Sarmazenil

Abstract: This study evaluated partial antagonism of tiletamine-zolazepam (TZ) anesthesia in cheetahs (Acinonyx jubatus) and differences between two benzodiazepine antagonists, flumazenil and sarmazenil, in this species. Four cheetahs were anesthetized three times at an interval of 14 days with an average intramuscular dose of 4.2 mg/kg TZ. In trials 2 and 3 flumazenil at 0.031 mg/kg and sarmazenil at 0.1 mg/kg, respectively, were applied intramuscularly 30 min after initial TZ injection. There was a highly significant difference between the duration of TZ anesthesia with and without antagonist. Use of the antagonists significantly shortened duration and recovery and eliminated excitatory behavior during the recovery phase. No significant differences could be determined between the two antagonists. We recommend the use of sarmazenil and flumazenil to antagonize TZ anesthesia in cheetahs.

Abstract: Two benzodiazepine analogues, [3H]flumazenil and [3H]sarmazenil, were used to study the GABAA/benzodiazepine receptor complex in human post-mortem brain using in vitro receptor assays on homogenates and whole hemisphere autoradiography. Both radioligands bound in a saturable manner to single binding sites in the tissue preparations from any brain region. The highest levels of binding were found in the cortical regions and in cortex cerebelli. Both [3H]flumazenil and [3H]sarmazenil were excellent radioligands for autoradiography with high binding in cerebral and cerebellar cortex with no or very low binding in areas with white matter. The addition of a high concentration of flumazenil or clonazepam did not inhibit the binding of [3H]sarmazenil to granule cells in the cerebellum while the binding of [3H]flumazenil was abolished completely in all regions. The results show that with the two different radioligands, one an antagonist and one a partial inverse agonist, the binding pattern to GABAA/benzodiazepine receptor complex is approximately similar in most brain regions. The additional binding seen in the cerebellum with [3H]sarmazenil is suggested to be due to binding to an α6-containing complex.

Abstract: The quinolizinones Ro 19-5663, Ro 19-5686 and Ro 41-3696 bind with high affinity to the benzodiazepine receptor (BZR) in vitro in the rat brain. These compounds exhibit anxiolytic-like effects in an operant punishment task in mice and rats and anticonvulsant effects by fully protecting against pentylenetetrazol-induced tonic seizures in mice and rats and fully protecting against audiogenic seizures in genetically susceptible mice. However, they produced at most only minimal motor impairment in the rotarod task in rodents. These compounds attenuated flunitrazepaminduced sleep in squirrel monkeys, thus antagonizing the effects of a BZR full agonist. In a precipitated withdrawal paradigm, chronic oral treatment in seizure-prone young DBA/2J mice or adult squirrel monkeys was followed by iv challenge with the BZR antagonist sarmazenil. Following the completion of a chronic treatment regiment with high doses of these quinolizinones, no signs of precipitated withdrawal were observed in mice and only weak signs of sarmazenil-induced withdrawal were observed in monkeys. In contrast, sarmazenil challenge after chronic treatment with the BZR full agonists triazolam and alprazolam elicited marked withdrawal reactions in mice and monkeys, respectively. In sum, these quinolizinones are BZR partial agonists which offer potential anxiolytic and anticonvulsant efficacy concomitant to reduced adverse effects, including a clear reduction of dependence liability, in comparison to BZR full agonists. © 1995 Wiley-Liss, Inc.

Abstract: A procedure is described for training mice to discriminate 30mg/kg pentylenetetrazol (PTZ) from saline when lever pressing was maintained under a fixed-ratio 20 schedule of milk presentation. To define the pharmacological profile of the PTZ stimulus in mice, generalization testing was conducted with oxazepam and Ro 15-4513 (sarmazenil). Consistent with data obtained by others in rats, oxazepam (1mg/kg) blocked the PTZ stimulus whereas Ro 15-4513 substituted for PTZ, but only at a dose (2mg/kg) that also decreased rates of responding. The effects of both a depressant and excitatory vapor in this model were also determined. The volatile anesthetic methoxyflurane (1000-2000 ppm) blocked the discriminative stimulus effects of PTZ in a concentration-dependent manner, while the convulsant vapor flurothyl (900 ppm) produced greater than 90% PTZ-lever responding without disrupting rates of responding. The PTZ-like discriminative stimulus effects of flurothyl were dose-dependently blocked by oxazepam (0.03-1.0mg/kg). As has been shown in numerous previous studies in rats, PTZ could be established as a discriminative stimulus in mice. PTZ discrimination could be blocked by a benzodiazepine agonist and shares some properties with a benzodiazepine inverse agonist. Substitution and antagonism studies can also be performed with vapors, illustrating the utility of this model for comparing their behavioral effects to those of more widely studied drugs.