Suppression of ethanol-induced locomotor stimulation by GABA-like drugs

Summary Ethanol (2.4 g/kg) was given intraperitoneally to mice and was found to cause a marked increase in spontaneous locomotor activity. When mice were pretreated with low doses of agents which mimic or augment the action of GABA (-hydroxybutyric acid, baclophen, or aminooxyacetic acid) the ethanol-induced locomotor stimulation was completely eliminated. Baclophen (10 mg/kg) was found to cause an initial increase followed by a later decrease in synthesis of catecholamines, as measured by the accumulation of dopa after inhibition of central aromatic l-amino acid decarboxylase, in dopamine-rich areas of rat brain. These data are consistent with previous findings that baclophen, as well as other agents which enhance the activity of GABA systems, reduce the firing of dopamine neurons, thus causing enhanced synthesis of dopamine via feedback mechanisms. These findings also indicate a potential interaction between GABA-like drugs and alcohol in man, and may be of heuristic value in the treatment of chronic alcoholism. The possibility that the mechanism of the inhibition of ethanol-induced locomotor stimulation by GABA-like drugs may be due to a selective interference with ethanol-induced dopamine release is discussed.     

Decrease in d-methamphetamine sensitivity in mice due to ethanol: apparent inhibitory and stimulatory effects of ethanol on d-methamphetamine-induced locomotor activity

The locomotor activity of mice was recorded after administration of d-methamphetamine-HCl (1.5, 2.5, 5.0 and 7.5 mg/kg body weight) and/or ethanol (0.8 and 1.6 g/kg body weight). Mice injected with lower doses of d-methamphetamine (1.5 or 2.5 mg/kg) showed a marked increase in locomotor activity, while in those with higher doses of d-methamphetamine (5.0 or 7.5 mg/kg), locomotor activity was not further enhanced, but slightly decreased. Administration of ethanol inhibited the stimulated locomotor activity caused by low doses of d-methamphetamine (1.5 or 2.5 mg/kg), while the stimulation of motility after higher doses of d-methamphetamine (5.0 or 7.5 mg/kg) was potentiated by administering ethanol. Although apparent inhibition and stimulation of d-methamphetamine-induced locomotor activity of mice due to ethanol was observed, it is suggested that mice administered ethanol showed the decreased sensitivity to d-methamphetamine by plotting total locomotor activity of mice against doses of d-methamphetamine administered. The half maximum effective dose of d-methamphetamine for locomotor activity was increased from 1.5 mg/kg to 3.0 mg/kg by concomitant administration of 1.6 g/kg ethanol.     

Effects of acute and long-term treatments with thyrotropin-releasing hormone on locomotor activity and jumping behavior in mice

The acute and chronic effects of thyrotropin-releasing hormone (TRH) on ambulation and, in combination with apomorphine, on jumping behavior were investigated in mice. A single administration of TRH (1-10 mg/kg SC) produced an initial hyperactivity in a dose-dependent manner. Following administration of TRH (1-10 mg/kg SC) for 21 successive days, the stimulatory effect on locomotion progressively increased. Haloperidol exerted a biphasic action on hyperlocomotion induced by acute and repeated TRH, i.e., stimulation at lower doses (0.01-0.02 mg/kg SC) and inhibition at higher doses (0.05-1 mg/kg SC). When TRH was administered in combination with low doses of apomorphine, locomotor activity was inhibited but jumping behavior occurred. The inhibitory effect of low doses of apomorphine on locomotion was shifted from doses of 0.1-0.25 mg/kg SC of apomorphine for acute TRH (10 mg/kg) to 0.25-0.35 mg/kg for repeated TRH (10 mg/kg), whereas the stimulatory effect of higher doses of apomorphine (0.5-1 mg/kg SC) on locomotion tended to decrease with repeated TRH. Jumping behavior induced by the combined treatment of TRH and apomorphine was proportional to the dose of TRH but exhibited an inverted-U response to the dose of apomorphine. Chronic TRH (10 mg/kg) in combination with apomorphine (0.1-1 mg/kg SC) also produced jumping behavior, but the dose-response curve for apomorphine was shifted to the right. The present results suggest that repeated treatment with TRH in mice produces hyperlocomotion, despite attenuation of both pre- and postsynaptic receptor activity, and that the inhibitory effect of repeated TRH on presynaptic receptors may be more potent than that on postsynaptic receptors.     

Antagonism of ethanol's central stimulation in mice by small doses of catecholamine-receptor agonists

Small doses of apomorphine (0.03–0.25 mg/kg i.p.) caused a dose-dependent suppression of the ethanol-induced (2.36 g/kg, 15% v/v, i.p.) locomotor stimulation in mice and higher doses (0.5–2 mg/kg i.p.) caused a delayed suppression. The delay increased with increased doses. Very small doses of clonidine (0.025 or 0.05 mg/kg i.p.), which per se did not or only slightly affect the activity of control mice, also markedly suppressed the ethanol-induced motor stimulation. Ethanol alone (2.36 g/kg i.p.) did not significantly affect the amount of Dopa accumulating in various mouse brain regions (limbic system, corpus striatum, hemispheres and brain stem) during 30 min following administration of 3-hydroxybenzylhydrazine (NSD 1015), an inhibitor of aromatic amino-acid decarboxylase. Both the hypothermia and the locomotor stimulation by ethanol were antagonized by NSD 1015. The reduction in Dopa accumulation induced by a small dose of apomorphine (0.25 mg/kg i.p.) in the dopamine-rich regions in the mouse brain was slightly enhanced by ethanol, whereas the clonidine-induced decrease in Dopa accumulation was, if anything, reduced.In conclusion, ethanol's behavioural stimulant action in mice can be largely suppressed by apomorphine or clonidine, drugs which in the small doses used probably inhibit central catecholamine (CA) neurons.     

GABA<Subscript>B</Subscript> receptor agonists reduce operant ethanol self-administration and enhance ethanol sedation in C57BL/6J mice

Rationale A growing number of studies suggest that -aminobutyric acid type-B (GABA_B) receptor agonists reduce alcohol use and craving.Objectives This study was designed to further clarify behavioral mechanism(s) by which GABA_B agonists may decrease alcohol reinforcement.Methods Male C57BL/6 J mice were trained to lever press on a concurrent schedule of ethanol (10% v/v) and water reinforcement during 16-h overnight sessions. Effects of the GABA_B agonist baclofen (0–17 mg/kg, IP) or SKF 97541 (0–1 mg/kg, IP) were examined on parameters of self-administration. Subsequently, potential motor inhibition and interaction with ethanol-induced sedation by GABA_B agonists was examined in ethanol naive and self-administering mice.Results Baclofen (10 mg/kg) and SKF 97541 (0.3 mg/kg) reduced ethanol-reinforced responding. In a locomotor activity test, these doses of the GABA_B agonists inhibited locomotion in the ethanol-experienced mice and in a group of ethanol-inexperienced mice; locomotor suppression was greater in the ethanol-inexperienced mice. These doses of the GABA_B agonists also potentiated the sedative effects of ethanol (4 g/kg) and converted a nonsedative dose of ethanol (2 g/kg) into a fully sedative dose. GABA_B agonist enhancement of the sedative effects of ethanol was less pronounced in ethanol self-administering mice, suggesting cross-tolerance at the low dose of ethanol.Conclusions GABA_B agonists decrease the reinforcing effects of ethanol at doses that inhibit locomotor activity and potentiate the sedative hypnotic effects of ethanol. These nonspecific effects of GABA_B agonists were reduced in alcohol experienced mice, suggesting cross-tolerance to the inhibitory properties of GABA_B positive modulation. These data question the safety of prescribing GABA_B agonists to alcoholics since these drugs may potentiate ethanols sedative/hypnotic effects during relapse.     

Pharmacological study of TA-0910, a new thyrotropin-releasing hormone (TRH) analog, (I): Effects on the central nervous system by oral administration

Effects of orally administered TA-0910, a new thyrotropin-releasing hormone (TRH) analog, on the central nervous system (CNS) were investigated and compared with those of TRH. TA-0910 shortened the duration of pentobarbital-induced sleep and antagonized reserpine-induced hypothermia at 0.3 mg/kg or more in mice. TA-0910 enhanced the spontaneous motor activity at the higher dose of 30 mg/kg in mice. The drug also activated acute spontaneous EEGs in rabbits at 1 mg/kg. TRH produced these effects at about 100 times higher doses than TA-0910. In antagonizing pentobarbital-induced sleep, the dose ratios of i.v. versus p.o. of TA-0910 and TRH were about 1/10 and 1/100, respectively. The duration of the antagonistic action of TA-0910 on pentobarbital-induced sleep in mice was about 8 times longer than that of TRH when administered orally as well as intravenously. These potent and long-acting TA-0910 effects on the CNS are discussed in connection with its biotransformation.     

Interactions of antidepressants and ethanol on spontaneous locomotor activity and rotarod performance in NMRI and C57BL/6 mice

In order to find appropriate doses for studying antidepressant-ethanol interaction in two mouse strains, spontaneous locomotor activity and rotarod performance were first studied in NMRI mice after amitriptyline 3-30 mg/kg, mianserin 3-30 mg/kg, nomifensine 1- 10 mg/kg, citalopram 3-100 mg/kg, and ethanol 1-3 g/kg intraperitoneally. Ethanol increased significantly locomotor activity at 1 g/kg and impaired rotarod performance at 2 and 3 g/kg. Amitriptyline and mianserin decreased dose-dependently locomotor activity at doses ≥ 10 mg/kg. Nomifensine and citalopram increased locomotor activity at 10 mg/kg and citalopram 100 mg/kg decreased it. Rotarod performance was affected only by amitriptyline 10 and 30 mg/kg and citalopram 100 mg/kg, which impaired performance. Interaction studies with the two strains using amitriptyline, mianserin, nomifensine and citalopram 10 mg/kg and ethanol 1 g/kg showed that C57BL/6 mice were less sensitive than NMRI mice to the stimu lating effects of ethanol and more sensitive to impairment of rotarod performance by amitrip tyline and mianserin. C57BL/6 mice had a significantly poorer baseline performance on rotarod, and the citalopram plus ethanol combination impaired their performance severely, although drugs alone did not impair this test. The results suggest that decreased locomotor activity as a measure of antidepressant-induced sedation does not parallel with impaired performance on rotarod and that significant strain differences can be seen in psy chopharmacological tests and responses to drugs in mice.     

The central action of pizotifen

The central action of the potential antidepressant drug pizotifen (Sandomigran) was studied in mice, rats and rabbits. Pizotifen in doses up to 10 mg/kg i.p. was ineffective in classic tests for antidepressant activity. It neither antagonized the effects of reserpine in rats (hypothermia, ptosis) nor potentiated the effects of amphetamine (in mice and rats), nialamide or L-dopa (in mice) on locomotor activity. However, its antidepressant activity was found in the despair test in rats.On the other hand, pizotifen inhibited the head twitch reaction induced by L-5-hydroxytryptophan in mice (ED₅₀=0.009 mg/kg, i.p.) and by 5-methoxytryptamine (+tranylcypromine) in rats (ED₅₀=0.45 mg/kg, i.p.). It also antagonized tryptamine-induced clonic convulsions of fore-paws in rats (ED₅₀=0.35 mg/kg, i.p.), and in doses of 5–10 mg/kg s.c. inhibited hyperthermia produced by LSD in rabbits. Finally, pizotifen (0.1–0.3 mg/kg, i.v.) inhibited or abolished LSD- or quipazine-induced stimulation of the hind limb flexor reflex of spinal rats; the above effect was not due to noradrenolytic action of the drug. These results suggest that pizotifen strongly blocks the central postsynaptic serotonin receptors.     

Influence of captopril and enalapril on some central effects of ethanol

The influence of captopril and enalapril on acute toxicity of ethanol, ethanol-induced hypothermia, ethanol sleeping time has been investigated in mice. Moreover, the combined effect of captopril and enalapril on spontaneous locomotor activity in mice has been examined. The captopril (5 and 20 mg/kg) and enalapril (5 and 20 mg/kg) were injected intraperitoneally i.p. The drugs were given as single or repeated doses for 10 days. It has been shown that the captopril and enalapril administered in single doses decreases, but chronic administration increases acute toxicity of ethanol. Captopril and enalapril in single doses enhanced, but chronic administration inhibits hypothermic effect of ethanol. Captopril and enalapril reduces ethanol sleeping time. Captopril and enalapril administered for 10 days and enalapril in a single dose 20 mg/kg decreases ethanol induced hyperactivity.     

Effect of intraperitoneally administered GABA on the locomotor activity of mice

Gammaaminobutyric acid (GABA) was injected intraperitoneally (i.p.) into mice at doses from 25–2000 mg/kg, and spontaneous locomotor activity was recorded for the following 20 min. A slight but significant decrease in the spontaneous locomotor activity was noted only with the highest dose. The stimulation of motor activity induced by ethanol (2.4 g/kg i.p.) was significantly counteracted by GABA (100 mg/kg i.p. and upwards). A further suppression of ethanol-induced hyperactivity was reached by pretreatment with aminooxyacetic acid (AOAA, 15 mg/kg i.p.). The stimulation of motor activity induced by morphine (10 mg/kg i.p.) remained unaffected by even high doses of i.p. GABA. Motility produced by activation of postsynaptic catecholamine receptors, i.e., by apomorphine (3 mg/kg i.p.) and clonidine (3 mg/kg i.p.) following reserpine (10 mg/kg i.p.) and -methyltyrosine (250 mg/kg i.p.) pretreatment, was not affected by i.p. GABA injections, whereas hypomotility caused by a low dose of haloperidol (150 g/kg i.p.) was enhanced.In conjunction with earlier biochemical data, these results suggest a certain access of blood-borne GABA to the CNS, leading to inhibition of dopaminergic neurons involved in motility regulation.     

The effect of doxepin on the central action of ethanol.

The effect of combined treatment with doxepin and ethanol was tested in mice, rats and rabbits. Doxepin was given in a single dose (5 or 10 mg/kg) or chronically (10 mg/kg/d for 21 days). Doxepin did not affect ethanol toxicity and ethanol-induced impairment of rota-rod performance, but potentiated ethanol-induced hypothermia (only acutely) and prolonged ethanol-induced sleep in mice. Given acutely it potentiated the inhibitory effect of ethanol on locomotor activity in mice, while given chronically it counteracted the ethanol-induced sedation. Doxepin did not interfere with ethanol-induced EEG effects in rabbits, and prevented the development of tolerance to hypothermic, but not to hypnotic effects of ethanol in rats. In general, the interference of doxepin with ethanol was more pronounced after single doses of the drug than after chronic treatment.     

Influence of felbamate on selected central effects of ethanol in experimental animals

Both felbamate and ethanol demonstrate complex action on central nervous system (CNS). There are several data indicating that ethanol influences pharmacokinetics of new generation of antiepileptic drugs. Investigation of CNS interaction of felbamate and ethanol may bring up some suggestions as for adverse reactions of concomitance of these substances and consequences of such reactions are concerned. The influence of felbamate on the action of ethanol in a rota-rod test (1.5 g/kg), the duration of ethanol sleeping time (4 g/kg) as well as on spontaneous locomotor activity (2 g/kg) and ethanol-induced hypothermia (2.5 g/kg) was investigated. Felbamate was administered at a single dose (200 mg/kg i.p.) or as daily injections dose (50 mg/kg for 10 days). At a single dose, felbamate prolonged ethanol-sleeping time, increased ethanol-induced disturbances of motor coordination and ethanol-induced hypothermia as well as prevented increased locomotor activity observed after ethanol intake. Felbamate administered for 10 days reduced ethanol sleeping time, did not effect ethanol on locomotor activity of mice, but augmented ethanol-induced changes in motor coordination and ethanol hypothermia. These interactions may be of pharmacodynamic character, but pharmacokinetic nature cannot be excluded, felbamate and ethanol are substrates for the cytochrome CYP2E1.     

Bromocriptine and quinpirole,but not 7-OH-DPAT or SKF 38393, potentiate the inhibitory effect of L-NAME on ethanol-induced locomotor activity in mice

The effects of N(G)-nitro- l-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, SKF 38393, bromocriptine (BRM), quinpirole (QPR) and 7-hydroxy-2-dipropylaminotetralin (7-OH-DPAT), dopamine receptor agonists, and combinations of the dopamine agonists and L-NAME on ethanol-induced locomotor activity in adult male Swiss-Webster mice were investigated. The mice were given ethanol (0.5-2 g/kg), L-NAME (15-60 mg/kg), SKF 38393 (5-20 mg/kg), BRM (2.5 and 5 mg/kg), QPR (0.25 and 0.5 mg/kg), 7-OH-DPAT (0.5 and 1.0 mg/kg), a combination of l-arginine (1 g/kg) and L-NAME (60 mg/kg), combinations of SKF 38393, BRM, QPR or 7-OH-DPAT with L-NAME (60 mg/kg) or ethanol (0.5 g/kg) and saline or vehicle by i.p. injection. Triple combinations (dopaminergic agonist, 60 mg/kg L-NAME and 0.5 g/kg ethanol) were also given. Locomotor activity was measured for 30 min immediately following ethanol injections. Ethanol (0.5 g/kg) significantly increased locomotor activity. L-NAME, BRM, QPR and 7-OH-DPAT blocked the ethanol (0.5 g/kg)-induced locomotor hyperactivity dose dependently and at doses that did not affect locomotor activity in naive mice when administered alone. The inhibitory effects of L-NAME (60 mg/kg) were not prevented by pretreatment with l-arginine. BRM and QPR, but not 7-OH-DPAT, significantly and dose-dependently potentiated the inhibitory effect of L-NAME. Our results suggest that L-NAME inhibits ethanol-induced locomotor hyperactivity in mice by a mechanism not involving NO. The inhibitory effect of L-NAME may be related to the activation of presynaptic dopamine D(2) receptors rather than dopamine D(3) receptors.     

Drugs that antagonize limb flick behavior induced by d-lysergic acid diethylamide (LSD) in cats

In cats observed in their home cages limb flicks (LF) are a sensitive measure of the behavioral effects of LSD. LF induced by LSD (50 g/kg) were blocked by dextrorphan (0.6 mg/kg), dextromethorphan (0.6 mg/kg), and imipramine (5 mg/kg) at doses that did not produce ataxia or sleep. Levorphanol (0.6 mg/kg), a narcotic that is a congener of dextrorphan, did not block LF induced by LSD possibly because it produced an excitatory effect when given alone. Pentobarbital at low doses (2 and 4 mg/kg) increased the number of LF induced by LSD but at a high dose (8 mg/kg) decreased LF induced by LSD either by producing ataxia, so the cats tended to remain immobile, or by producing sleep. Chlorpromazine (CPZ) at three doses (2,4, and 8 mg/kg) attenuated the effects of LSD on LF, but did not block LF as completely as the above three blocking drugs, and produced ataxia and sleep.     

The effects of neurotensin, β-endorphin and bombesin on ethanol-induced behaviors in mice

The effects of the three peptides neurotensin, beta-endorphin, and bombesin on ethanol-induced behaviors were studied in mice. Intracisternal administration of these peptides to mice prolonged the duration of sleep induced by ethanol (5.2 g/kg). Neurotensin and beta-endorphin also enhanced ethanol-induced hypothermia. None of the peptides, when administered alone, produced sleep. However, all three compounds impaired the aerial righting reflex and induced sleep when followed by an IP dose of ethanol (3.5 g/kg), which alone did not induce sleep. These results, taken together with previous findings, suggest that neuropeptides may be involved in the complex mechanisms of action of ethanol on the CNS.     

Thyrotropin-releasing hormone (TRH): Enhancement of dopamine dependent circling behavior and its own circling-inducing effect in unilateral striatal lesioned animals (author's transl)]

Enhancement by TRH of the dopamine(DA) agonist-induced circling behavior and effect of TRH itself on circling behavior were investigated. TRH(2.5--20 mg/kg, i.p.) remarkably enhanced the circling behavior induced by apomorphine or-L-DOPA in the mice lesioned unilaterally in the caudate nucleus by injection of 6-hydroxydopamine (60OHDA) or by tissue aspiration with subsequent reserpinization. TRH also enhanced the apomorphine-induced stereotypy in reserpinized normal mice. The above TRH-enhancing action of the circling behavior was potentiated, suppressed or unaffected by alpha-methyl-para-tyrosine (alpha-MT) or GABA-ergic drugs. In the 6-OHDA lesioned mice treated with TRH, the cyclic AMP formation by DA or apomorphine was clearly enhanced in the triatal slices taken from the lesioned side but not from the intact side. In the rats lesioned unilaterally in the nigrostriatal DA pathway by 6-OHDA, high doses of TRH injected i.p. (100 mg/kg) or into the non-lesioned caudate nucleus (50 micrograms) produced circling toward the lesioned side, which was suppressed by haloperidol or alpha-MT. TRH(10(-5)--10(-3)M) increased the 14C-DA release from the rat striatal slices in vitro. These results suggest that TRH at low doses facilitates the DA postsynaptic transmission in association with an increase of DA-stimulated cyclic AMP formation in the striatum under supersensitization of the DA receptors, and also at high doses enhances the DA neuronal activity by increasing the DA release from the striatal nerve terminals.     

Investigation of the involvement of opioid receptors in the action of anticonvulsants

This study investigates the possible involvement of opioid receptors in the action of a variety of anticonvulsant agents. The opioid antagonist naloxone (0.3, 1 mg/kg IP) and the selective -opioid antagonist cyprodime (3 mg/kg IP) significantly inhibited the increase in electroshock seizure threshold induced by phenytoin (3 mg/kg IP) in mice. The anticonvulsant effects of ethanol (1 g/kg IP) were also significantly antagonised by naloxone (1 mg/kg IP) but not by a 0.3 mg/kg IP dose or by cyprodime (3 mg/kg IP). The results with naloxone were confirmed using higher doses of phenytoin (10 mg/kg IP) and ethanol (1.5 g/kg IP). In contrast to the above findings, naloxone (0.3, 1 mg/kg IP) had no effect on the increase in seizure threshold induced by sodium valproate (200 mg/kg IP) or dizocilpine (MK801, 0.5 mg/kg IP) and paradoxically potentiated the increase in seizure threshold produced by phenobarbitone (15 mg/kg IP); carbamazepine (10 mg/kg IP) and the benzodiazepine agonist loprazolam (1 mg/kg IP), clearly differentiating these compounds from phenytoin and ethanol. These findings suggest that the anticonvulsant effects of phenytoin and ethanol (as assessed by their ability to prevent tonic hindlimb extension in the mouse electroshock model) may be mediated, at least in part, by the release of endogenous opioids and subsequent activation of opioid receptors (, in the case of phenytoin, but non-, in the case of ethanol) although direct activity at opioid receptors cannot be precluded.     

Influence of thyrotropin releasing hormone (TRH) on drug-induced narcosis and hypothermia in rabbits

Thyrotropin releasing homone (TRH) administered via the intracerebroventricular (icv) route in doses ranging between 0.1 and 100 g decreased the duration of pentobarbital-induced narcosis in rabbits. Antagonism of narcosis occurred whether TRH was administered before or after the barbiturate. TRH doses above 10 g produced, in addition, behavioral excitation and hyperthermia. The antagonism of phenobarbital-induced narcosis was not as profound; animals were aroused only for a short period of time, after which the narcotized state returned. However, TRH exerted a prolonged antagonism or reversal of the phenobarbital-induced hypothermia. The central nervous system depression and analgesia produced by morphine were unaffected by TRH, but hypothermia and respiratory depression were reversed. TRH may represent an arousal factor in mammalian brain.     

Potentiation of the Ambulation-increasing effect induced by combined administration of MK-801 with ethanol in mice

Although both MK-801 (dizocilpine: 0.1 mg/kg, IP) and ethanol (1.6 nd 2.4 g/kg, PO) only slightly increased ambulatory activity in mice, their combination produced a marked enhancement of the ambulation-increasing effect. The combination of MK-801 (0.03 mg/kg) with ethanol (1.6 and 2.4 g/kg) also elicited a significant increase in the mouse's ambulation. A significant enhancement of the effect was produced by the combination of ketamine (3 and 10 mg/kg) with ethanol only (2.4 g/kg). The ambulation increment induced by the combination of MK-801 (0.1 mg/kg) plus ethanol (1.6 g/kg) was dose-dependently inhibited by YM-09151-2 (0.0001–0.01 mg/kg IP), SCH 23390 (0.001–1 mg/kg IP), reserpine (0.1–1 mg/kg, IP) and ceruletide (0.00001–0.001 mg/kg, IP), and the highest dose of each drug was effective for complete inhibition of the ambulation. Naloxone (0.05–5 mg/kg IP), apomorphine (0.001–0.1 mg/kg IP) and -methyl-p-tyrosine (50–200 mg/kg, IP) partially reduced the ambulatory activity induced by the combination of MK-801 with ethanol. These results suggest that the dopaminergic system, particularly via presynaptic changes in the release of stored dopamine, as well as the opioid system, are involved in the interaction of MK-801 with ethanol.     

Reduced lethality from ethanol or ethanol plus pentobarbital in mice exposed to 1 or 12 atmospheres absolute helium-oxygen

The present experiments investigated the effects of 1 and 12 atmospheres absolute (ATA) helium-oxygen on potentially lethal doses of ethanol given alone or in combination with pentobarbital. Drug-naive, male C57BL/6J mice were injected IP with 5.4–6.5 g/kg ethanol, 4.5–6.9 g/kg ethanol plus 20 mg/kg pentobarbital, or 50–110 mg/kg pentobarbital plus 2.5 g/kg ethanol. Following injection, the mice were placed into chambers and exposed to environments of 1 ATA air, 1 ATA helium-oxygen, or 12 ATA helium-oxygen. Exposure to 1 or 12 ATA helium-oxygen significantly reduced the lethal effect (percent mortality at given doses and LD₅₀) of ethanol given alone or with 20 mg/kg pentobarbital when compared to animals exposed to 1 ATA air. The pattern and degree of reduction in lethality for the 1 and 12 ATA helium-oxygen treatments were similar, suggesting that the antagonism resulted from increased helium or decreased nitrogen and not from increased atmospheric pressure. Exposure to these environments did not reduce lethality in mice given 2.5 g/kg ethanol in combination with relatively high doses (50–110 mg/kg) of pentobarbital. These findings suggest that helium-oxygen breathing mixtures may be useful in the treatment of some overdose patients.