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Generally, compounds discriminated by animals possess psychotropic effects in animals and humans. As with many other drugs of abuse, strength of the ethanol discriminative stimulus is dose related. The majority of studies show that doses close to 1.0 g/kg are close to the minimum at which the discrimination can be learned easily. Substitution studies suggest that anxiolytic, sedative, atactic, and myorelaxant effects of ethanol all play an important role in the formation of its intercoeptive stimulus. Low doses of ethanol produce more excitatory cues, similar to amphetamine-like subjective stimuli, whereas higher doses produce rather sedative/hypnotic stimuli similar to those elicited by barbiturates. Substitution studies have shown that the complete substitution for ethanol may be exerted by certain GABA-mimetic drugs acting through different sites within the GABA(A)-benzodiazepine receptor complex (e.g., diazepam, pentobarbital, certain neurosteroids), gamma-hydroxybutyrate, and antagonists of the glutamate NMDA receptor. Among the NMDA receptor antagonists both noncompetitive (e.g., dizocilpine) and competitive antagonists (e.g., CGP 40116) are capable of substituting for ethanol. Further, some antagonists of strychnine-insensitive glycine modulatory sites among the NMDA receptor complex (e.g., L-701,324) dose-dependently substitute for the ethanol discriminative stimulus. On the other hand, neither GABA-benzodiazepine antagonists nor NMDA receptor agonists produce contradictory effects (i.e., reduce the ethanol discriminative stimulus). There is influence of a particular training dose of ethanol on the substitution pattern of different compounds. For example, 5-HT(1B/2C) agonists substitute for intermediate (1.0 g/kg) but not higher (2.0 g/kg) ethanol training doses. Discrimination studies with ethanol and drugs acting on NMDA and GABA receptors consistently indicate asymmetrical generalization. For example, ethanol is able to generalize to barbiturates and benzodiazepines, but neither the benzodiazepine nor barbiturate response generalizes to ethanol. Only a few drugs are able to antagonize, at least to some extent, the discriminative stimulus of ethanol (e.g., partial inverse GABA-benzodiazepine receptor antagonist Ro 15-4513 and the opioid antagonist naloxone). The ethanol stimulus effect may be increased (i.e., stronger recognition) by N-cholinergic drugs (nicotine), dopaminergic drugs (apomorphine), and 5-HT3 receptor agonists (m-chlorophenylbiguanide). Thus, the ethanol stimulus is composed of the several components, with the NMDA receptor and GABA(A) receptor complex being of particular importance. This suggests that a drug mixture may be more capable of substituting for ethanol (or block its stimulus) than a single compound. The ability of drugs to substitute for the ethanol discriminative stimulus is frequently, although not preclusively, associated with the reduction of voluntary ethanol consumption. The examples of positive correlation are gamma-hydroxybutyrate, possibly memantine and certain serotonergic drugs such as fluoxetine. However, it remains uncertain to what extent the discriminative stimulus of ethanol can be seen as relevant in the understanding of the complex mechanisms of dependence.

Ethanol has a concentration dependent dual effect on electrical activity of rat CA1 hippocampal neurons. Low concentrations of ethanol (0.001%) enhance whereas high concentrations (0.5%) suppress synaptic transmission. Ethanol has no effect on cell input resistance and orthodromic or somatic threshold of action potentials. Cholera toxin, an activator of stimulatory guanine nucleotide binding regulatory protein (Gs), prevented the ethanol effects on field excitatory postsynaptic potentials (EPSPs). Staurosporine, an inhibitor of protein kinases, bisindolylmaleimide, an inhibitor of protein kinase C, and phorbol-12,13-dibutyrate (PDBu), an activator of protein kinase C, blocked the effect of ethanol on field EPSPs. Our results show that ethanol at extremely low concentrations is able to affect synaptic transmission and suggest that the molecular mechanism of ethanol action involves the activation of Gs protein and protein kinase C.

The interaction of mianserin with ethanol in central nervous system (CNS) was investigated. Mianserin was administered at a single dose of 5 or 20 mgkg(-1) i.p. or as daily injections in a dose of 2.5 mgkg(-1) given for 14 days. The influence of mianserin on acute ethanol toxicity (LD(50)), on ED(50) of ethanol in rota-rod test, on the duration of ethanol sleeping time as well as on spontaneous locomotor activity and ethanol-induced hypothermia was investigated. Moreover, the influence of mianserin administered in a dose of 10 mgkg(-1) i.p. on post-ethanol changes in the bioelectric brain activity (EEG) recordings in rabbits was also investigated. The electrodes were implanted into midbrain reticular formation (MRF), dorsal hippocampus (Hp) and frontal cortex (C). Mianserin administered as a single dose of 5 mgkg(-1) was found to decrease LD(50) of ethanol and its ED(50) in rota-rod test. Mianserin administered as a single dose of 5 or 20 mgkg(-1) prolongs ethanol sleeping time in mice but given daily for 14 days has no influence on this time. Mianserin-induced hypothermia was observed after administration of single dose as well as increase of ethanol-induced hypothermia after administration of higher dose (20 mgkg(-1)). Mianserin administered daily for 14 days had no influence on post-ethanol changes in body temperature. Single dose of mianserin 20 mgkg(-1) decreases locomotor activity in mice while repeated administration has no influence on locomotor activity. In contrast, both single dose and repeated administration of mianserin prevents increased locomotor activity of animals observed after ethanol (2.5 mgkg(-1)). Mianserin administered to rabbits (10 mgkg(-1)) induces increase of share of low frequency 0.5-4 cps and decrease of share of frequencies 4-7 and 7-10 cps in EEG recordings from MRF and Hp. The recordings from frontal cortex show increase of share of frequencies 10-13 cps. Ethanol increases the share of low frequencies in EEG recordings and decreases the share of fast frequencies. Mianserin increases its influence on fast frequencies.

In this study we have decided to examine acute interaction of ethanol with some drugs that belong to selective serotonin inhibitor (SSRI) group. Therefore, the influence of sertraline, fluoxetine and citalopram on the effect of ethanol on EEG of rabbits (frontal cortex, hippocampus, MRF) was tested. Sertraline (10mg/kg i.p.), fluoxetine (10mg/kg i.p.) and citalopram (5mg/kg i.p.) were given 30min before ethanol injection in a dose 0.8g/kg i.v. Ethanol caused the increase of the slow frequencies (0.5-4cps) in the recording, as well as a marked decrease of the fastest frequencies (13-30 and 30-45cps). Sertraline, fluoxetine and citalopram (given before ethanol) prevented the increase in the slow frequencies (0.5-4cps) in the recordings from the frontal cortex and hippocampus, which indicates on antagonism inhibitory action of ethanol. These drugs administered together with ethanol may increase its influence on fast frequencies. This effect depends on brain structure and drug.

Recent evidence indicates involvement of excitatory amino acid receptors sensitive to N‐methyl‐d‐aspartate (NMDA) in the action of ethanol (EtOH). Pronounced inhibition of NMDA receptor function is seen in vitro with concentrations of EtOH corresponding to those present during alcohol intoxication in humans. The present study was devoted to investigate the role of NMDA receptors in the action of EtOH in rats. Acute experiments showed antagonism by EtOH of convulsions induced by intracerebroventricular injection of NMDA. A similar effect was seen with a high dose of diazepam. Convulsions induced by an agonist of another excitatory amino acid receptor subtype, kainate, were also inhibited by EtOH. An uncompetitive antagonist of NMDA receptors, 5‐methyl‐10, 11‐dihydro‐5H‐dibenzo‐cyclohepten‐5, 10‐imine maleate (MK‐801), potentiated EtOH‐induced loss of righting, but attenuated the hypothermic action of EtOH. Moreover, MK‐801 inhibited audiogenic convulsions in EtOH withdrawn rats. At the same time the effect of a proconvulsive dose of NMDA was not enhanced. Tolerance to the myorelaxant action of both EtOH and MK‐801 upon repetitive administration was seen. Also some degree of cross‐tolerance was observed. Moreover, MK‐801 failed to modify EtOH preference in rats. The present results support involvement of NMDA receptors in expression of some acute and subchronic actions of EtOH and in expression of EtOH withdrawal.

Ethanol has been reported to alter NMDA receptor-mediated biochemical and electrophysiological responses in vitro. The aim of the present study was to evaluate the effects of an uncompetitive NMDA receptor antagonist memantine, in animal models of alcoholism. Male Wistar rats were trained to drink 8% ethanol in a free-choice, limited access procedure. A separate group of animals was trained to lever press for 8% ethanol in an operant procedure where ethanol was introduced in the presence of sucrose. The selectivity of memantine's actions was assessed by studying its effects on food or water consumption in separate control experiments. Memantine (4.5-24 mg/kg) significantly, but not dose dependently, affected ethanol drinking in the limited access procedure. However, only 6 mg/kg memantine selectively decreased ethanol drinking. Memantine did not alter ethanol intake in rats trained to lever press for ethanol in the operant procedure. Only 9 mg/kg memantine reduced operant responding in the extinction procedure in the rats trained to lever press for ethanol. The same dose of memantine significantly reduced the operant behaviour of rats trained to respond for water. These results indicate that: (i) single doses of memantine only moderately and not dose dependently reduce alcohol drinking in the limited access procedure; (ii) memantine produces non-selective effects on operant behaviour in rats trained to lever press for ethanol in an oral self-administration procedure.

ABSTRACTEthanol (Et) abusers may also be exposed to excessive amounts of cadmium (Cd). Thus, the study was aimed at estimating the influence of Et on the body turnover of Cd in a rat model reflecting excessive alcohol consumption in humans chronically exposed to moderate and relatively high levels of this metal. For this purpose, Cd apparent absorption, retention in the body and concentration in the blood, stomach, duodenum, liver, kidney, spleen, brain, heart, testis and femur as well as its fecal and urinary excretion in the rats exposed to 5 and 50mg Cd l−1 (in drinking water; for 16 weeks from the fifth week of the animal's life) and/or Et (5 g kg−1 b.w. per 24 h, by oral gavage; for 12 weeks from the ninth week of life) were estimated. Moreover, the duodenal, liver and kidney pool of the nonmetallothionein (Mt)‐bound Cd was evaluated. The administration of Et during the exposure to 5 or 50mg Cd l−1 increased Cd accumulation in the gastrointestinal tract and its urinary excretion, and decreased Cd concentration in the blood, femur and numerous soft tissues (including liver and kidney) as well as the total pool of this metal in internal organs. Et modified or not the pool of the non‐Mt‐bound Cd, depending on the level of treatment with this metal. The results show that excessive Et consumption during Cd exposure may decrease the body burden of this metal, at least partly, by its lower absorption and increased urinary excretion. Based on this study, it can be concluded that Cd concentration in the blood and tissues of alcohol abusers chronically exposed to moderate and relatively high levels of this metal may be lower, whereas its urinary excretion is higher than in their nondrinking counterparts. However, since Et is toxic itself, the decreased body burden of Cd owing to alcohol consumption does not allow for the conclusion that the risk of health damage may be lower at co‐exposure to these xenobiotics. In a further study, it will be investigated how the Et‐induced changes in the body status of Cd influence the effects of its toxic action. Copyright © 2012 John Wiley & Sons, Ltd.

The Warsaw High Preferring (WHP) and Warsaw Low Preferring (WLP) lines were bred from Wistar foundation stock to obtain lines of rats that differ in their preference for ethanol solutions. The WHP line has met several major criteria for an animal model of alcoholism. The WHP rats voluntarily drink excessive amounts of ethanol while the WLP rats consume negligible amounts of ethanol. The WHP rats attain physiologically active blood ethanol concentrations with chronic free-choice drinking. They also develop subtle but visible signs of physical dependence (the withdrawal signs). The patterns of ethanol consumption in WHP and WLP lines are stable in time and independent of the manner of access to ethanol solutions. Notably, when exposed to the increasing ethanol concentrations WHP rats gradually increased total ethanol intake whereas the WLP rats consumed invariably very low amounts of ethanol. Furthermore, the WHP rats show an increased responsiveness to the stimulatory effects of low dose of ethanol.