NMDA enhances the central depressant properties of ethanol in mice.

Male Swiss-Webster mice were used to examine the effect of NMDA on the ethanol-induced loss of the righting reflex (LORR). The LORR was used as a measure of CNS depression. Immediately after animals regained the righting reflex following ethanol injection (4.0 g/kg, IP) mice received an ICV injection of saline or NMDA (10, 50, 100, or 500 nmol/kg) in a volume of 5 microliters. Upon ICV injection of NMDA, mice again lost the righting reflex and this effect of NMDA in the presence of ethanol occurred rapidly and in a dose-dependent manner. In another experiment DL-2-amino-5-phosphonovaleric acid (APV), a competitive antagonist of NMDA, was given ICV with NMDA (50 nmol/kg) in the presence of ethanol. APV (10 and 100 nmol/kg, ICV) significantly attenuated the response of NMDA to enhance the depressant action of ethanol. When bicuculline methiodide, an antagonist of GABA, was given ICV with NMDA (50 nmol/kg), bicuculline methiodide reduced the effect of NMDA to produce a second loss of the righting reflex (return to the LORR) in the presence of ethanol. When NMDA (100 nmol/kg, ICV) was injected in the absence of ethanol into mice, NMDA by itself did not produce a loss of the righting reflex. In this investigation, the results suggest that NMDA can augment ethanol-induced depression possibly through an interaction between glutamatergic and GABAergeric systems in the CNS.     

The interaction between ethanol and cysteine on the central depressant effects of ethanol in mice

In this study male Swiss-Webster mice were used to examine the effects of cysteine (ICV), a precursor in the biosynthesis of taurine, on ethanol-induced loss of the righting reflex. The interaction of ethanol with gamma-aminobutyric acid (GABA) and isethionic acid, a metabolite of taurine, was also investigated on ethanol-induced central nervous system depression as measured by loss of the righting reflex experiments. Immediately after the animals regained the righting reflex following ethanol injection (IP) mice received an ICV injection of saline, cysteine (1, 15 or 25 mumol/kg), GABA (1, 15 or 25 mumol/kg) or isethionic acid (25 or 50 mumol/kg). Upon ICV administration of cysteine or GABA the mice again lost the righting reflex. This effect occurred immediately and in a dose-dependent manner. The compound, isethionic acid, failed to cause a second loss of the righting reflex following ethanol administration (IP). In the absence of ethanol cysteine or GABA (25 mumol/kg, ICV) did not produce a substantial loss of the righting reflex in mice. In another experiment mice were pretreated (IP) with L-2-oxothiazolide-4-carboxylate (OTC) 2 hr prior to ethanol administration (IP). OTC is a compound which can be converted to cysteine in the body. In the presence of ethanol OTC (15 mmol/kg) caused an enhancement of ethanol-induced central nervous system depression under certain conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pressure reversal of the depressant effect of ethanol on spontaneous behavior in rats

This study deals with the interaction between high pressure and a sub-hypnotic dose of ethanol in rats. Male Sprague-Dawley rats were given either ethanol 1.5 g/kg or saline IP and subsequently exposed to 1 atmosphere absolute pressure (ATA) air or to 1, 12, 24 or 48 ATA of helium-oxygen (heliox). The gas temperature was adjusted to offset ethanol and helium-induced hypothermia. Ethanol induced a characteristic unsteady pattern of locomotion which was completely reversed at 48 ATA, partially reversed at 24 ATA, but not affected at 12 ATA. Other behavioral effects of ethanol such as depression of total motor activity and rearing were similarly affected. Blood and brain concentrations of ethanol in the pressure groups did not differ significantly from concentrations measured in the 1 ATA groups. A similar pattern of reversal was observed whether the compression was initiated 4, 10 or 16 min after injection. These results show that hyperbaric exposure antagonizes the depressant effect of ethanol on spontaneous behavior in rats. This antagonism does not appear to be due to changes in ethanol distribution or elimination.     

The effect of piracetam on the central action of ethanol in mice and rabbits

The effect of combined single administration of ethanol and piracetam on the rabbit EEG and on locomotor activity and ethanol sleep in mice was investigated. In addition, the effect of prolonged administration of piracetam together with ethanol on rabbit EEG and after-discharges evoked by electrical stimulation of the hippocampus was studied. The blood ethanol concentrations were also monitored. Single administration of piracetam did not change the effects of ethanol, while when given prolongly with ethanol piracetam attenuated the effects of ethanol. Piracetam did not affect the ethanol blood level.     

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.     

Genetic influences on the central nervous system depressant and membrane-disordering actions of ethanol and sodium valproate

The effects of the two central nervous system (CNS) depressant drugs ethanol and sodium valproate were compared using two pairs of mouse lines that had been selected from a heterogeneous stock for differential sensitivity to ethanol. The LS/SS lines differ in sensitivity to ethanol-induced sedation, and the WSP/WSR lines differ in the severity of their withdrawal convulsions after chronic ethanol treatment. We used these lines to test the hypothesis that ethanol and valproate act by the same mechanism. CNS depressant action was assessed by determining the brain drug concentration at which the mice lost their ability to balance on a stationary wooden dowel. LS mice were about twice as sensitive as SS mice to valproate-induced ataxia, in agreement with their reported relative sensitivity to ethanol. The WSR and WSP mice did not differ significantly in sensitivity to ethanol or valproate in this test. The intrinsic order and sensitivity to disordering of synaptosomal plasma membranes prepared from the four lines were measured using fluorescence polarization with the probe 1,6-diphenyl-1,3,5-hexatriene and EPR spectroscopy with 5-doxylstearic acid. No differences in the intrinsic membrane order of the four lines were detected with either technique. The sensitivities of the membranes from the four lines to ethanol- or valproate-induced disordering were not significantly different when measured by fluorescence polarization, but EPR spectroscopy revealed line differences in disordering sensitivity that correlated with the relative sensitivity of the four lines to the CNS depressant action of these drugs. These studies show that genetic factors modulate sensitivity to ethanol and valproate in a similar manner both in vivo and in vitro, suggesting that these drugs act by the same membrane-disordering mechanism.     

The occurrence of tolerance to a central depressant effect of nicotine

1. Rats were injected with 0.8 mg nicotine/kg, 0.8 mg amphetamine/kg or with saline immediately before being tested for 30 min in activity boxes.2. During the first 3 trials the nicotine group were less active than the controls but from trial 5 onwards nicotine had a stimulant effect. The stimulant effect of the amphetamine did not alter with repeated injection.     

Stimulant and depressant properties of sedative-hypnotics in mice selectively bred for differential sensitivity to ethanol

A genetic analysis of sedative-hypnotic response in selectively bred Long-Sleep (LS) and Short-Sleep (SS) mice showed LS mice to be more depressed by acetaldehyde, ethanol (ETOH), and t-butanol, but less sensitive to pentobarbital. Intermediate inheritance was shown by the two reciprocal F₁ hybrids for the alcohols, but dominance to the LS genotype occurred for the aldehyde and the barbiturate. At severa subhypnotic doses of ETOH in two experiments, LS mice showed less locomotor stimulation and greater disruption of coordination than the SS mice. The two reciprocal F₁ hybrids did not differ form one another and had dose-response curves intermediated to the two parental lines. Study of the effects of t-butanol on locomotor activity revealed a pattern of line differences similar to that for ETOH. The genetic selection for LS and SS mice appears to have differentiated loci that pleiotropically influence a variety of behavioral responses to alcohols.     

Influences of changes in calcium concentration and verapamil on the cardiac depressant effect of ethanol in cat papillary muscle.

1. In isolated cat heart papillary muscle electrically driven at a constant rate the depressant effects of increasing concentrations of ethanol on peak tension developed (PTD) was studied in Ringer-Locke solution with different calcium concentrations and with the addition of verapamil. 2. Ethanol induced a concentration dependent decrease in PTD that was significantly greater for each concentration of ethanol in hypocalcic medium (1.1 mM) than in normocalcic medium (2.2 mM). 3. In normocalcic (2.2 mM) medium, verapamil (5.1 x 10(-4) mM) plus ethanol (48.6 and 97.2 mM) produced a decrease in PTD to values significantly greater than those obtained by the addition of ethanol and verapamil alone. Therefore a potentiation of the effects of ethanol by verapamil was observed when both drugs act simultaneously. 4. In hypercalcic medium (4.4 mM), verapamil plus ethanol (48.6 and 97.2 mM) produced a slight decrease in PTD that was significantly less than that observed in normocalcic and hypocalcic mediums. 5. In hypocalcic medium (1.1 mM) verapamil plus ethanol (48.6 and 97.2 mM) produced a decrease in PTD that was of the same relative magnitude (%) as that observed in normocalcic medium. However no potentiation of the combined effects of verapamil plus ethanol was observed in hypocalcic medium.     

Time course of the locomotor stimulant and depressant effects of a single low dose of ethanol in mice

The acute effects of alcohol on spontaneous locomotor activity in male Swiss mice were studied at various times after an IP injection of 2 g/kg ethanol. Subjects were placed alone in a novel arena and videotape recordings were made of behaviour: trials were of 500-s duration and commenced at either 30, 60, 120, or 180 min after alcohol administration. Measures of behaviour included various indices of ambulation and immobility, together with a more detailed ethological analysis of the frequencies of all other acts and postures shown by test animals. Ambulation showed a biphasic response to alcohol treatment, consisting of an initial stimulation followed by a suppression after 3 h. Immobility was also increased by alcohol, and showed peak stimulation in trials commencing 30 min after administration: thereafter there was a progressive return to baseline levels. Many behavioural elements were suppressed including rearing, digging, shaking, and abbreviated grooming. Ethanol thus appeared to produce two distinct types of depression, in terms of increased immobility (and suppression of other behaviour) and in terms of decreased ambulation, the latter occurring when immobility had returned to baseline levels.     

Prostaglandin synthetase inhibitors antagonize the depressant effects of ethanol

Several studies indicate that ethanol may depress the central nervous system by altering neurotransmitter release. Evidence obtained from the peripheral nervous system suggests that prostaglandins act as negative feedback inhibitors of transmitter release. If a similar process occurs in the brain, then perhaps ethanol affects transmitter release via a mechanism involving prostaglandins. Prostaglandin synthetase inhibitors were administered to adult HS/Ibg male mice prior to intraperitoneal injection of a hypnotic dose of either ethanol, propanol, or t-butanol. A significant decrease in the length of alcohol sleep time was found: in the ethanol study, this was coupled with a significant increase in waking blood alcohol levels. These rresults indicate that inhibition of prostaglandin synthesis alters CNS sensitivity to the depressant effects of alcohol. When the same inhibitors were administered prior to other sedative hypnotics, i.e., pentobarbital and chloral hydrate, no effect was found. This suggests that prostaglandins may be specifically involved in the biochemical mechanism of alcohol depression.     

Syntheses and central depressant activity in mice of uracil derivatives. Studies on development of new sedative-hypnotics. II]

Fifteen kinds of uracil derivatives, which were substituted with functional groups such as benzyl (Bn), methoxymethyl (MOM), n-propyl (Pr) or allyl (A) group at the N1 and/or N3 position of uracil, were synthesized. Sedative-hypnotic activity, pentobarbital (PB)-induced sleep prolongation and acute toxicity as indices of their pharmacological activities were evaluated using mice. Spontaneous activities of mice treated with N1-benzyluracil (N1-BnU, 7), N3-benzyluracil (N3-BnU, 8), N1,N3-dibenzyluracil (DBnU, 9), N1-benzyl-N3-allyluracil (BnAU, 14) and N1-allyl-N3-benzyluracil (ABnU, 15) were measured. Ten kinds of uracil derivatives showed hypnotic activity. ED50's values of ABnU (15) and N1-propyl-N3-benzyluracil (PrBnU, 13) were 155 and 172 mg/kg, i.p., respectively. Those effects were more potent than that of barbital (179 mg/kg, i.p.) Ten kinds of uracil derivatives tested significantly prolonged the PB-induced sleeping time. N3-BnU (8) increased the spontaneous activity of mice at a dose of 80 mg/kg, i.p., while ABnU (15) depressed the spontaneous activity at a dose of 160 mg/kg, i.p. The other compounds did not show any significant effect on the spontaneous activity of mice. LD50's values of ABnU (15), PrBnU (13) and N1-methoxy-methyl-N3-benzyluracil (MOMBnU, 11) were 199, 229 and 363 mg/kg, i.p., respectively. LD50's values of the other derivatives were more than 480 mg/kg, i.p. These results indicate that the benzyl group at the N3 position of uracil is important for exhibiting sedative-hypnotic activity of uracil derivatives, and that ABnU (15) has the most potent central depressant activity among the uracil derivatives tested.     

Enhancement of the ambulation-increasing effect of opioid analgesics by ethanol in mice.

The interaction between opioid analgesics (morphine and buprenorphine) and central depressants (ethanol, pentobarbital and diazepam) was investigated by means of ambulatory activity in mice. The ambulation-increasing effect of both morphine (10 mg/kg, s.c.) and buprenorphine (1 mg/kg, s.c.) was enhanced by the combined administration of ethanol (0.8-3.2 g/kg, p.o.) in a dose-dependent manner. Naloxone (0.1 mg/kg, s.c.) was effective for reducing the enhanced ambulatory activity. The pretreatment with Ca-cyanamide (5 mg/kg, p.o., 30 min before) reduced the enhancement of the ambulation-increasing effect induced by the combined administration of opioid analgesics with ethanol, although it scarcely modified that of morphine and buprenorphine alone. On the other hand, neither pentobarbital (1-30 mg/kg, s.c.) nor diazepam (0.25-2 mg/kg, s.c.) modified markedly the ambulation-increasing effect of morphine and buprenorphine. The present results suggest that ethanol specifically interacted with opioid analgesics when the mouse's ambulatory activity was used as the indicator.     

白花败酱草乙醇提取物对小鼠抗氧化作用的影响

目的：研究白花败酱草乙醇提取物对小鼠抗氧化作用的影响。方法取昆明种小鼠32只,随机分为生理盐水组,5.0、10.0、20.0 mg/kg白花败酱草乙醇提取物组。连续给药10 d,次日小鼠拉颈椎脱臼处死,取心、脑、肝等组织,检测心、脑、肝等组织中的超氧化物歧化酶(SOD)的活性、丙二醛(MDA)的含量。结果10.0、20.0 mg/kg白花败酱草乙醇提取物能显著升高小鼠心、脑、肝等组织中SOD活性(P<0.05或P<0.01),显著降低心、脑、肝等组织中MDA含量(P<0.05或P<0.01)。结论白花败酱草乙醇提取物可清除体内脂质过氧化物,减轻机体的过氧化损伤,具有明显的抗氧化作用。     

The effect of posture at the time of administration on the central depressant effects of the new hypnotic zopiclone.

Nine healthy volunteers swallowed 7.5 mg zopiclone in the standing and lying positions on different occasions. Plasma concentrations of zopiclone and psychometric tests, including simple and complex reaction time, and critical flicker fusion threshold, were performed at regular intervals after drug administration. The results show that when the drug was swallowed in the supine position, there was a significant delay in the onset of the impairment of psychomotor function, with prolongation in time to peak impairment by 30-40 min (P less than 0.02). The overall impairment in psychomotor performance was found to be significantly less after administration of the drug in the supine position (P less than 0.005). Pharmacokinetic analysis revealed a prolongation in lag time of greater than 20 min before absorption began (P less than 0.002) after supine drug administration, with a significantly lower rate constant of absorption (P less than 0.02). Area under the plasma concentration-time curve extrapolated to infinity and rate constant of elimination were not significantly different between the two modes of administration. We conclude that to obtain a rapid and complete effect from the hypnotic zopiclone, the tablet should be swallowed in the standing position.