action of ethanol. ORG 5878 (0.1, 1 mg/kg i.p.) did not have any intrinsic effects on locomotion, seizure threshold or body temperature in mice. These results are the first demonstration that ORG 5878 may act as an ethanol antagonist in some paradigms.

The effects of ethanol alone and in combination with sulphanilyl fluoride on some of the antioxidant defences in the stomach of rats have been examined. These effects were correlated with lesion formation in the gastric mucosa. Oral administration of ethanol induced gastric lesions which were prevented by sulphanilyl fluoride pre-treatment. N-Ethylmaleimide antagonized the anti-lesion action of sulphanilyl fluoride. Ethanol administration lowered the glucose-6-phosphate dehydrogenase activity in the gastric mucosa, an effect potentiated by N-ethylmaleimide pre-treatment. The total superoxide dismutase activity was unaffected by the drugs used in the present study. Ethanol, however, markedly increased mucosal catalase activity which was reduced by sulphanilyl fluoride pretreatment and reversed by N-ethylmaleimide. It is concluded that the ulcerogenic mechanism of ethanol is mediated at least in part by the depression of the hexose monophosphate shunt and the production of active oxygen species, whereas the anti-lesion action of sulphanilyl fluoride is probably not mediated through these mechanisms.

It was previously shown that adenosine agonists and antagonists potentiate and decrease ethanol-induced motor disturbances, respectively. This interaction of adenosine and ethanol was functionally correlated with a significant increase in Bmax of cerebellar cortical high affinity adenosine A1 receptors after a single ethanol injection. Quantitative autoradiographic analysis of adenosine A1 and A2 binding sites in rat brain was carried out in animals treated acutely with saline or ethanol. Adenosine agonist binding at A1 receptors was increased in the molecular layer of cerebellum 15 min after ethanol injection. This increase returned to control values by 60 min. Adenosine antagonist binding at A1 receptors was not altered by ethanol treatment. Inclusion of a poorly hydrolyzable analogue of GTP in the incubation medium decreased binding throughout the brain for adenosine agonists but had less effect on agonist binding in the cerebellum and hippocampus of ethanol-treated rats 15 min after injection. The inhibitory effect of the GTP analogue was equal in saline- and ethanol-treated rats after 60 min. These findings suggest that acute ethanol treatment elicits a transitory increase in adenosine A1 receptor binding that is limited to the cerebellum and hippocampus and that this increased binding reflects an increased (or stabilized) coupling of the receptors to GTP-binding proteins. Acute ethanol treatment did not alter agonist binding at the high affinity A2a subtype of adenosine receptors in striatum.

The possible involvement of voltage sensitive calcium channels (VSCCs) in both locomotor activity and striatal homovanillic acid (HVA) alterations in acutely low (0.5 g/kg) and high (2 g/kg) dose ethanol-treated rats was investigated. Both doses of ethanol produced inhibitory effects on both locomotor activity and striatal HVA levels. Bay K 8644 significantly potentiated and nifedipine reversed the locomotor inhibitory effect of low-dose ethanol, whereas both drugs did not alter locomotor activity and striatal HVA levels, when used alone. On the other hand, both Bay K 8644 and nifedipine significantly reversed the decrease in striatal HVA levels induced by the low and high doses of ethanol.

The effects of chronic administration of ethanol on the lipid composition of erythrocytes and liver of rats were investigated. Ethanol was chronically administered alone or in combination with Evening Primrose Oil (containing 10% v/v gamma-linolenic acid) in a nutritionally balanced milk diet. Chronic administration of ethanol alone significantly decreased the content of arachidonic acid in erythrocyte membranes, whereas the concomitant administration of Evening Primrose Oil reversed this effect. The triacylglycerol content was significantly increased in the microsomal fraction of the liver after chronic ethanol administration. Ethanol also significantly increased the ratio of cholesterol:cholesteryl esters in the microsomal fraction. The arachidonic acid content of the whole liver fraction was significantly reduced after chronic administration of ethanol, whereas concomitant administration of Evening Primrose Oil did not reverse this effect. The administration of Evening Primrose Oil during chronic ethanol intake may have beneficial effects, as it reverses some of the effects of ethanol on erythrocyte and hepatocyte membrane lipids which may be detrimental to health.

The effect of nicotinic acid (NA) on sleeping time induced by a single dose of ethanol or pentobarbital was studied in rats. It was found that sleeping time was markedly reduced by NA in a dose-dependent manner. The effect was observed when NA was administered 10 min before or after ethanol or pentobarbital, but not when given 60 min in advance. NA did not affect the rate of ethanol elimination measured up to 5 hr after ethanol administration. Rats pretreated with NA 60 min before ethanol slept longer than controls. This latter effect was not observed with pentobarbital. These observations, together with the known lack of effect of high liver NAD+ levels on ethanol metabolism and the rather stable NAD+ concentration in brain cells, suggest that the effect of NA on sleeping time is not mediated by an increase in ethanol metabolism in liver or by NAD+ or NAD+-dependent reactions in brain. Our results are consistent with a direct action of NA, or some rapidly formed derivative, on a structure or process associated with brain cell functions or membranes.

The incorporation of 14C-valine into liver protein was studied in isolated rat liver parenchymal cells. Various glucose levels in the incubation media did not affect the rate of 14C-valine incorporation into proteins. The insulin stimulated incorporation of 14C-valine into proteins was also unaffected by the various glucose levels. Ethanol decreased the incorporation of 14C-valine into liver proteins, affecting stationary and export proteins to the same extent. This inhibitory action of ethanol on valine incorporation was reversed by increasing exogenous glucose concentrations. The combination of insulin and high glucose level totally prevented the ethanol inhibition.

The effect of peripherally administered drugs that modify monoaminergic function, on ethanol (2.0 g kg-1, intragastrically)-induced changes in urine output has been examined in rats. The alpha-noradrenoceptor agonist, clonidine (0.05-0.15 mg kg-1) produced marked urine output and potentiated slightly the diuretic effect of ethanol. The alpha-noradrenoceptor antagonist, phentolamine (1-5 mg kg-1) dose-dependently decreased ethanol-induced diuresis. p-Chloroamphetamine (0.8-2.0 mg kg-1) produced significant diuresis and potentiated the diuresis produced by ethanol. Methysergide (1.25, 2.5 mg kg-1), a 5-hydroxytryptamine receptor antagonist, had no effect on urine output while it depressed the ethanol-induced increase in urine output. Apomorphine (0.8, 1.5 mg kg-1), a dopamine receptor agonist, did not modify urine output in either control or ethanol-treated animals, while the dopamine receptor antagonist, pimozide (0.75-3.0 mg kg-1), dose-dependently decreased ethanol-induced diuresis, but had no effect on urine output in control animals. Since our previous research indicates that the intraventricular administration of drugs that alter dopaminergic and 5-HT function does not alter ethanol-induced diuresis, the interaction of these types of agents with ethanol-induced diuresis in the present study suggests that the interaction was mediated peripherally.

Rabbits were treated with 0.5 g/kg ethanol intravenously and alterations of limbic-midbrain interactions in both feeding and escape elicited by threshold electrical stimulation of the lateral (LH) and ventromedial hypothalamus (VMH) were observed. Decrease of the VMH excitability and abolishing of inhibitory effects of the dorsal hippocampus (HPC) and facilitatory influences of the midbrain reticular formation (MRF) on both motivational hypothalamic centres were found in animals after ethanol administration. Subsequent single injection of substance P (SP) (30 microgram-kg i.v.) just at the height of alcohol manifestations in central mechanisms of feeding and escape led to restoration of the VMH excitability and facilitatory MRF influences on this motivational centre. SP administration was also found to restore the inhibitory hippocampal and facilitatory MRF effects on the excitability of the LH feeding centre. Partial and selective SP restoration of ethanol-induced alterations in feeding and escape which are observed in the present study, as well as the data of some other researchers, led to the suggestion that peptides could be used as factors of enhancing tolerance to ethanol or curing deleterious acute alcohol-induced effects in motivated behaviours in animals.

Paracetamol given orally or subcutaneously did not produce any observable gastric mucosal damage, nor did it change the acidity of the residual secretion in rat stomachs. However, it delayed the gastric emptying rate and increased the residual volume of gastric secretion. Pretreatment with paracetamol 250 mg kg-1 significantly prevented ethanol-induced gastric ulceration. Although it did not influence ethanol-stimulated acid secretion, it increased the mucosal mucus content in the ethanol-treated animals. The findings suggest that the protective mechanism of paracetamol against ethanol-induced damage is likely to be due to improved gastric mucosal integrity, through an increase in the adherent mucosal mucus which protects the underlying delicate cellular structures.

Aspirin (ASA) was tested in a group of 8 Oriental and 3 Occidental subjects who were shown in a previous study to respond to small doses of ethanol (0.06-0.25 g/kg) with facial flushing. They were compared to a similar group of 11 non-flushing Occidental subjects following a larger ethanol dose (0.37 g/kg) to determine if similar effects could be produced in less sensitive individuals. Control tests of blood ethanol and acetaldehyde (AcH) levels (calculated from breath), facial and neck skin temperatures, body sway (Romberg test), blood pressure, heart rate and 10 Subjective High Assessment Scales (SHAS-Judd, 1977) were conducted before and at 15, 30, 60 and 90 minutes after drinking ethanol as vodka in orange juice. The tests were repeated one week later one hour after receiving 0.64 gm of ASA orally. ASA produced slight changes in the early absorption of ethanol and small decreases in AcH levels in the flushing and non-flushing groups. Facial flushing was markedly reduced in the flushing group, but was slightly increased in the non-flushing Occidentals. Body sway was reduced by ASA in both groups. An alcohol-induced increase in heart rate in the flushing group was reduced with no change in blood pressure. SHAS subjective parameters were widely variable, but indicated that ASA produced reduced sleepiness and earlier relaxation in the flushing group. It is concluded that ASA can block alcohol-induced facial flushing in sensitive subjects and also reduces body sway in the Romberg test and alters some subjective feelings of alcohol intoxication.

These experiments examined the effects of naloxone on alcohol-induced changes in striatal concentrations of DOPAC and HVA, on endogenous dopamine release from striatum in vitro, and on duration of sleep time in vivo. The results emphasize the role of opioid peptides in alcohol's effects on dopaminergic function and on behaviour.