槟榔碱对小鼠酒精急性中枢抑制作用的影响

目的:探讨非选择性毒蕈碱受体(M受体)激动剂—槟榔碱,对小鼠酒精急性中枢抑制作用的影响。方法:测定小鼠的自主活动,观察槟榔碱对酒精诱导的小鼠低活动性的影响。建立酒精诱导小鼠翻正反射消失(loss of therighting reflex,LORR)的模型,观察槟榔碱对LORR潜伏期和持续时间的影响。结果:酒精(1.0、2.0、3.0 g.kg-1)和槟榔碱(0.25、0.51、.0 mg.kg-1)均可剂量依赖性地抑制小鼠的自主活动,但槟榔碱对酒精诱导的小鼠低活动性无影响。槟榔碱(0.25、0.5、1.0 mg.kg-1)对酒精诱导小鼠LORR的潜伏期无影响,但可显著缩短LORR的持续时间。结论:槟榔碱可以拮抗酒精诱导小鼠LORR的药理作用,提示槟榔碱可能具有一定的醒酒作用。     

Corticotropin-releasing factor overexpression decreases ethanol drinking and increases sensitivity to the sedative effects of ethanol

Rationale Corticotropin-releasing factor (CRF) may play a significant role in drug and alcohol abuse.Objective To evaluate the role of CRF in these processes, we examined several ethanol (EtOH) related behaviors in mice that carry a transgene that causes overexpression of CRF.Methods We examined voluntary EtOH drinking, loss of the righting reflex (LORR), EtOH-induced conditioned taste aversion (CTA), and EtOH clearance in littermate transgenic (TG) and non-transgenic (non-TG) mice. In addition, because preliminary results indicated that age exacerbated differences in EtOH consumption between the two genotypes, we performed a cross-sectional and longitudinal evaluation of this trait at two ages (100 and 200 days old).Results We found that TG mice consumed significantly less EtOH and had a lower preference for EtOH-containing solutions compared with their non-TG littermates. We also found that the older drug-naive TG mice drank less EtOH as compared with the younger mice of the same genotype; however, the same relationship did not exist for drug-naive non-TG mice. Prior experience in drinking EtOH when 100 days old led to decreased EtOH drinking when 200 days old in both genotypes. Duration of LORR was longer in the TG mice, EtOH-induced CTA was marginally greater in non-TG mice at the highest dose tested, and there were significant but small differences in EtOH clearance parameters.Conclusions These data show that CRF overexpressing mice voluntarily consume less EtOH. This difference is associated with greater sensitivity to the sedative-hypnotic effects of EtOH, but not with increased sensitivity to the aversive effects of EtOH.     

Brain temperature and ethanol sensitivity in C57 mice: a radiotelemetric study

This study investigated the relationship between ethanol sensitivity and brain temperature using radiotelemetric techniques. Radiotelemetric brain probes were implanted in the lateral cerebral ventricle of C57BL/6 mice. Rectal and brain temperatures, duration of loss of righting reflex (LORR), and blood and brain ethanol concentrations at the return of righting reflex (RORR) were measured following intraperitoneal (IP) injection with 3.6 g/kg ethanol and exposure to 12, 15, 22 or 34 degrees C. Rectal and brain temperatures were significantly correlated in untreated and intoxicated mice. Brain temperatures were lower than rectal temperatures in untreated mice, but were not different than rectal temperatures in intoxicated mice. Ethanol sensitivity, measured by the duration of LORR and ethanol concentrations at RORR, was significantly correlated with brain as well as rectal temperatures at RORR. Brain probe implantations did not significantly affect ethanol sensitivity. The direct positive relationship between brain temperature and ethanol sensitivity in C57 mice fits predictions based on membrane actions of ethanol and supports the hypothesis that temperature-induced changes in behavioral sensitivity to ethanol are mediated through changes in brain membrane temperature.     

Voluntary wheel running reduced the effects of acute ethanol on activity and avoidance in C57BL/6J mice.

C57BL/6J mice were given five weeks of voluntary wheel running and then studied for behavioral impairment after an intoxicating dose of ethanol. Forty-four mice, 22 males and 22 females, were assigned to Wheel (free access to a running wheel in the home cage) or No Wheel conditions. At the end of the training period, animals were removed from the exercise cages and tested for noise avoidance after 2.4 g/kg ethanol (EtOH) or physiological saline (Sal). Mice could avoid 87.5-dB noise by entering and remaining in a randomly designated "safe corner." In unexercised animals, EtOH caused a strong suppression of locomotor activity and avoidance behavior: No Wheel EtOH mice differed significantly from No Wheel Sal mice on both measures. In exercised animals, EtOH failed to cause significant suppression: Wheel EtOH animals did not differ significantly from Wheel Sal animals on either measure. The present results suggest that prior exercise training may be effective in offsetting the effects of acute ethanol intoxication.     

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.     

Isolate housing alters ethanol sensitivity in long-sleep and short-sleep mice

Beginning at 45 days of age, male long-sleep (LS) and short-sleep (SS) mice were placed into individual cages for 21-22 days. Control animals were group-housed for the same amount of time. At 65-66 days of age, animals were given anesthetic doses of ethanol, IP. Measures taken were sleep time, body temperature at 30 and 60 minutes postinjection and blood ethanol content (BEC) at regain of righting response. Compared to the same measures in group-housed animals, sleep times and hypothermia were attenuated in isolate-housed LS and SS mice. Isolate housing resulted in a 15% increase, compared to levels observed in group-housed animals, in BEC at regain of righting in LS; there was no significant difference in BEC in SS mice. The results indicated an isolation-related decrease in sensitivity to the anesthetic effects of ethanol in LS; the effect of isolation in SS may be an increased clearance rate of ethanol.     

Periadolescent exposure to ethanol and diazepam alters the aversive properties of ethanol in adult mice

Evidence suggests that the developing adolescent brain may be especially vulnerable to long-term neurobehavioral consequences following ethanol exposure and withdrawal. In the present study, we examined the long-term effect of adolescent ethanol withdrawal on a subsequent EtOH-induced conditioned taste aversion (CTA). Periadolescent and adult C3H mice were exposed to 64 h of continuous (single withdrawal) or intermittent (multiple withdrawal) ethanol vapor. Following each ethanol exposure, animals received either 0, 1, 2, or 3 mg/kg diazepam (DZP) in an attempt to counteract the possible effect of ethanol withdrawal. About 6 weeks following ethanol and DZP treatment, animals were tested for an EtOH-induced CTA. As expected, exposure to EtOH during adolescence attenuated the EtOH-induced CTA as compared to controls. Unexpectedly, administration of DZP during withdrawal did not spare but rather mimicked the attenuation of the EtOH-induced CTA seen in animals exposed to ethanol in adolescence. This attenuation was not evident when EtOH and/or DZP was administered in adulthood. Given the similar mode of action of EtOH and DZP on the GABA system, the principal implication of the present findings is that the intoxicating effect of ethanol on the developing brain can result in long-term changes in the aversive properties of EtOH.     

Augmentative effect of spinosin on pentobarbital-induced loss of righting reflex in mice associated with presynaptic 5-HT1A receptor

Objectives This study investigated whether spinosin potentiates pentobarbital‐induced loss of righting reflex (LORR) in mice via 5‐HT_1A receptors. Methods Our primary endpoint for sedation was LORR. In addition, the basal rectal temperature was measured. Key findings The results demonstrated that the 5‐HT_1A agonist 8‐OH‐DPAT (s.c.) induced reductions in duration of LORR at 0.1, 0.5 and 1.0 mg/kg (P < 0.01), and prolongation of LORR latency at 0.5 and 1.0 mg/kg (s.c., P < 0.01) in pentobarbital (45 mg/kg, i.p.)‐treated mice. This effect of 8‐OH‐DPAT was antagonized either by 5‐HT_1A antagonist p‐MPPI (5 mg/kg, i.p.) or by spinosin (15 mg/kg, i.g.) with significance, respectively. Co‐administration of spinosin and p‐MPPI both at ineffective doses (spinosin at 5.0 mg/kg, i.g. and p‐MPPI at 1.0 mg/kg, i.p.) showed significant augmentative effects in reducing latency to LORR, and increasing LORR duration (P < 0.01) in pentobarbital‐treated mice. On the other hand, spinosin inhibited 8‐OH‐DPAT‐induced hypothermia, which has been generally attributed to the activation of somatodendritic 5‐HT_1A autoreceptors in mice. Conclusions Based on our previous results and the present data, it should be presumed that presynaptic 5‐HT_1A autoreceptor mechanisms may be involved in the inhibitory effect of spinosin on 8‐OH‐DPAT‐induced hypothermia and also in the potentiating effect of spinosin on pentobarbital‐induced LORR in mice.     

Cysteine sulfinic acid can enhance the central depressant effect of ethanol in mice.

The interaction between ethanol and cysteine sulfinic acid was examined in male Swiss-Webster mice. The loss of the righting reflex (LORR) was used as a measurement of central nervous system depression. In addition, the interaction between ethanol and cysteic acid, a metabolite of cysteine sulfinic acid, was studied. Immediately after the animals regained the righting reflex following ethanol injection (IP), mice were given an ICV injection of saline, cysteine sulfinic acid (1, 15 or 25 mumol/kg) or cysteic acid (1, 15, or 25 mumol/kg). There occurred a return to the LORR within 30 s after the ICV injection of drugs. The return to the LORR by the administration of the amino acids in the presence of ethanol occurred in a dose-dependent fashion. When cysteine sulfinic acid or cysteic acid (25 mumol/kg, ICV) was injected in the absence of ethanol, no loss of the righting reflex occurred. In other experiments, bicuculline methiodide was given ICV with cysteine sulfinic acid (25 mumol/kg), cysteic acid (25 mumol/kg), or GABA (25 mumol/kg) in the presence of ethanol. Bicuculline methiodide, a GABA antagonist, reduced the effects of the three amino acids to produce a return to the LORR in the presence of ethanol. These results indicate that cysteine sulfinic acid, an excitatory amino acid, and cysteic acid can enhance the central depressant properties of ethanol. Since bicuculline antagonized the effects of these two amino acids, a GABAergic mechanism may be involved in the interaction between ethanol and cysteine sulfinic acid or cysteic acid.     

Interactions between ethanol and cocaine,amphetamine, or MDMA in the rat: thermoregulatory and locomotor effects

Rationale (±)-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is often taken recreationally with ethanol (EtOH). In rats, EtOH may potentiate MDMA-induced hyperactivity, but attenuate hyperthermia. Objective Experiment 1 compared the interactions between EtOH (1.5 g/kg) and MDMA (6.6 mg/kg) with EtOH + cocaine (COCA; 10 mg/kg) and EtOH + amphetamine (AMPH; 1 mg/kg) on locomotor activity and thermoregulation. Experiment 2 used a weaker dose of MDMA (3.3 mg/kg) and larger doses of COCA (20 mg/kg) and AMPH (2 mg/kg). Materials and methods Drug treatments were administered on four occasions (2, 5, and 2 days apart, respectively; experiment 1) or two (2 days apart; experiment 2). Results All psychostimulants increased activity, and EtOH markedly increased the effect of MDMA. AMPH alone-related hyperactivity showed modest sensitization across treatment days, while MDMA + EtOH activity showed marked sensitization. AMPH, COCA, and MDMA induced hyperthermia of comparable amplitude (+1 to +1.5°C). Co-treatment with EtOH and AMPH (1 mg/kg) or COCA (10 mg/kg) produced hypothermia greater than that produced by EtOH alone. Conversely, EtOH attenuated MDMA-related hyperthermia, an effect increasing across treatment days. These results demonstrate that the interaction between MDMA and EtOH may be different from the interaction between EtOH and AMPH or COCA. Conclusion Because of potential health-related consequences of such polydrug misuse, it is worth identifying the mechanisms underlying these interactions, especially between EtOH and MDMA. Given the different affinity profiles of the three drugs for serotonin, dopamine, and norepinephrine transporters, our results appear compatible with the possibility of an important role of serotonin in at least the EtOH-induced potentiation of MDMA-induced hyperlocomotion.     

Behavioral and neurochemical interactions between Group 1 mGluR antagonists and ethanol: potential insight into their anti-addictive properties

Blockade of the mGluR5 subtype of Group 1 metabotropic glutamate receptor (mGluRs) reduces the rewarding effects of ethanol (EtOH), while the effects of mGluR1a blockade remain under-investigated. The present study compared the effects of pretreatment with the mGluR5 antagonist MPEP and the mGluR1a antagonist CPCCPOEt upon behavioral and neurochemical variables associated with EtOH reward in alcohol-preferring C57BL/6J mice. Pretreatment with either antagonist (0-10 mg/kg, IP) dose-dependently reduced measures of EtOH reward in an operant self-administration paradigm and the maximally effective antagonist dose (10 mg/kg) also blocked the expression of EtOH-induced place conditioning, as well as EtOH consumption under 24-h free-access conditions. MPEP pretreatment did not significantly alter the EtOH dose-locomotor response function; however, it prevented EtOH-induced changes in extracellular dopamine, glutamate and GABA in the nucleus accumbens (NAC). In contrast, CPCCOEt shifted the EtOH dose-response function downwards, enhanced the capacity of higher EtOH doses to elevate NAC levels of GABA and lowered extracellular dopamine and glutamate below baseline following EtOH injection. It is suggested that the "anti-alcohol" effects of MPEP may involve an attenuation of the neurochemical signals mediating EtOH reward, whereas those of CPCCOEt may involve an increased sensitivity to the inhibitory effects of EtOH upon brain and behavior.     

Essential amino acid supplementation decreases liver damage induced by chronic ethanol consumption in rats

The liver sustains the greatest damage from ethanol (EtOH) abuse. EtOH and its metabolites impair hepatocyte metabolism, causing intracellular accumulation of proteins and lipids and increasing radical oxygen species production. These processes are toxic to the mitochondrial respiratory chain and to mitochondrial DNA. We have recently shown that supplementating the diet of rodents with an essential amino acid-enriched mixture (EAAem) significantly increases mitochondrial mass and number in cardiac and skeletal muscles and improves mitochondrial function in aged animals. Thus, in this study we sought to test whether EAAem supplementation could reduce EtOH-induced liver damage. Groups of adult male Wistar rats were fed a standard diet and water ad libitum (the control group), drinking water with 20 percent EtOH (the EtOH group), or drinking water with 20 percent EtOH and EAAem supplementation (1.5 g/kg/day) (the EtOH+EAAem group) for 2 months. The blood EtOH concentration was measured, and markers for fat (Oil-Red-O), mitochondria (Grp75, Cyt-c-ox), endoplasmic reticulum (Grp78), and inflammation (Heme Oxigenase 1, iNOS, and peroxisomes) were analyzed in the liver of animals in the various experimental groups. EAAem supplementation in EtOH-drinking rats ameliorated EtOH-induced changes in liver structure by limiting steatosis, recruiting more mitochondria and peroxisomes mainly to perivenous hepatocytes, stimulating or restoring antioxidant markers, limiting the expression of inflammatory processes, and reducing ER stress. Taken together, these results suggest that EAAem supplementation may represent a promising strategy to prevent and treat EtOH-induced liver damage.     

Confirmation of quantitative trait loci for ethanol sensitivity and neurotensin receptor density in crosses derived from the inbred High and Low Alcohol Sensitive selectively bred rat lines

Rationale Genetically influenced alcohol sensitivity is thought to be an important risk factor for the development of alcoholism. An effective first step for identifying genes that mediate variation in alcohol sensitivity is through quantitative trait loci (QTL) mapping in model organisms.Objective Fourteen provisional QTLs related to alcohol sensitivity were previously mapped in an F₂ derived from the IHAS1 and ILAS1 rat lines. The objective of the current study was to confirm those QTLs in an independently derived F₂ and in congenics that were bred for two of the loci.Materials and methods IHAS1 X ILAS1 F₂ (n=450) were tested for alcohol-induced loss of righting reflex (LORR), blood ethanol concentration at regain of righting reflex (BECRR), sensitivity and acute tolerance on the Rotarod, and neurotensin receptor density (NTR1). Rats were genotyped at the 14 candidate loci and QTL mapping was conducted. Reciprocal congenic strains were bred for loci on chromosomes 2 and 5 and tested for LORR and BECRR.Results Four LORR QTLs were mapped at the suggestive or significant level (chromosomes 2, 5, 12, and 13). BECRR was mapped to chromosomes 5, 12, and 13 either in the original or current experiment. Results of the congenic experiment also support QTLs for LORR and BECRR on chromosomes 2 and 5. QTLs for NTR1 density and behavior on the Rotarod were not confirmed.Conclusions QTL mapping in crosses derived from the IHAS1 and ILAS1 has successfully identified loci related to alcohol sensitivity. Recombinant congenics are now being bred to more finely map the confirmed QTLs.     

Influence of brain catalase on ethanol-induced loss of righting reflex in mice.

The effect of lead acetate and 3-amino-1, 2, 4-triazole (AT) on ethanol-induced loss of righting reflex (LORR) and brain catalase activity was studied in an attempt to confirm earlier observations on the involvement of catalase in ethanol-induced effects. Lead acetate (0 or 100 mg/kg) or AT (0 or 500 mg/kg) was injected (acutely) into mice 7 days or 5 h before testing. Other mice were exposed to drinking fluid containing 500 ppm lead acetate for 60 days. On the test day, mice received an intraperitoneal injection of ethanol (4.0 or 4.5 g/kg) and the duration of LORR was recorded. Acute lead-treated animals demonstrated a reduction in the duration of the LORR. However, both chronic administration of lead acetate and AT treatment increased the duration of ethanol-produced LORR. Furthermore, brain catalase activity in acute lead pretreated animals showed a significant induction, whereas it was reduced in chronic lead and AT treated mice. These results suggest that brain catalase activity, and by implication centrally formed acetaldehyde, may modulate ethanol-induced LORR.     

Potentiation of the immunotoxicity of ethanol by acetaminophen in mice.

To investigate the influences of acetaminophen (APP) on the immunotoxicity of ethanol (EtOH) in ICR mice, APP at a dose of 100 mg/kg was orally administered to mice daily for 28 consecutive days. Mice treated with EtOH were given freely with 20% w/v EtOH during the experimental period, and normal mice were given vehicle. The results of this study are summarized as follows: the combination of APP and EtOH significantly decreased the circulating leukocytes and the relative weights of liver, spleen and thymus, compared with the treatment of EtOH alone. In mice receiving the combination of AAP and EtOH when compared with the treatment of EtOH alone, there were also significant reductions in the splenic plaque forming cells (PFC) and hemagglutination (HA) titers to sheep red blood cells (SRBC), and the secondary IgG antibody response to bovine serum albumin (BSA). A tendency toward suppression of delayed-type hypersensitivity (DTH) reaction and phagocytic activity was also observed in the combination of AAP and EtOH. In addition, the combination of AAP and EtOH greatly increased serum alanine aminotransaminase (ALT) and total protein levels, compared with the treatment of EtOH alone. Significant decreases in serum albumin and A/G ratio were observed in EtOH alone-fed mice compared with those in normal animals, and their reductions were further induced in mice treated with AAP and EtOH. These findings indicate that EtOH-induced immunotoxicity is aggravated by the combination of APP and EtOH.     

Effects of intracerebroventricular NMDA and non-NMDA receptor agonists or antagonists on general anesthesia of propofol in mice

The effects of intracerebroventricular (icv) agonists and antagonists of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors on the general anesthesia of propofol were studied. A total of 144 Kunming mice, male and female with body mass of (22±3) g, were used. Part One of the Experiment: a total of 104 Kunming mice, male and female, were randomly divided into 13 groups. Intracerebroventricular artificial cerebral fluid (aCSF) or different doses of NMDA, AMPA, MK-801 or NBQX was injected immediately after intravenously administered propofol 25 mg/kg and the recovery time following the loss of righting reflex (LORR) was recorded. Part Two of the Experiment: a total of 40 Kunming female mice were divided randomly into 5 groups and injected with icv aCSF or NMDA, AMPA, MK-801 or NBQX after intraperitoneally administered propofol 50 mg/kg. The pain threshold of the mice was then investigated by hot-plate test (HPPT). NMDA (0.05 or 0.075μg, icv) or AMPA (0.05 μg, icv) exhibited no effects on the LORR, but NMDA (0.1 μg, icv) or AMPA (0.075 or 0.1 μg, icv) prolonged the LORR significantly compared with the aCSF group (P<0.05, P<0.01). The LORR of the 2 μg MK-801 group had no changes, while those of the 4 or 8 μg MK-801 groups were prolonged significantly. The LORR of the 0.5, 2 or 4 μg NBQX groups were all prolonged significantly. NMDA 0.05 μg or AMPA 0.05 μg decreased the pain threshold slightly but did not differ in effect compared with the aCSF group; 2 μg MK-801 or 0.5 μg NBQX both increased the pain threshold significantly. Our results indicate that propofol produces general anesthesia partly through an interaction with brain NMDA and AMPA receptors in mice.     

Endogenous gamma-aminobutyric acid (GABA)(A) receptor active neurosteroids and the sedative/hypnotic action of gamma-hydroxybutyric acid (GHB): a study in GHB-S (sensitive) and GHB-R (resistant) rat lines

In the rat brain, gamma-hydroxybutyric-acid (GHB) increases the concentrations of 3alpha-hydroxy,5alpha-pregnan-20-one (allopregnanolone, 3alpha,5alpha-THP) and 3alpha,21-dihydroxy,5alpha-pregnan-20-one (allotetrahydrodeoxycorticosterone/3alpha,5alphaTHDOC), two neurosteroids acting as positive allosteric modulators of gamma-aminobutyric acid (GABA)(A) receptors. This study was aimed at assessing whether neurosteroids play a role in GHB-induced loss of righting reflex (LORR). Basal and GHB-stimulated brain concentrations of endogenous 3alpha,5alpha-THP and 3alpha,5alpha-THDOC were analyzed in two rat lines, GHB-sensitive (GHB-S) and GHB-resistant (GHB-R), selectively bred for opposite sensitivity to GHB-induced sedation/hypnosis. Basal neurosteroid concentrations were similar in brain cortex of the two rat lines. However, in male GHB-S rats, administration of GHB (1000 mg/kg, i.p., 30 min) increased brain cortical concentrations of 3alpha,5alpha-THP and 3alpha,5alpha-THDOC 7- and 2.5-fold, respectively, whilst male GHB-R animals displayed only a 4- and 2-fold increase, respectively. In GHB-S rats this increase lasted up to 90 min and declined 180 min following GHB administration, a time course that matches LORR onset and duration. In contrast, in GHB-R rats, which failed to show GHB-induced LORR, brain cortical 3alpha,5alpha-THP and 3alpha,5alpha-THDOC had returned to control values within 90 min. At onset of LORR, a similar increase in brain cortical levels of 3alpha,5alpha-THP and 3alpha,5alpha-THDOC (2-3-fold) was observed in GHB-S female rats and in the few female GHB-R rats that lost the righting reflex after GHB administration, but not in female GHB-R rats failing to show LORR. Sub-hypnotic doses (7.5 and 12.5 mg/kg, i.p.) of pregnanolone, administered 10 min before GHB, dose-dependently facilitated the expression of GHB-induced LORR in GHB-R male rats. These results suggest that the GHB-induced increases of brain 3alpha,5alpha-THP and 3alpha,5alpha-THDOC concentrations are implicated in the eliciting of the sedative/hypnotic action of GHB.     

Increased responsiveness to ethanol with advancing age in rats

Male CD strain rats of three different ages (young—5 months; middle—15; old—27 months) were tested for their responsiveness to doses of ethanol sufficient to produce hypothermia or hypnosis. Comparison dosages of ethanol across age groups were based upon the estimated equivalent dilution of the drug into the body water compartments of subjects. In the hypnosis study, there were no statistically significant differences among the groups with regard to the time elapsed until the righting reflex was lost or in total sleep time. However, old animals recovered the righting reflex in the presence of lower blood ethanol concentrations than those observed for young and middle animals, suggesting a greater sensitivity of target tissues to the hypnotic effects of ethanol in old rats. The responsiveness of old rats to the hypothermic effect of ethanol was greater than that of younger rats only when the experiment was conducted at an ambient room temperature of 10°C.     

Folic acid reduces the ethanol-induced morphological and behavioral defects in embryonic and larval zebrafish (Danio rerio) as a model for fetal alcohol spectrum disorder (FASD)

The objective of this work was to determine whether folic acid (FA) reduces the embryonic ethanol (EtOH) exposure induced behavioral and morphological defects in our zebrafish fetal alcohol spectrum disorder (FASD) model. Teratogenic effects, mortality, the excitatory light-dark locomotion (ELD), sleep (SL), thigmotaxis (TH), touch sensitivity (TS), and optomotor response (OMR) tests were evaluated in larvae (6–7 days post-fertilization) using four treatment conditions: Untreated, FA, EtOH and EtOH + FA. FA reduced morphological defects on heart, eyes and swim bladder inflation seen in EtOH exposed fish. The larvae were more active in the dark than in light conditions, and EtOH reduced the swimming activity in the ELD test. EtOH affected the sleep pattern, inducing several arousal periods and increasing inactivity in zebrafish. FA reduces these toxic effects and produced more consistent inactivity during the night, reducing the arousal periods. FA also prevented the EtOH-induced defects in thigmotaxis and optomotor response of the larvae. We conclude that in this FASD model, EtOH exposure produced several teratogenic and behavioral defects, FA reduced, but did not totally prevent, these defects. Understanding of EtOH-induced behavioral defects could help to identify new therapeutic or prevention strategies for FASD.     

Potentiation of ethanol-induced loss of the righting reflex by ascorbic acid in mice: interaction with dopamine antagonists

The present investigation was carried out to determine the effect of ascorbic acid on ethanol-induced loss of the righting reflex (LORR) and the interactions between ascorbic acid and dopamine receptor antagonists in affecting this action of ethanol in mice. To test the effect of each drug on ethanol-induced LORR, ascorbic acid (31.25, 62.5, 125, 250, 500, 1000 mg/kg intraperitoneally [IP]) and dopamine receptor antagonists (haloperidol 0.5, 1.0 mg/kg; L-sulpiride 20, 40, 80 mg/kg; clozapine 0.625, 1.25, 2.5 mg/kg; SCH 23390 0.5, 1.0, 2.0 mg/kg subcutaneously [SC]) were administered, respectively, 30 min before ethanol (4.0 g/kg IP) administration. Ascorbic acid, at the dose of 1000 mg/kg, significantly potentiated ethanol-induced LORR in mice. Dopamine D(2) antagonists haloperidol (0.5, 1.0 mg/kg SC), and L-sulpiride (80 mg/kg SC) also significantly prolonged the duration of LORR induced by ethanol. Clozapine and SCH 23390, at the doses used, did not affect ethanol-induced LORR. In the interaction study, the synergistic effect of ascorbic acid (1000 mg/kg IP) on ethanol-induced LORR was significantly enhanced by dopamine D(2) antagonists haloperidol, L-sulpiride, and clozapine, and the highest dose of dopamine D(1) antagonist SCH 23390. These results suggest that ascorbic acid may potentiate ethanol-induced LORR partially via a mechanism mainly linked to blockade of dopamine D(2) receptors.