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PubMed2001

Effects of morphine on pentobarbital-induced responses in mu-opioid receptor knockout mice.

Effects of morphine on the potentiation of pentobarbital-induced responses were investigated using mu-opioid receptor knockout mice. The duration of loss of righting reflex, hypothermia, and loss of motor coordination induced by pentobarbital were measured after pretreatment with either morphine or saline. Morphine pretreatment failed to show potentiation of both pentobarbital-induced loss of righting reflex and hypothermia in mu-opioid receptor knockout mice, while it significantly potentiated these responses in the wild-type controls. For motor incoordination test, morphine potentiated pentobarbital-induced motor incoordination in the wild-type mice. However, morphine may have opposite effects in the mu-opioid receptor knockout mice. These results demonstrate that synergism between morphine and pentobarbital is not detected in mu-opioid receptor knockout mice and that potentiation of pentobarbital-induced loss of righting reflex and hypothermia by morphine is mediated through mu-opioid receptor. It was interesting to note that pentobarbital-induced decrease in body temperature was less severe in mu-opioid receptor knockout mice than in wild-type mice.

Animals↗

PubMed2001

Intravenous midazolam significantly enhances the lethal effect of thiopental but not that of ketamine in mice.

Intravenous (i.v.) drug combinations are used in clinical anaesthesia in order to combine the desired effects and minimize toxicity from large doses of single agents. This fundamental assumption has not been systematically evaluated. We examined its validity by testing the influence of midazolam on the lethal effect of i.v. thiopental and ketamine in mice. Dose-response curves were constructed for the lethal effect of i.v. thiopental and ketamine, and for the loss of righting reflex effect by midazolam, in sexually mature male ICR mice weighing 20-40 g. For each curve, six or seven groups of eight to 10 mice each were used. A quarter of the median effective dose (ED50) for loss of righting reflex by midazolam was combined with the two other drugs to deduce dose-response curves for the lethal effect of the combinations. The ED50 for loss of righting reflex by i.v. midazolam was 43.5 mg x kg(-1) (95% confidence interval [CI], 40.4-46.5). The median lethal dose (LD 50) of i.v. thiopental was 50.6 mg x kg(-1) (95% CI, 50.0-54.9) and that of ketamine 42.9 mg x kg(-1) (95% CI, 32.3-52). In the presence of 10 mg x kg(-1) midazolam, the LD50 of thiopental was reduced to 20 mg x kg(-1) (17.7-22.2), but that of ketamine remained 44.4 mg x kg(-1) (37.7-54.9). Midazolam increased the lethal effect of thiopental 2.5-fold, but did not affect that of ketamine. Interactions at the toxic level between commonly used anaesthetic agents may differ from those at the hypnotic or analgesic levels, which should prompt evaluation of such combinations before their introduction to routine clinical use.

Anesthetics, Dissociative↗

PubMed1991

Commonalities between gas anesthetics (nitrous oxide, nitrogen and/or argon) and ethanol intoxication in hot and cold selection line mice.

Argon, nitrogen, nitrous oxide were administered hyperbarically in doses (atmosphere) that caused loss of righting reflex (LORR). Nitrous oxide requires pressure somewhat less than two atmospheres, eighteen atmospheres were required for argon and thirty-six atmospheres roughly for nitrogen all in 0.5 atmospheres oxygen. Loss of righting reflex was assessed by using a rolling cage method of Wilson and Miller. Since nitrogen is the least liposoluble and nitrous oxide the most liposoluble of these three gases, greater pressures were needed for nitrogen to attain sufficient concentration in the membrane for anesthesia. Due to the low lipid solubility (1.4), nitrous oxide was administered hyperbarically at a compression rate of less than 0.5 atm/min at chamber temperature of 86 degrees plus or minus 2 degrees. Body temperatures were measured by minimitter transmitters. Two types of transmitters: an AM frequency and an FM frequency were used; a comparison of the two systems were made. The ED50 (atmospheres) required to produce a given score on the LORR were determined for each strain or line of mice. This ED50 value was determined for the Hot and Cold selection lines which have been specifically bred to differ as much as possible in a hypothermic response to acute doses of ethanol. These experiments demonstrate quite clearly a degree of commonality exists among CNS depressants with regard to anesthesia, loss of righting reflex and hypothermia.

Anesthetics↗

PubMed1999

The nitric oxide-cGMP system of the locus coeruleus and the hypnotic action of alpha-2 adrenergic agonists.

Dexmedetomidine (Dex), a potent, selective alpha-2 adrenergic agonist, injected bilaterally directly into the locus coeruleus (LC), 7 microgram/LC, or ip, 100 microgram/kg, produced a maximum decrease in LC cGMP (-38 and -46%, respectively). Atipamezole, a selective alpha-2 adrenergic antagonist, given into the LC, 10 microgram/LC, prevented the decrease in LC cGMP induced by Dex, given i.p. or into the LC. Dex produced a loss of righting reflex in about 80% of the animals, an effect which was prevented by pretreatment with atipamezole. The nitric oxide synthase antagonist L-Name injected bilaterally into the LC, 20 microgram/LC, produced by itself a maximum decrease in LC cGMP of 54.5%. Dex, 100 microgram/kg, ip, given after L-Name, did not further decrease LC cGMP. L-Name, by itself, did not produce a loss of righting reflex, while 6 out of 9 rats pretreated with L-Name lost their righting reflex in response to Dex. A role of the nitric oxide-cGMP system of the LC in the modulation of the hypnotic effect of alpha-2 adrenergic agonists remains uncertain.

Adrenergic alpha-2 Receptor Agonists↗

PubMed1988

Genetically determined differences in ethanol sensitivity influenced by body temperature during intoxication.

The present study investigated the importance of body temperature during intoxication in mediating differences between five inbred strains of mice (C57BL/6J; BALB/cJ; DBA/2J; A/HeJ; 129/J) in their acute sensitivity to the hypnotic effects of ethanol. Mice exposed to 22 degrees C after ethanol injection became hypothermic and exhibited statistically significant differences between strains in rectal temperatures at the return of the righting reflex (RORR), duration of loss of the righting reflex (LORR), and blood and brain ethanol concentrations at RORR. Exposure to 34 degrees C after injection offset ethanol-hypothermia and markedly reduced strain-related differences in rectal temperatures and blood and brain ethanol concentrations at RORR. Brain ethanol concentrations at RORR were significantly lower in C57, BALB, DBA and A/He mice exposed to 34 degrees C compared to mice exposed to 22 degrees C during intoxication suggesting that offsetting hypothermia increased ethanol sensitivity in these strains. Taken with previous in vitro studies, these results suggest that genetically determined differences in acute sensitivity to the behavioral effects of ethanol reflect differences in body temperature during intoxication as well as differences in sensitivity to the initial actions of ethanol at the cellular level.

Acclimatization↗

PubMed2000

Enantioselectivity of pregnanolone-induced gamma-aminobutyric acid(A) receptor modulation and anesthesia.

This study reports the actions of enantiomer pairs of anesthetic steroids 3alpha5alphaP/ent-3alpha5alphaP and 3alpha5betaP/ent-3alpha5betaP as modulators of gamma-aminobutyric acid (GABA)(A) receptors and as anesthetics. The enantiomers of structurally related 17-carbonitrile analogs also are examined. These studies were aimed at 1) determining whether the steroid recognition site could distinguish between molecules differing in shape, but not other physical properties (enantioselectivity); 2) providing further insight into the structure-activity relationships of anesthetic steroids; and 3) determining whether modulation of GABA(A) receptor function correlates with anesthetic potency for anesthetic steroid enantiomers. Stereoselective actions of the compounds were evaluated in four different bioassays: 1) noncompetitive displacement of [(35)S]t-butylbicyclophosphorothionate from the picrotoxin site of GABA(A) receptors present in rat brain membrane preparations; 2) modulation of GABA currents in cultured rat hippocampal neurons; 3) loss of righting reflex in tadpoles; and 4) loss of righting reflex in mice. The data indicate that 5alpha-reduced steroids, but not 5beta-reduced steroids, show a high degree of enantioselectivity/enantiospecificity in their actions as modulators of GABA(A) receptors and as anesthetics. For all compounds studied, the effects on GABA(A) receptor function closely tracked with anesthetic effects. These data show that the anesthetic steroid recognition site is capable of distinguishing enantiomers, suggesting a protein-binding site of specific dimensions and shape. The results are compatible either with a structural model of the binding site that can accommodate 3alpha5alphaP, 3alpha5betaP, and ent-3alpha5betaP, but not ent-3alpha5alphaP, or with two different binding sites for steroid anesthetics.

Anesthetics↗

PubMed1991

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.

Animals↗

PubMed1996

A dose-response analysis of the behavioral effects of (+)MK-801 in guinea pig: comparison with CPP.

The noncompetitive N-methyl-D-aspartate (NMDA) antagonist, dizocilpine maleate {(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5, 10-imine maleate} [(+)MK-801], has attracted considerable interest because of its potential use as an anticonvulsant and neuroprotectant. However, its cognitive side effects in humans have limited its use in human pharmacotherapy. Although the behavioral effects of (+)MK-801 have been documented in mouse, rat, pigeon, and rhesus monkey, there are no available data on its effects in guinea pig. The objective of this study was to conduct a dose-response analysis of the effects of (+)MK-801 on stereotyped behavior, ataxia, locomotor activity, and righting reflex latency in guinea pig. In the dose range used (0.0625-0.5 mg/kg, IP), we found no significant differences between (+)MK-801 and vehicle in terms of stereotyped behavior and locomotor activity; however, at higher doses, (+)MK-801 caused significant ataxia and impairment of the righting reflex. By comparison, the competitive NMDA receptor antagonist, 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP,5 mg/kg, IP), produced neither stereotyped behavior nor impairment of the righting reflex; at higher doses (10 mg/kg, IP), it produced only ataxia and an increase in locomotor activity.

Animals↗

PubMed1983

Congenital rubella syndrome: function of equilibrium of 80 cases with deafness.

The equilibrium function of 80 deaf children with congenital rubella syndrome, aged 12, was examined by the caloric and righting reflex tests. Of these 80 children, 24 (30%) had vestibular hypofunction, 6 (7.5%) were suspect, and the remaining 50 (62.5%) were normal. Of all 160 ears tested, vestibular hypofunction was proven in 21.3%, suspect in 5.6%, and normal in the rest. There was no correlation between the incidence of vestibular hypofunction and the degree of hearing loss. Of the 30 children with vestibular hypofunction, 14 (47%) showed a normal righting reflex, suggesting the working of a compensatory mechanism. Of the 50 children with normal caloric responses, 26% revealed an abnormal righting reflex. This discrepancy might be accounted for by an otolith organ injury or minimal brain dysfunction.

Caloric Tests↗

PubMed2003

alpha2-gamma-Aminobutyric acid (GABA)A receptors are the molecular substrates mediating precipitation of narcosis but not of sedation by the combined use of diazepam and alcohol in vivo.

Classical benzodiazepines such as diazepam are widely used tranquillisers and hypnotics in various neuropsychiatric diseases including alcohol-related disorders. One of the major drawbacks of benzodiazepine therapy, however, is an exacerbation of the sedative and hypnotic effects associated with alcohol intake, even at low doses. Even though the gamma-aminobutyric acid (GABA)A receptor complex is a common target for the actions of both classes of drugs, the molecular mechanisms underlying the enhanced pharmacological properties of the combined use of benzodiazepines and alcohol remain to be identified. The present experiments aimed at clarifying which of the GABAA receptor subtypes mediate the augmented hypnotic-like and sedative effects of combined diazepam and alcohol using the righting reflex and motor activity assays, respectively, in histidine-to-arginine point mutated mice that possess diazepam-insensitive alpha1-, alpha2-, alpha3- or alpha5-GABAA receptors. The combination of diazepam (2 or 3 mg/kg) and ethanol (3 g/kg) induced loss of righting reflex with a significantly dose-dependent increase of the latency to its full recovery in wild-type, alpha1(H101R), alpha3(H126R) and alpha5(H105R) but not in alpha2(H101R) mice. A combined treatment with diazepam (1 mg/kg) and ethanol (2.5 g/kg) precipitated motor inhibition similarly in wild-type and alpha2(H101R) mice. Responsiveness of the alpha2(H101R) mice to ethanol alone was similar to that of wild-type mice. These results demonstrate that induction of loss of righting reflex by combined diazepam and alcohol is closely dependent on the activation of the alpha2-GABAA receptors by the benzodiazepine whereas precipitation of sedation involves GABAA receptors other than the alpha2-GABAA receptors.

Anesthesia↗

PubMed1987

Behavioral interactions of ethanol and methylxanthines.

The effect of the methylxanthines caffeine, theophylline and isobutylmethylxanthine (IBMX) on ethanol-induced ataxia and loss of righting reflex was investigated in three strains of mice. A significant potentiation of ethanol-induced ataxia was produced in all strains of mice at 20, 45 and 75 min after ethanol in mice pretreated with 62.5 mg/kg caffeine and 12.5 mg/kg IBMX. In mice pretreated with 40 mg/kg caffeine potentiation of ethanol-induced ataxia was observed only at 20 min after ethanol. Theophylline pretreatment produced no alteration in ethanol-induced ataxia. The results of methylxanthine pretreatment on ethanol-induced ataxia were similar, regardless of a shorter (10 min) or longer (75 min) pretreatment time. The methylxanthines produced no effect on motor coordination or behavior when administered separately. Although ethanol-induced loss of righting reflex was shortened by theophylline, neither caffeine nor IBMX altered the duration of loss of righting reflex. It is possible that inhibition of adenosine uptake, a known effect of the methylxanthines, may be a more likely explanation for the modulation of the behavioral effects of ethanol.

1-Methyl-3-isobutylxanthine↗

PubMed2003

Caffeine reduces hypnotic effects of alcohol through adenosine A2A receptor blockade.

The role of the adenosine A(2A) receptor in the hypnotic effects of ethanol was assessed in mice. The duration of the loss of righting reflex following acute ethanol administration was shorter for A(2A) receptor-deficient mice (A(2A)R KO) than for wild-type mice (A(2A)R WT), whereas the fall in body temperature was not different between the two phenotypes. In contrast, the duration of the loss of righting reflex was increased in A(2A)R KO mice versus controls after administration of pentobarbital. Dipyridamole, an inhibitor of adenosine uptake, increased the sleep time observed following administration of ethanol in CD1 mice and in A(2A)R WT but not in A(2A)R KO mice. SCH 58261, a selective A(2A) receptor antagonist, unlike DPCPX, a selective A(1) receptor antagonist, shortened the duration of the loss of righting reflex induced by ethanol, thus mimicking the lack of receptor in deficient mice. Finally, the non-selective adenosine receptor antagonist caffeine (25 mg/kg) reduced ethanol-induced hypnotic effects. These results indicate that the activation of A(2A) receptors that follows an increase in extracellular adenosine levels caused by the administration of high doses of ethanol plays a role in its hypnotic effects. Thus, A(2A) receptor antagonists may be useful therapeutic agents for alleviating ethylic coma.

Adenosine A1 Receptor Antagonists↗

PubMed2000

Brain allopregnanolone regulates the potency of the GABA(A) receptor agonist muscimol.

Allopregnanolone (ALLO), a potent positive-allosteric modulator of the action of GABA at GABA(A) receptors, is synthesized in the brain from progesterone by the sequential action of two enzymes: 5alpha-reductase and 3alpha-hydroxysteroidoxidoreductase. The concentration of ALLO in various parts of the mouse brain varies substantially, from 15 pmol/g in the olfactory bulb, to approximately 6 pmol/g in the frontoparietal cortex, and 2.7 pmol/g in the cerebellum. The systemic administration of 48 micromol/kg of the Type I and Type II 5alpha-reductase inhibitor, (17beta)-17-[bis (1-methylethyl) amino carbonyl)] androsta-3, 5-diene-3-carboxylic acid (SKF 105,111), reduced brain ALLO content by 80-90% in 30 min; the rate constant (k) of ALLO decrease in each brain area can be utilized to establish the rate of ALLO biosynthesis, which is higher in the olfactory bulb (62 pmol/g/h) than in the frontoparietal cortex (24 pmol/g/h) or cerebellum (11 pmol/g/h). The duration of the righting reflex loss elicited by the potent GABA(A) receptor agonist muscimol was reduced in SKF 105,111-treated ALLO-depleted mice. SKF 105,111 treatment had no effect on muscimol metabolism or on brain levels of pregnenolone and progesterone; however, the brain levels of 5alpha-DHP, the precursor of ALLO, were also decreased. Administration of ALLO at a dose of 15 micromol/kg i.p. by itself did not alter the muscimol-induced loss of the righting reflex; but it completely blocked the effect of SKF 105,111. To elucidate the possible molecular mechanism by which a decrease of brain ALLO content can shorten the duration of the righting reflex loss elicited by muscimol, we patch-clamped neocortical pyramidal neurons of mice pretreated with SKF 105,111 or vehicle, and studied the efficiency of muscimol in eliciting Cl- currents. The current amplitude was significantly smaller in neurons from SKF 105,111-treated mice, especially at lower doses (0.1-1 microM) of muscimol, and the muscimol dose-response (0.1-10 microM) relationship displayed cooperativity (nH=1.4). These data suggest that ALLO synthesized in brain plays an important physiological permissive role in the modulation of GABA-gated Cl- channel function.

5-alpha-Dihydroprogesterone↗

PubMed1976

Prevention and reversal of tolerance to barbiturates by intraventricular injection of hemicholinium-3.

Intracerebroventricular (i.c.v.) injection of phenobarbital, 800 mug, or intraperitoneal (i.p.) injection of hexobarbital, 100 mg/kg, into rats resulted in a loss of righting reflex lasting 15.4 +/- 0.2 min and 20.7 +/- 0.7 min, respectively. A 40-60% reduction in this response was obtained following administration of phenobarbital either i.c.v. (800 mug 4 times daily) or i.p. (80 mg/kg/day) for 4 days. Although these treatments also increased hepatic mixed function oxidase activity, this enzyme induction was shown to be unrelated to the development of tolerance to loss of righting reflex. I.c.v. injection of hemicholinium-3 (HC-3) in doses which reduce brain acetylcholine levels (4-20 mug) profoundly affected tolerance to the central depressant effect of the barbiturates. Thus, depending upon the time of administration, HC-3 either retarded or prevented development of this tolerance. Moreover, if tolerance was allowed to progress normally, administration of HC-3 on day 4 or 5 returned the duration of the loss of righting reflex toward normal values. HC-3 did not influence either the duration of this response in non-tolerant rats or the induction of the hepatic mixed function oxidase activity. These results suggest that brain ACh plays an important role in the development and maintenance of tolerance to the central depressant effects of barbiturates.

Animals↗

PubMed2002

A novel method to assess initial sensitivity and acute functional tolerance to hypnotic effects of ethanol.

Loss of righting reflex (LRR) has traditionally been used to estimate hypnotic sensitivity to ethanol in rodents. Traditional methods of monitoring ethanol-induced sedation seems to lack accuracy in estimating blood ethanol concentration (BEC) at initial LRR, a measure of initial sensitivity. Herein, we present a novel method that improves detection of the onset of LRR by using a new apparatus and a loss-of-function criterion of 5 s. DBA/2J and C57BL/6J mice were placed in cylindrical restrainers after injection of 3 g/kg (20% v/v) ethanol. Restrainers were then turned until mice were no longer able to right themselves within 5 s from a position on their back, which represented the endpoint of the initial loss of righting reflex. Initial sensitivity and acute functional tolerance (AFT) to ethanol were assessed in the same group of mice by quantifying BEC at the initial loss and subsequent recoveries of righting reflex over four sequential injections [3 g/kg + (3 x 0.5 g/kg)]. Initial brain sensitivity was calculated from BEC at the first LRR, using the parameters of ethanol uptake kinetics. These values of initial sensitivity were similar for the two strains. On the other hand, DBA/2J mice recovered at higher BEC than C57BL/6J animals. AFT calculated as a difference between the maximum BEC at any recovery and the value of initial sensitivity was greater in DBA/2J mice. These results show that the novel method is a sensitive tool for the measurement of initial sensitivity and detection of AFT to the hypnotic effects of ethanol.

Algorithms↗

PubMed1986

Thyroid status during postnatal maturation of the brain in mice genetically bred for differences in ethanol sensitivity.

The long-sleep (LS) and short-sleep (SS) mice represent established lines, genetically selected from a heterogeneous stock (HS) of mice for differences in the duration of the loss of righting reflex (sleep-time response) to acute ethanol administration. Presently, the dose of ethanol (20% v/v i.p.) required for approximately a 50-min sleep-time response is 2-fold higher in adult SS (5.0 mg/g) than in adult LS (2.5 mg/g) mice. The waking isohypnotic serum and brain ethanol levels for HS mice are intermediate to those for LS and SS mice. Ethanol sensitivity of the two lines of mice at different stages of postnatal central nervous system maturation has not been examined. We report that the central nervous system sensitivity to a 1-mg/g dose of ethanol is the same in 9-day-old LS and SS mice, since the sleep-time response and corresponding waking serum ethanol concentrations are not different. The SS mice do not lose the righting reflex by 11 days postpartum after a dose of ethanol of 1 mg/g. By day 13, LS mice also do not lose their righting reflex after 1 mg/g of ethanol. The difference in ethanol sensitivity to a dose of 4.1 mg/g continues to develop at day 14 and approaches adult levels by day 20. This postnatal change in ethanol sensitivity in LS and SS mice occurs during a time when significant base-line differences in the thyroid status occur.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1996

Tolerance to the ataxic effects of diazepam in guinea pig is not associated with a reduced sensitivity of GABAA receptors in the vestibular nucleus.

Some studies have suggested that drug tolerance observed following repeated benzodiazepine exposure may be associated with the development of a subsensitivity to gamma-aminobutyric acid (GABA) in dorsal raphe and hippocampal neurons. In other areas such as the substantia nigra such subsensitivity has not been found. The aim of the present study was to determine whether tolerance develops to the ataxic effects of diazepam on the righting reflex following low (i.e. 2 mg/kg i.p.), multiple daily doses and, if so, whether it is correlated with the development of a subsensitivity of medial vestibular nucleus neurons to the selective GABAA receptor agonist, isoguvacine. Guinea pigs which received i.p. vehicle injections three times daily for 5 days, or single daily doses of 2 or 6 mg/kg diazepam, showed increased righting reflex latencies in response to a 6 mg/kg diazepam challenge dose. However, guinea pigs which received 2 mg/kg diazepam i.p., three times daily for 5 days, exhibited minimal or no ataxia when given the same diazepam challenge dose, indicating the development of tolerance. Brain stem slices including the medial vestibular nucleus were removed from guinea pigs which had received the same diazepam and vehicle three times daily injection schedules, and recordings were made from single neurons during superfusion of isoguvacine. Although medial vestibular nucleus neurons from animals which received chronic diazepam administration showed smaller decreases in firing rate in response to 10(-8) M isoguvacine, the difference was not statistically significant compared to neurons from animals which received vehicle treatment or acute diazepam treatment. Resting activity was also similar between the diazepam and vehicle groups, in contrast to a previous study which had shown hyperexcitability in medial vestibular nucleus cells from animals which had received single daily injections for up to 60 days. These results suggest that, in contrast to studies which have employed single daily doses, tolerance to the ataxic effects of diazepam on the righting reflex occurs rapidly with divided daily doses. However, this tolerance is not correlated with significant changes in the sensitivity of GABAA receptors on medial vestibular nucleus neurons.

Animals↗

PubMed2004

Role of angiotensin II and the subfornical organ in the pharmacological actions of ethanol.

AIMS: The current study was designed to evaluate if angiotensin II mediates the hypothermic effects of ethanol, and to determine if the effects of angiotensin are mediated centrally. We also tested the hypothesis that the subfornical organ (SFO) is a site responsible for the alterations in body temperature and aerial righting reflex mediated by ethanol and for the modulation of ethanol consumption in rats. METHODS: Male Sprague-Dawley rats were used in a series of experiments to evaluate the role of both peripheral and central administration of losartan, a selective angiotensin type 1 receptor antagonist on ethanol-induced hypothermia. Subsequent studies were undertaken in SFO-lesioned rats to evaluate the effects of SFO-lesion on alcohol intake, the thermal response to alcohol and angiotensin, and the aerial righting reflex. RESULTS: Selective antagonism of the angiotensin II type 1 receptor, administered either peripherally or centrally, attenuated not only the fall in colonic temperature but also attenuated the transient rise in tail skin temperature that was associated with administration of ethanol. The thermal responses to both angiotensin and ethanol were similarly attenuated in SFO-lesioned rats. Likewise the aerial righting reflex, which has previously been shown to be impaired by losartan treatment, was also significantly attenuated in SFO-lesioned animals. Alcohol intake, as determined by a 48 h, two-bottle preference test also revealed that SFO-lesioned animals consumed significantly less alcohol (ethanolic beer) than did controls. CONCLUSION: Collectively, the results demonstrate that ethanol-induced temperature responses are mediated by the renin-angiotensin system and that this interaction is mediated centrally. In addition, the results demonstrate that the SFO is a site that mediates several neurobiological effects of ethanol, possibly via the renin-angiotensin system.

Angiotensin II↗