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Lithium, a mood-stabilizing drug, is widely used to treat bipolar affective disorder. Recent studies have demonstrated that lithium has neuroprotective and neurotrophic properties, which may relate to its clinical effectiveness. Ethanol is a deleterious agent that causes various kinds of neuronal damage to both the developing and adult brain. In this study, we investigated the potential of lithium to produce recovery of ethanol-induced suppressed neuronal differentiation at ethanol concentrations lower than those that affect the viability of neural stem cells (NSCs). We evaluated the effect of lithium on neuronal differentiation of NSCs obtained from rat embryos. To elucidate the molecular mechanisms underlying the altered neuronal differentiation induced by lithium and ethanol, we focused on neuron-restrictive silencer factor (NRSF), which represses transcription of neuronal genes in the terminal stage of NSC differentiation. Lithium increased neuronal differentiation and decreased ethanol-induced suppression of neuronal differentiation of NSCs. Furthermore, lithium reduced the DNA binding activity and protein level of NRSF enhanced by ethanol. Based on our findings, we speculate that lithium may be efficacious in the treatment of ethanol-induced neurological deficits.

Opioid receptor antagonist naltrexone has shown some efficacy in decreasing ethanol consumption in humans. However, naltrexone treatment is not always efficacious and produces several aversive effects such as nausea, anxiety and weight loss. Serotonin-3 (5-HT3) receptor antagonists also modulate some of the behavioral effects of alcohol and may decrease alcohol consumption. We examined the effects of the combination of 5-HT3 receptor antagonist ICS 205-930 ((3-tropanyl-indole-1-carboxylate, tropisetron) and naltrexone on ethanol and food intake in Sprague-Dawley rats. Both naltrexone (0.56-10 mg/kg) and ICS 205-930 (5.6 mg/kg), when administered intraperitoneally 30 min before the scheduled 3-h access to ethanol, significantly suppressed ethanol intake. Naltrexone (1 mg/kg) when given in combination with ICS 205-930 (5.6 mg/kg) was significantly more efficacious in suppressing ethanol intake in comparison with naltrexone (1 mg/kg) administered alone. The drug combination did not affect the food intake. These data suggest that 5-HT3 receptor antagonist ICS 205-930 may be used as an effective adjunct for pharmacotherapy of alcoholism., (Copyright 2004 Elsevier B.V.)

The effects of arginine8-vasopressin on the stimulation of locomotor activity induced by ethanol, cocaine and amphetamine were examined in DBA/2N mice. Locomotor activity was measured by photocell beam interruption for a period of 45 min following ethanol, cocaine or amphetamine administration. Pretreatment with vasopressin alone in a dose of 2 (but not 1) microg/mouse s.c. reduced locomotor activity. The low dose of vasopressin did not modify the stimulation of locomotor activity induced by i.p. administration of ethanol in doses of either 1.5 or 2 g/kg. The high dose of vasopressin reduced locomotor activity induced by both doses of ethanol, in an apparently additive manner. Cocaine in doses of 15 and 20 mg/kg strongly stimulated locomotor activity, but this stimulation was completely antagonized by pretreatment with 1 microg of vasopressin. Similarly, the stimulation of locomotor activity induced by amphetamine (5 mg/kg) was also blocked by pretreatment with vasopressin. These findings raise the possibility that the effect of vasopressin varies with the extent and nature of dopaminergic involvement in the drug-induced stimulation of activity. For drugs like cocaine or amphetamine which stimulate locomotor activity primarily through the mesolimbic dopaminergic system, vasopressin can completely antagonize the stimulation. For ethanol, which stimulates locomotor activity through action on a number of other neurotransmitters as well as dopamine, vasopressin treatment only reduces its stimulation of locomotor activity in an additive manner. These results suggest a close interaction between vasopressin and dopamine action.

A variety of L-type Ca2+ channel antagonists, including the dihydropyridine derivative nimodipine, have been shown to be effective in reducing ethanol intake and preference in animal models of alcoholism. The behavioral mechanism involved in the anti-alcohol effects of nimodipine are, however, not clear yet. The aim of the present study was to investigate the possibility that the effects of nimodipine on ethanol intake are based on stimulus substitution. Therefore, rats were trained to discriminate ethanol (12.5% w/v, 1000 mg/kg i.p.) from saline in a two-lever food-reinforced drug discrimination procedure (dose range of ethanol tested: 125-1000 mg/kg i.p., ED50 value: 488 mg/kg). In cross-generalization tests with nimodipine (0.15-15 mg/kg i.p.), stimulus substitution was not noted. In addition, a cross-familiarization conditioned taste aversion paradigm was utilized. In rats, 1000 mg/kg i.p. ethanol was used as the reference drug producing a conditioned taste aversion. Effects of preexposure to ethanol (500-1500 mg/kg i.p.) and nimodipine (7.5-30 mg/kg i.p.) on the magnitude of the ethanol-induced conditioned taste aversion were investigated as an index for stimulus similarity between preexposure and reference drug. Preexposure to both ethanol and nimodipine prevented the development of a conditioned taste aversion. Contrary to the drug discrimination results, these latter findings suggest that there may be similarities between the stimulus properties of nimodipine and ethanol. Moreover, the apparent discrepancy between the results obtained in drug discrimination and cross-familiarization conditioned taste aversion suggests that different stimulus properties of ethanol control behavior in both procedures. The finding that, under particular conditions, ethanol and nimodipine appear to share common stimulus properties needs to be further evaluated, as this may be related to the reported anti-alcohol effects of nimodipine and other Ca2+ channel antagonists.

It has been shown that acamprosate (calcium-acetyl homotaurinate) decreases voluntary ethanol drinking in laboratory animals as well as relapse behaviour in human alcoholics. Although glutamatergic mechanisms have been implicated in several recent studies in the action of acamprosate, the basic mechanism remains unknown. In order to gain more insight into possible mechanisms underlying the ethanol intake-suppressing effects of acamprosate, we investigated this compound in an ethanol discrimination test. Male Wistar rats were trained in a two-lever operant drug discrimination paradigm to make differential responses for food following ethanol (1 g/kg i.p.; 12% v/v ethanol solution) or saline vehicle injections with a fixed ratio schedule of food reinforcement (FR 10) and a post-administration interval of 10 min. Once rats had acquired the discrimination, the criterion for stimulus control was set as at least 90% ethanol- or vehicle appropriate responding during ten consecutive sessions, an ethanol dose-response test (0.25-1.5 g/kg i.p.) was conducted. The effects of acamprosate on the discrimination were assessed in two ways: (i) Generalization test: acamprosate (25-250 mg/kg i.p.) was given either 30 or 120 min before the animals were put in the operant chambers. (ii) Antagonism test: acamprosate (25-250 mg/kg i.p.) was given 120 min before the animals were injected with ethanol, 10 min later the animals were tested. Data obtained in the dose-response test showed a dose-dependent effect with an ED50 of 0.53 g/kg ethanol. The results of generalization testing revealed that acamprosate failed to substitute for the ethanol cue, whereas, in comparison, dizocilpine (0.01-0.2 mg/kg i.p.) completely generalized for the ethanol cue (ED50 = 0.05 mg/kg). Acamprosate also had no effect when tested as an antagonist. Thus, neither the ethanol nor the saline discrimination was altered by acamprosate pretreatment. Furthermore, acamprosate had no effect on response latencies at all doses tested. In conclusion, acamprosate does not generalize for the ethanol cue, suggesting that it is not a substitution drug. Further, acamprosate does not seem to act via the dizocilpine binding site of the N-methyl-D-aspartic acid (NMDA) channel.

The effect of the dihydropyridine Ca2+ channel antagonist, isradipine, on ethanol discrimination was assessed in rats trained to discriminate 1.5 g/kg ethanol from water in a T-maze, food-reinforced drug discrimination procedure. Pretreatment with isradipine (0, 1.0, 3.0 and 5.0 mg/kg i.p.) resulted in a dose-dependent blockade of ethanol discrimination. The results of the present study suggest that L-type Ca2+ channels are involved in the mediation of ethanol discriminative stimulus effects.

Somatostatin 14 and various derivatives protect rat gastric mucosa against ethanol-induced lesions. Their mechanism of action is unknown. We investigated the effect of two somatostatin derivatives, octreotide and 5-(L)-citrullin-octreotide, on ethanol-induced hemorrhagic lesions, microcirculatory stasis and elevated vascular permeability in the rat stomach, with the goal to elucitate the pharmacological and microcirculatory mechanisms behind the gastroprotective effect. Radioligand studies revealed a high affinity of octreotide for the somatostatin receptor (IC50 = 5 x 10(-10) mol/l), in contrast to 5-(L)-citrullin-octreotide (IC50 = 3 x 10(-6) mol/l). This was in good agreement with the inhibition of growth hormone release from rat anterior pituitary cells (octreotide: IC50 = 1.2 x 10(-10) mol/l; 5-(L)-citrullin-octreotide: IC50 = 3 x 10(-6) mol/l). Intragastric administration of ethanol to rats resulted in lesions of the gastric mucosa affecting 18.9 +/- 3.1% of the area of the glandular stomach. Octreotide reduced the area to 6.4 +/- 1.7% (P < 0.05). The dose-response curve was bell-shaped. 5-(L)-citrullin-octreotide was totally devoid of any protective activity (dose range: 0.1 ng/kg to 0.1 mg/kg). We further investigated the effect of the two peptides on ethanol-induced microcirculatory stasis and elevated vascular permeability. Ethanol in a concentration of 50% induced an increase in microvascular permeability, measured by the extravasation of the tracer fluorescein-isothiocyanate-dextran (molecular weight 150,000). Pretreatment with octreotide (0.1 ng/kg s.c.) prevented stasis and reduced capillary permeability significantly. 5-(L)-citrullin-octreotide had no effect on ethanol-induced microcirculatory stasis and elevated vascular permeability in rat gastric mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study examined the effect of naloxone on ethanol- and gamma-hydroxybutyric acid-induced narcosis in mice and the changes induced by these drugs on striatal dopamine metabolism. The results show that naloxone (1-10 mg/kg s.c.) markedly reduced ethanol-induced narcosis but failed to modify the duration of sleep induced by gamma-hydroxybutyrate. Naloxone (10 mg/kg) modified neither ethanol- nor gamma-hydroxybutyrate-induced changes in striatal dopamine and dihydroxyphenylacetic acid (DOPAC) content. The results suggest that gamma-hydroxybutyrate- and ethanol-induced narcosis are mediated by different mechanisms and that opioid receptors are not involved in the changes in dopamine metabolism induced by these compounds.

Acute ethanol exposure (8-570 mM) induced potent contractile responses of rings in both basilar and middle cerebral arteries, from dogs, sheep, piglets and baboons, in a dose-dependent manner. The contractions were reproducible and not tachyphylactic. The middle cerebral arteries were found to be more sensitive to ethanol than the basilar arteries. No known pharmacological antagonist, tested, exerted any effects on ethanol-induced contractions. No differences in responsiveness to ethanol in canine cerebral arteries were found between male and female animals or between the presence and the absence of endothelial cells. Removal of extracellular Ca2+ ([Ca2+]o) partially attenuated ethanol-induced contractions, while withdrawal of extracellular Mg2+ ([Mg2+]o) potentiated such contractions. In the complete absence of [Ca2+]o, caffeine and ethanol induced similar, transient contractions followed by relaxation in K(+)-depolarized cerebral vascular tissue. Ethanol-induced contractions were completely abolished by pretreatment of tissues with caffeine. Our results suggest that: (a) acute ethanol intoxication can induce direct contractions (independent of amine, prostanoid or opioid mediation) of diverse mammalian cerebral vascular tissues, including those from primates; (b) these contractile responses are heterogeneous along the cerebrovascular tree and independent of endothelial cells; (c) in addition to a need for [Ca2+]o, an intracellular release of Ca2+ is needed for ethanol to induce contractions; and (d) hypomagnesemia or Mg deficiency potentiates the contractile effects of ethanol on brain vessels and may be a risk factor for ethanol-related, ischemic stroke events.

Naltrindole, a specific delta-opioid antagonist, infused by reverse dialysis in the nucleus accumbens of freely moving rats completely prevented the increase in extracellular dopamine concentrations elicited in the nucleus accumbens by ethanol (1.0 g/kg i.p.) as well as by the delta-opioid receptor agonist [D-Ala2]deltorphin II (50 microM), also perfused by reverse dialysis, but not by cocaine (15 mg/kg s.c.). The results provide in vivo evidence for a critical role of delta-opioid receptors in the dopamine-releasing properties of ethanol in vivo.

In an in vitro electrophysiological single-cell recording model, ethanol had an inhibitory effect on locus coeruleus (LC) neurons at both low (0.1 mmol/l) and high (500 mmol/l) concentrations. In order to test if the benzodiazepine-GABA (gamma-aminobutyric acid) receptor complex could be implicated in this effect, we tested the interaction of these ethanol concentrations with picrotoxin (100 mmol/l) and RO 15-1788 (10 nmol/l). RO 15-1788 reversed the inhibitory effect induced by ethanol 500 mmol/l, but not by ethanol 0.1 mmol/l; picrotoxin reversed the effects of both concentrations. This indicates that the mechanisms of action of ethanol on LC neurons are not the same for high and low concentrations. Furthermore, the effect of concentrations related to a behavioral effect (greater than 10 mmol/l) was reversed by a low-calcium medium that abolishes transmitter release. Therefore, the inhibition induced by ethanol 500 mmol/l seems to be due to the release of an endogenous benzodiazepine-like compound.

We investigated the involvement of the GABAergic and cholinergic neuronal systems and benzodiazepine (BZP) receptors in ethanol-induced amnesia using a passive avoidance task. Pretraining administration of ethanol impaired the passive avoidance response. The BZP agonist chlordiazepoxide potentiated the amnesia, while the GABA antagonists bicuculline and picrotoxin failed to affect it. The acetylcholine esterase inhibitor physostigmine partially attenuated the ethanol-induced amnesia. These results suggest that ethanol-induced amnesia is related to BZP receptors and a dysfunction of the cholinergic neuronal system.

Effects of selective alpha 2-adrenoceptor antagonists, atipamezole and idazoxan, on ethanol-induced hypothermia were investigated in mice. Ethanol significantly reduced (P less than 0.001) core temperature whilst both alpha 2-adrenoceptor antagonists were without effect when administered alone. However, both the 1 and 3 mg/kg doses of atipamezole significantly (P less than 0.05) attenuated the ethanol-induced reduction in body temperature 20 and 40 min after administration. The 3 mg/kg dose of idazoxan (but not the 1 mg/kg dose) also significantly (P less than 0.05) attenuated ethanol's hypothermic effect 20 min after administration but this effect was not statistically significant at 40 min. In a subsequent experiment using lower doses of atipamezole (0.03-1.0 mg/kg) the attenuation of ethanol-induced hypothermia caused by atipamezole was found to be dose-related. The effect of the benzodiazepine inverse agonist Ro 15-4513 on ethanol-induced hypothermia was also investigated. This compound possessed an intrinsic hypothermic action but neither attenuated nor enhanced the hypothermic effect of ethanol. These results suggest that alpha 2-adrenoceptor can, at least partially, modulate the hypothermic effects of ethanol.

In mice, Ro 15-4513 reduced the anaesthesia induced by ethanol and some other general depressant drugs, but was less effective against others. The order of potency was, from greatest reduction to least, ethanol, t-butanol, trichloroethanol, urethane, chlormethiazode, pentobarbitone. Of the two gaseous anaesthetics that were tested, ether anaesthesia was reduced but halothane was not. These results appeared independent of the doses of depressant or of Ro 15-4513; the effect of Ro 15-4513 in reducing ethanol anaesthesia was blocked by flumazenil (Ro 15-1788). It would appear that the benzodiazepine receptor complex is of importance in the induction of anaesthesia, most significantly with ethanol and to a diminishing degree with the other general depressants tested.

In two separate research centres the ability of RO 15-4513 to protect rats against the lethal effects of ethanol (7.5 and 15 g/kg) was investigated. In neither study did RO 15-4513 offer protection against ethanol-induced lethality or the loss of righting reflex caused by these doses of ethanol. These data fail to replicate the results of an earlier report and suggest that RO 15-4513 is unlikely to be clinically useful treating acute severe ethanol toxicity.

The ability of ethanol to stimulate opiate receptors was investigated. Administration of ethanol 2-3.5 g/kg in rats induced analgesia as tested by the tail flick method, reduced body temperature, impaired sensorimotor performance and induced "sleep". Naloxone HCI (0.5-10 mg/kg) did not significantly attenuate these ethanol-induced behavioural changes. [3H]Etorphine binding to opiate receptors in membrane preparations from rat and mouse brains was unchanged by ethanol concentrations of 0.05-3% (v/v). It was concluded that the ethanol effects studied were not mediated by naloxone-sensitive opiate receptors.