ro-19-8022 and Seizures

Repeated administration of partial agonist of benzodiazepine receptors Ro 19-8022 (a derivative of quinolizine class) does not elicit withdrawal in adult rats. Our older data demonstrated that single injection of Ro 19-2088 to immature rats induces increased sensitivity to convulsant action of pentylenetetrazol as a withdrawal phenomenon. To know if repeated administration of the partial agonist has the same effect we injected rats at postnatal days 7 to 11 with an anticonvulsant dose of Ro 19-8022 (0.5 mg/kg i.p.) and tested them 24 h, 48 h and 4 days after the last injection. Repeated administration of Ro 19-8022 resulted also in an increased sensitivity to convulsant action of pentylenetetrazol in immature rats (higher incidence and severity of seizures). This effect was significant 24 h after the last injection but only outlined 48 h after administration. No signs of hypersensitivity were seen at 4-day interval. There is a difference between immature and adult brain in an appearance of withdrawal symptom after administration of the partial agonist of benzodiazepine receptors Ro 19-8022.

Topics: Age Factors; Animals; Anticonvulsants; Brain; Carrier Proteins; Disease Models, Animal; Drug Administration Schedule; Drug Partial Agonism; Male; Pentylenetetrazole; Pyrrolidines; Quinolizines; Rats; Rats, Wistar; Receptors, GABA-A; Seizures; Substance Withdrawal Syndrome; Time Factors

The purpose of our study was to determine whether a single administration of anticonvulsant doses of two ligands of benzodiazepine receptors, clonazepam and Ro 19-8022, leads to development of rebound phenomena in immature 12-day-old rats. Three tests were used: pentylenetetrazole (PTZ)-induced seizures, isolation-induced ultrasonic vocalizations, and motor performance. Susceptibility to the convulsant effects of PTZ decreased 24 hours, but increased 48 hours, after clonazepam administration. Ultrasonic vocalizations were completely suppressed 30 minutes and 3 hours after clonazepam; a moderate inhibitory effect persisted even at 48 hours. Motor abilities were slightly compromised up to 3 hours. Similar effects of Ro 19-8022 on PTZ-induced seizures and ultrasonic vocalizations were observed 24 and 48 hours after administration; motor performance was not affected. Rebound proconvulsant effects followed different time courses after administration of the two benzodiazepine receptor ligands in developing animals. Anxiolytic-like effects of these drugs were still present at the time when animals exhibited rebound proconvulsant effects.

Topics: Analysis of Variance; Animals; Animals, Newborn; Clonazepam; Disease Susceptibility; GABA Modulators; Male; Motor Activity; Pentylenetetrazole; Pyrrolidines; Quinolizines; Rats; Rats, Wistar; Receptors, GABA-A; Seizures; Vocalization, Animal

The action of a partial benzodiazepine receptor agonist Ro 19-8022 [(R)-1-[(10-chloro-4-oxo-3-phenyl-4H-benzo[a]quinolizin-1-yl)carbo nyl] -2-pyrrolidine-methanol] in doses from 0.01 to 150 mg/kg was studied using motor seizures induced by pentylenetetrazol (PTZ) in rats 7, 12, 18, 25 and 90 days old. Generalized tonic-clonic seizures were suppressed in all age groups, the three youngest groups being more sensitive than older animals. The highest dose of Ro 19-8022 did not exhibit anticonvulsant action in the 25-day-old rats. The other types of seizures (minimal clonic) induced by PTZ were suppressed by Ro 19-8022 only in 18-day-old and older rats in which PTZ reliably elicited these types of seizures. The doses of 50, 100 and 150 mg/kg were ineffective against minimal seizures. On the contrary, incidence of minimal seizures was significantly increased by Ro 19-8022 in 7-and 12-day-old rat pups. Motor performance of rat pups was not compromised by Ro 19-8022 (0.5 and 50 mg/kg) in contrast to the full agonist midazolam (1 and/or 2 mg/kg). The duration of anticonvulsant effects studied with a dose of 0.5 mg/kg was longer in 12-day-old than in adult rats. This dose of Ro 19-8022 resulted in a rebound proconvulsant effect 24 and 48 h after the administration in 12-day-old rats only. Ro 19-8022 exhibited an excellent anticonvulsant action especially against generalized tonic-clonic seizures; this action was lost with very high doses. It did not compromise the motor system, but in some tests motivation was probably lost.

Topics: Aging; Animals; Anticonvulsants; Convulsants; Dose-Response Relationship, Drug; GABA-A Receptor Antagonists; Male; Midazolam; Motor Skills; Pentylenetetrazole; Pyrrolidines; Quinolizines; Rats; Rats, Wistar; Seizures; Time Factors

The partial agonist at benzodiazepine receptors, Ro 19-8022, has been characterized as a putative anxiolytic drug with an improved side effect profile. This orally active compound is a representative of a quinolizinone structure class and shows potent anticonflict activity in mice and rats. It protects rodents from convulsions induced by pentylenetetrazol, N-methyl-D-aspartic acid and maximal electroshock, as well as against audiogenic seizures, with an efficacy comparable to that of the full agonist alprazolam. No appreciable sedative or motor-impairing effects could be detected up to a very high dose (100 mg/kg) in the horizontal wire test or the rotarod performance test in mice and rats and in spontaneous behavior in monkeys. Consistent with its characterization as a partial agonist, Ro 19-8022 antagonized the motor impairment induced by the full agonists diazepam or meclonazepam measured in horizontal wire and rotarod tests in rodents, and reduced flunitrazepam-induced effects in squirrel monkeys, with an efficacy comparable to that of the benzodiazepine receptor antagonist flumazenil. After subchronic administration of Ro 19-8022 to mice, antagonist-precipitated withdrawal syndrome was dramatically weaker than after alprazolam treatment, which is indicative of a lower physical dependence liability of Ro 19-8022. Pharmacodynamic effects recorded in convulsion and reversal of motor impairment tests after i.v. administration suggest a long duration of action of this compound. Taken together, such preclinical data suggest that benzodiazepine receptor partial agonists with a neurological and behavioral profile such as that of Ro 19-8022 may offer an innovative therapeutic approach to the treatment of anxiety disorders.

Topics: Acoustic Stimulation; Animals; Anti-Anxiety Agents; Anticonvulsants; Conditioning, Operant; Diazepam; Drug Evaluation, Preclinical; Mice; Motor Activity; Pyrrolidines; Quinolizines; Rats; Receptors, GABA-A; Saimiri; Seizures; Species Specificity