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At least 631 records · Page 35Linked to original sources

PubMed1978

Antiextensor effects of 3,3-diphenyl-n-propylamine in the mouse.

Diphenylpropylamine has antiextensor activity in the MES test and worsens clonic seizures produced by pentylenetetrazol. The drug also prevents tonic hindlimb extension produced by large doses of pentylenetetrazol. Diphenylpropylamine appears, therefore, to be a phenytoin-like compound. However, unlike most antiextensor agents, diphenylpropylamine has neuroexcitatory effects and antagonizes barbital-induced loss of the righting reflex.

Animals↗

PubMed1981

Characterization of alpha-adrenoceptors participating in the central hypotensive and sedative effects of clonidine using yohimbine, rauwolscine and corynanthine.

The central alpha-adrenoceptors responsible for mediating the clonidine-induced central hypotension in anaesthetized cats and sedation in mice have been characterized according to their sensitivities to the alpha-adrenoceptor antagonist yohimbine and its two diastereomeric congeners rauwolscine and corynanthine. Yohimbine and rauwolscine (1-10 microgram/kg) dose-dependently antagonized the central hypotensive response to clonidine (1 microgram/kg) applied 15 min later. Greater amounts of corynanthine (30-100 micrograms/kg) had to be administered to diminish the central depressor effect of clonidine. In these studies the drugs were infused via the left vertebral artery. The prolongation of the hexobarbitone-induced loss of the righting reflex in mice by clonidine (0.3 mg/kg, i.p.) was inhibited by previous treatment with yohimbine and rauwolscine (0.04-5 mg/kg, i.p.) in a dose-dependent manner, but not by corynanthine. Binding experiments with rat isolated cerebral membranes demonstrated the higher affinity of yohimbine and rauwolscine for the [3H] clonidine- than for the [3H]prazosin-specific binding sites. The reverse was found for corynanthine. The relative potencies of yohimbine, rauwolscine and corynanthine in inhibiting these central effects of clonidine are comparable to their order of efficacies in blocking peripheral alpha 2-adrenoceptors. Accordingly, clonidine-induced central hypotension and sedation are mediated by alpha 2-adrenoceptors.

Adrenergic alpha-Antagonists↗

PubMed1982

Changes in brain piperidine levels under anesthesia: mass fragmentographic analysis.

Piperidine is a biogenic alicyclic amine possessing potent pharmacological activity. Interest has recently been focussed on its possible role as an endogenous hypnogenic substance. Using a mass fragmentographic technique with deuterium-labelled piperidine as an internal standard, the time relations of the change in brain levels of piperidine and the anesthetic activity of urethane were determined in mice. The brain piperidine level increased prior to the loss of the righting reflex and the elevated level declined prior to the reappearance of the reflex. The change in brain piperidine level correlated with neither that in spontaneous motility nor that in body temperature. The findings favor the idea that piperidine might at least partly regulate the level of consciousness.

Anesthesia↗

PubMed1984

A possible alpha 2-adrenergic component in the in vivo activity of pirenperone.

The study used the loss of the righting reflex in response to the alpha 2-agonist xylazine in an in vivo rat assay to determine possible effects of the LSD antagonist pirenperone at alpha 2-adrenoceptors. Pirenperone antagonized the response and was more potent (ED50: 0.32 mg/kg) than yohimbine (1.25 mg/kg) and piperoxan (3.30 mg/kg). The data suggest that pirenperone may act at alpha 2-adrenoceptors in vivo.

Animals↗

PubMed1986

Correlation of the hypnotic potency of benzodiazepines with inhibition of voltage-dependent calcium uptake into mouse brain synaptosomes.

Nine benzodiazepines were tested for their ability to inhibit 45Ca2+ uptake into mouse whole brain synaptosomes and for hypnotic activity as indicated by their ability to produce loss of the righting reflex. Eight of the benzodiazepines significantly inhibited fast-phase voltage-dependent 45Ca2+ uptake and five exhibited hypnotic activity. There was a direct correlation between the hypnotic potency of these five benzodiazepines and their ability to inhibit 45Ca2+ uptake. There does not appear to be a correlation between the anticonvulsant potency of the benzodiazepines and their potency for inhibiting 45Ca2+ uptake. These results support previous findings with other sedative/hypnotic drugs and suggest that inhibition of presynaptic calcium uptake may be linked with hypnotic but not anticonvulsant actions of benzodiazepines.

Animals↗

PubMed1988

Blockade of alpha 2-adrenoceptors by 1-(2-pyrimidinyl)-piperazine (PmP) in vivo and its relation to the activity of buspirone.

The effect of 1-(2-pyrimidinyl)-piperazine (PmP) and the parent drug, buspirone in counteracting the behavioral and biochemical effects of clonidine were evaluated in the rat. Intraperitoneal or oral administration of PmP, buspirone and yohimbine, but not of prazosin, antagonized the slowing of gastrointestinal motility induced by subcutaneous clonidine (0.1 mg/kg). The doses that inhibited the effect of clonidine on the transit time by 50% were 0.5 mg/kg i.p. and 0.7 mg/kg p.o. for PmP, 7 mg/kg i.p. and 9 mg/kg p.o. for buspirone and 0.5 mg/kg i.p. for yohimbine. PmP (0.5 mg/kg) did not block the antitransit effect of clonidine when administered by intracerebroventricular injection. The antitransit effect of a low dose of morphine (0.05 mg/kg i.p.) was not blocked by PmP (2 mg/kg i.p.). The prolongation of the hexobarbital-induced loss of the righting reflex that occurs after clonidine (0.25 mg/kg i.p.) administration was inhibited by pretreatment with PmP (0.1-2 mg/kg p.o.) or yohimbine (1 mg/kg i.p.) but not by pretreatment with prazosin (2 mg/kg i.p.). Buspirone (1-20 mg/kg) also reduced the effect of clonidine after oral administration, with a maximal effect at 5 mg/kg, whereas the same dose administered i.v. had less effect. PmP (2 mg/kg) and buspirone (15 mg/kg) raised the levels of total 3-methoxy-4-hydroxyphenylgycol (MHPG) in rat cerebral cortex, and prevented the decrease in MHPG induced by clonidine. These findings show that buspirone, in doses at which it is active as an anxiolytic, suppresses the central and peripheral effects of clonidine. This action occurs through alpha 2-adrenoceptors and is mediated primarily by the metabolite, PmP.

Adrenergic alpha-Antagonists↗

PubMed1988

Behavioural and neurochemical effects of medetomidine, a novel veterinary sedative.

The effects of the novel veterinary sedative, medetomidine, were studied in rats. In addition to a dose-dependent sedation, which at high doses (greater than 100 micrograms/kg) included loss of the righting reflex and hypothermia, there was a concurrent decrease in the turnover rate of biogenic amines in the brain. Noradrenaline turnover was dose dependently decreased as judged by (i) the decrease in the brain concentration of its metabolite, MHPG-SO4, (ii) a decrease in the ability of alpha-methyl-p-tyrosine methyl ester to deplete brain noradrenaline stores and (iii) a dose-dependent decrease in the level of unconjugated MHPG in the CSF of freely moving rats. Brain dopamine turnover was also inhibited at higher doses as judged by the alpha-methyl-p-tyrosine method and by a decrease in the concentration of HVA in the rat brain 4 h after medetomidine. Serotonin turnover as estimated by the ratio of biogenic amine to its metabolite was also significantly depressed. These changes in brain biogenic amine turnover were inhibited by prior or simultaneous administration of alpha 2-adrenoceptor antagonists, either yohimbine or the more specific, novel alpha 2-antagonist, atipamezole.

Adrenergic alpha-Agonists↗

PubMed1988

RO 15-4513 does not protect rats against the lethal effects of ethanol.

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

Animals↗

PubMed1989

Antagonism of methoxyflurane-induced anesthesia in rats by benzodiazepine inverse agonists.

Injection of the partial benzodiazepine inverse agonist Ro15-4513 (1-32 mg/kg i.p.) or nonconvulsant i.v. doses of the full benzodiazepine inverse agonist beta-CCE immediately following cessation of exposure of rats to an anesthetic concentration of methoxyflurane significantly antagonized the duration of methoxyflurane anesthesia as measured by recovery of the righting reflex and/or pain sensitivity. This antagonism was inhibited by the benzodiazepine antagonist Ro15-1788 at doses which alone did not alter the duration of methoxyflurane anesthesia. In addition, high-dose Ro15-4513 pretreatment (32 mg/kg) antagonized the induction and duration of methoxyflurane anesthesia but was unable to prevent methoxyflurane anesthesia or affect the induction or duration of anesthesia induced by the dissociative anesthetic ketamine (100 mg/kg). These findings indicate that methoxyflurane anesthesia can be selectively antagonized by the inverse agonistic action of Ro15-4513 and beta-CCE.

Anesthesia↗

PubMed1990

Anaesthesia effects on in vivo acetylcholine transmission; comparisons of radioenzymatic and HPLC assays.

The effect of general anaesthesia on extracellular levels of acetylcholine (ACh) in the caudate-putamen of freely moving rats was studied by microdialysis. ACh concentrations were determined in the same perfusate samples by radioenzymatic and HPLC/electrochemical procedures in order to compare the assays. The concentration of ACh in perfusate samples was estimated to be 0.30 microM in conscious unrestrained rats. However, when these rats were administered chloral hydrate (400 mg/kg i.p.), the level of ACh was decreased immediately by 50%, attaining a value of 0.06 microM within 20-40 min following the injection. Upon recovery of the righting reflex, ACh levels were once again re-elevated. The levels of choline (Ch), the precursor of ACh, were unaffected by anaesthesia. It was apparent that the level of consciousness (i.e. awake vs. anaesthetized) is an important factor determining ACh overflow. Radioenzymatic and HPLC assays proved to give identical results for the analysis of ACh and Ch.

Acetylcholine↗

PubMed1987

Hypnotic action of pentobarbital in mice: a possible mechanism.

The effect of GABA receptor agonists (THIP and baclofen) on the hypnotic activity (loss of righting reflex and sleep time) of pentobarbital in mice was investigated. Combinations of either THIP-pentobarbital or baclofen-pentobarbital interacted synergistically by increasing hypnotic activity. The GABAa receptor antagonist, bicuculline, decreased the hypnotic effect of THIP-pentobarbital combinations but not that of baclofen-pentobarbital combinations. These results suggest that the hypnotic activity of pentobarbital involves GABAa receptor function.

Animals↗

PubMed1995

Behavioral and metabolic consequences of neonatal exposure to diazepam in rat pups.

The short-term consequences of a neonatal exposure to diazepam (DZP) on neurobehavioral development and postnatal changes in local cerebral metabolic rates for glucose (LCMRglcs) in selected regions were studied in rats. Rat pups received a daily subcutaneous injection of 10 mg/kg DZP or of the dissolution vehicle from Postnatal Day 2 (P2) to 21 (P21). DZP did not affect the static righting reflex tested at P4 but increased suspension time at P10 and time to complete a 180 degrees pivoting on an inclined plane at P9. In a locomotor coordination test performed at P20, swimming or climbing on a vertical pole was not affected by DZP while the drug impaired the ability of the rat to place its hind-paws on the horizontal platform after climbing. Likewise, DZP induced marked decreases (19-45%) in LCMRglcs in most structures studied at P10, P14, and P21. The results of the present study show that neonatal DZP treatment induces motor deficits that appear to be quite subtle, to concern mainly posture and body balance. They are not apparent in tasks such as swimming or climbing but become obvious in more difficult tasks such as achieving a horizontal quadruped position on a platform after a climbing phase. Decreases in cerebral energy metabolism appear to be mainly located in areas controlling posture and body balance and are partly correlated with the locomotor impairments recorded in the present study.

Animals↗

PubMed1991

The effects of benzodiazepine-receptor antagonists and partial inverse agonists on acute hepatic encephalopathy in the rat.

Two benzodiazepine-receptor partial inverse agonists (Ro 15-4513, Ro 15-3505) and one benzodiazepine-receptor antagonist (flumazenil) were administered to rats with hepatic encephalopathy due to acute liver ischemia. Significant improvement (P less than 0.002) of both the clinical grade of hepatic encephalopathy and the electroencephalographic abnormalities was observed after administration of the benzodiazepine-receptor partial inverse agonists: comatose rats with no spontaneous righting reflex regained consciousness immediately after injection of the drug. Only slight improvement in clinical hepatic encephalopathy grade was seen after administration of 25 mg/kg of flumazenil. The present data strongly support a role of increased gamma-aminobutyric acid-ergic tone in the pathogenesis of acute hepatic encephalopathy and provide a rationale for trials of benzodiazepine-receptor partial inverse agonists to restore consciousness in hepatic encephalopathy in humans in the near future.

Animals↗

PubMed1976

[An experimental study of the psychostimulant action of amantadine].

According to previous experimental and clinical data, we have tested the hypothetic psycho-stimulating activity of amantadine on experimental sensitized models. We obtained a strong action on the spontaneous sleep of rats at a dose of 10 mg/kg and a less striking action in diminishing the effects of barbitol on the righting reflex of mice and in reducing the narcosis of rats induced by mebubarbital. This action does not seem to be due to a release of catecholamine because the lesions produced by electrocoagulation in the ascending aminergic pathways or pretreatment by alpha-methylparatyrosine (AMPT) do not block it. It is suggested that there may be a non-aminergic receptor of amantadine which is different from the amphetamine receptor.

Amantadine↗

PubMed1982

Naloxone or TRH fails to improve neurologic deficits in gerbil models of "stroke".

The effects of naloxone or thyrotropin releasing hormone (TRH) upon neurologic outcome were evaluated in gerbil models of cerebral ischemia. Following temporary bilateral carotid occlusion, hypotension was transiently reversed by these endorphin antagonists. However, neither drug altered time to awaken, time to death, or the severity of neurologic signs (ptosis, movement, retracted paws, circling, righting reflexes, seizures, or opisthotonus) when evaluated by a blinded rater. Hot plate escape and roto-rod performance were also unaltered by naloxone or TRH; TRH, but not naloxone, increased respiratory rates. Thus, the transient improvement of cardiorespiratory function produced by these drugs is unrelated to the morbidity and mortality associated with temporary cerebral ischemia in the gerbil. Additional studies evaluating the effects of naloxone or TRH upon neurologic outcome following permanent unilateral carotid occlusion also failed to show any therapeutic effects of these drugs. Both morphine and TRH exacerbated the effects of ischemia. Of gerbils which developed neurologic impairment, the deficit was usually ipsilateral to the occluded carotid. Collectively, these results indicate that neither naloxone nor TRH prevents ischemic deficits in the gerbil. Further studies with different cerebral ischemia models in other species are required to clarify the possible therapeutic effects of these drugs in experimental stroke.

Animals↗

PubMed1986

Marked variation in diazepam sensitivity in Swiss albino mice.

Using the righting reflex as the critical level, sleep was measured in Swiss albino mice at a dose of 35 mg/kg diazepam, i.p. Sleep times varied markedly from zero to 120 min with a mean +/- s.d. of 44 +/- 37 (N = 202). The distribution is skewed to the left with a coefficient of skewness of 0.33 +/- 0.17. The sleep times of the two sexes, when analyzed separately, showed similar range, mean and s.d., except that the distribution tended to be more clearly bimodal in males than in females. These animals also exhibited marked variations in their response to either ethanol (4 g/kg) or pentobarbital (45 mg/kg). The diazepam sleep time failed to correlate with the ethanol sleep time. Significant correlation, however, was obtained between diazepam and pentobarbital sleep times. On further analysis with least-squares fit to a straight line, the data yielded a line with a slope of 0.16; thus despite the correlation reaching a significant level, there is no significant difference in the pentobarbital sleep times between mice that have the longest or the shortest diazepam sleep times. By monitoring the plasma and brain levels of diazepam and N-desmethyldiazepam in mice at awakening, it was found that the variations in sleep time cannot be explained by individual differences in drug disposition. The phenomenon is discussed in terms of individual variations in diazepam sensitivity and the possibility of development of tolerance to diazepam almost immediately after diazepam administration.

Animals↗

PubMed1989

Attenuation of ethanol intoxication by alpha-2 adrenoceptor antagonists.

The interaction of a highly potent and selective alpha-2 adrenoceptor antagonist, atipamezole with ethanol was investigated in tests assessing a number of ethanol's behavioral effects. Atipamezole antagonized ethanol's effects on directed exploration in a holeboard test, reduced observer-rated intoxication and also reduced the duration of loss of righting reflex caused by ethanol. Similar effects were produced by another alpha-2 adrenoceptor antagonist idazoxan. The magnitude of the effects was comparable to that produced in the same animal models by the imidazodiazepine Ro 15-4513, which antagonizes ethanol by an action at central benzodiazepine receptors. Whereas Ro 15-4513 possesses marked behavioral effects on its own, atipamezole is comparatively inactive in all paradigms so far tested. The data suggest that alpha-2 adrenoceptors can play an important role in modulating the intoxicating effects of ethanol.

Adrenergic alpha-Antagonists↗

PubMed1990

Diazepam sensitive mice: differential sensitivity to the depressant and anticonvulsant effects of diazepam.

A mouse line was developed by selecting for increased sensitivity to the hypnotic effect of diazepam. These "diazepam sensitive" mice showed a mean duration of loss of righting reflex (LORR) of approximately 150 min at a dose of 20 mg/kg diazepam, this dose failed to induce LORR in the control outbred mice. Rotarod treading times of the diazepam sensitive mice were significantly shorter than that of the control mice over the same dose range indicating that these mice are also more sensitive to the sedative/muscle relaxant effects of diazepam. On the contrary, the ability of diazepam to protect against pentylenetetrazole-induced convulsion was found to be the same in the sensitive and control mice. These observations strongly suggest that the heightened sensitivity to the sedative-hypnotic effects of diazepam in the sensitive mice is unlikely to be due entirely to changes in drug disposition.

Animals↗