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Male rats of the alcohol-preferring AA line were placed in an operant conditioning chamber with one lever delivering 10% alcohol solution and a second giving water. Free food and water were also continually available in the chamber so the animals should not have been motivated to obtain alcohol for reasons of hunger or thirst. The rats had never had alcohol previously. No shaping was used. The rats simply lived for the next 2 weeks in the operant chamber. All of them eventually learned to work for alcohol. Ethanol responding was significantly higher than pressing for water throughout the second week: on the last day, all rats pressed more than 300 times for alcohol and less than 40 times for water, took in a mean of 5.3 +/- 0.2 g/kg of ethanol, and obtained 72% of their total fluid as earned ethanol solution despite the presence of free water. Their acquisition was, however, much slower than that observed in male AA rats that had previously had prolonged access to drinking alcohol in their home cages. Living continually in the operant chamber is thought probably to have been an important factor in enabling the naïve rats to learn to work for alcohol.

Daily injections of the alcohol dehydrogenase inhibitor 4-methylpyrazole (4MP) were administered to C57BL/6J mice offered continuous free access to food, water and 10% v/v ethanol. There was a significant correlation (r = -0.82) between the rate of ethanol consumption during pretreatment and the effect of 4MP on subsequent intake. Mice drinking more than 2.5 g/kg per day decreased their intake, while subjects drinking less than this amount increased the quantity of ethanol self-administered. The elevated concentrations of plasma ethanol which resulted from voluntary consumption were sufficient to produce intoxication but did not induce physical dependence. Presenting mice with 10% ethanol as their only fluid or offering them a choice of water and saccharin-sweetened ethanol increased intake but failed to raise plasma ethanol to the concentrations observed in mice offered unflavored ethanol and water, and treated with 4MP. The evidence suggests that plasma ethanol does not limit voluntary drinking in untreated mice and that concentrations of 135 to 250 mg/dl are not avoided by C57 mice in a free-choice situation.

This study was designed to test the hypothesis that chronic prenatal ethanol exposure decreases basal and stimulated L-glutamate release in the hippocampus of young, postnatal guinea pigs. Timed, pregnant guinea pigs were randomly assigned to one of the following three chronic treatment groups: 4 g ethanol/kg maternal body weight/day, isocaloric-sucrose and pair-feeding to the ethanol group, and water. Each oral treatment was given daily throughout gestation. Spontaneous locomotor activity was increased on postnatal day (PD) 10, and brain and hippocampal weights were decreased on PD 12 in the offspring of the ethanol group compared with the isocaloric-sucrose/pair-fed and water groups. On PD 12, the 45 mM K(+)- and 10 microM veratridine-stimulated release of glutamate in transverse hippocampal slices was decreased in the ethanol group compared with the two control groups. This alteration in glutamate release produced by chronic prenatal ethanol exposure may decrease the efficiency of excitatory synaptic transmission in the hippocampus during postnatal life.

The purpose of this study was to determine the effects of chronic ethanol ingestion on components of mid-latency auditory evoked potentials (MAEPs). Male Sprague-Dawley rats were administered 10% ethanol in drinking water for 10 months. MAEPs were obtained and compared to age-matched controls provided tap water. Data were obtained for varying frequencies (4, 8, 16, 24, and 32 kHz) and intensities (65, 75, and 85 dB sound pressure level). Ethanol treatment was associated with increased latencies, as well as decreased amplitudes of Na and Pa. The effects were most prominent for MAEP component Pa, but also appear for component Na. We suggest that chronic alcohol consumption induces structural and/or neurochemical alterations in substrates for cortical information processing.

To examine whether exposure to ethanol influences subsequent ethanol consumption using a continuous access procedure, two groups of rats were given differing initial exposure to ethanol. One group underwent a sucrose-substitution initiation procedure. The second group received abbreviated initiation consisting of one-session exposure to each ethanol/sucrose combination used in standard initiation. The animals were then provided with 23 h/day access to ethanol (10%, v/v) from a retractable drinking tube. Food pellets were available following a single-lever press, and water was available from a sipper tube. After 5 weeks, the data indicated that few significant differences existed between the groups on total ethanol (g/kg), food or water consumed. The overall intake (g/kg/day), number of ethanol bouts per day, and amount consumed per bout (g/kg/bout) were substantially lower than observed in previous research using ethanol presented in a dipper. However, differences in g/kg per ethanol bout did differ significantly between the two groups with the group receiving standard initiation showing more ethanol consumed per bout. These data agree with our previous work indicating that initiation results in larger drinking bouts.

In the hippocampus of human alcoholics, prolonged ethanol treatment reduces the number of muscarinic ligand binding sites present at autopsy suggesting a decrease in functional muscarinic receptors. Whether these changes are due to alcohol-induced brain damage or ethanol dependence and represent a reduced level of cholinergic function is unknown. The present studies tested the impact of ethanol dependence or long-term ethanol treatment and subsequent withdrawal on the function of pre- and postsynaptic muscarinic receptors in the CA1 region of the rat hippocampus. Field excitatory postsynaptic potentials (EPSPs) were inhibited in a concentration-dependent manner by 0.1-100 microM carbachol. This presynaptic inhibitory action of carbachol involving muscarinic receptors was not significantly reduced either by ethanol treatment (12 days), causing physical dependence, or by long-term ethanol treatment (97-120 days) and abstinence (3-6 months). Postspike after hyperpolarizations (AHPs) were inhibited in a concentration-dependent manner by carbachol (6-2000 nM). This postsynaptic excitatory action of muscarinic receptors also was not significantly reduced either by 12-day ethanol treatment or by long-term ethanol treatment. Taken together, these results suggest that neither pre- nor postsynaptic muscarinic receptor function measured electrophysiologically is reduced by either ethanol dependence or long-term ethanol consumption and abstinence in the rat as suggested by reduced muscarinic ligand binding in the hippocampus of human alcoholics.

Carbamazepine (CBZ) has been used in the treatment of alcohol withdrawal (AW). However, cases of induction of euphoric feelings when mixed with alcohol have been reported. We verified whether CBZ could potentiate ethanol stimulatory effects in animals. Two groups of mice were injected with saline (group I) or 2 g/kg ethanol (group II) IP, for 20 days. On the next day, each group was divided into two subgroups that received either a single dose of CBZ (10 mg/kg) or vehicle IP, followed, 30 min later, by saline or ethanol injection. Locomotor activity was measured. Acute CBZ did not change locomotor activity of ethanol-treated mice. Treatment with CBZ or vehicle continued for 6 days. Finally, on the 28th day, 30 min after the last CBZ or vehicle injection, an ethanol challenge was given to group II and a saline injection to group I. The results showed a significant potentiation of ethanol stimulatory effects by chronic CBZ treatment. Data indicated that CBZ should be cautiously administered to alcohol-dependent patients.

Nitric oxide (NO) mediated transmission in the dorsal raphe nucleus (DRN) has been shown to be involved in the modulation of anxiety-like behaviors. We investigated whether inhibition of nitric oxide synthase (NOS) in the DRN would prevent anxiety-like behavior induced by ethanol withdrawal. Male Wistar rats were treated with ethanol 2-6% (v/v) for a period of 21 days. Ethanol withdrawal was induced by abrupt discontinuation of the treatment. Experiments were performed 48 h after ethanol discontinuation. Rats with a guide cannula aimed at the DRN received intra-DRN injections of the non-selective NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME), selective neuronal NOS (nNOS) inhibitor N(ω)-propyl-l-arginine (NPLA), or selective inhibitor of inducible NOS (iNOS) N-([3-(aminomethyl)phenyl] methyl) ethanimidamidedihydrochloride (1400W). Five minutes later, the animals were tested in the elevated plus maze (EPM). Plasma ethanol levels were determined by gas chromatography. There was a reduction in plasma ethanol levels 48 h after ethanol withdrawal. Rats from the ethanol withdrawal group showed decreased exploration of the open arms of the EPM with no change in the exploration of enclosed arms. Intra-DRN treatment with l-NAME (100 nmoles/0.2 μL) and 1400W (1 nmol/0.2 μL), but not NPLA (10 nmoles/0.2 μL) in the DRN attenuated the decrease in the exploration of the open arms of the EPM induced by ethanol withdrawal. The major new finding of the present study is that iNOS in the DRN plays a role in the anxiety-like behavior induced by ethanol withdrawal.

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.