ro-19-8022 and Substance-Withdrawal-Syndrome

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 aim of the present study was to ascertain whether withdrawal from alprazolam can increase anxiety-like and aggressive behavior during intra species conflict in mice and, if so, whether a partial benzodiazepine agonist Ro 19-8022 is able to reverse these behavioral changes without untoward effects such as sedation. An experimental model consisting of interactions of pairs of singly-housed male mice with non-aggressive group-housed male mice was used. Alprazolam (1 mg/kg) was given orally twice daily for 8 days and once on the 9th day. When withdrawn from alprazolam (3 days after the last dose), mice reduced social investigation and increased the incidence of aggressive behavior in comparison to the pre-withdrawal level. However, the increase of aggression was moderate and occurred only in subjects with low pre-treatment levels of aggression. Ro 19-8022 (10 mg/kg) significantly antagonized the decrease of social behavior and the increase of aggression after alprazolam withdrawal without causing sedation or ataxia.

Topics: Aggression; Alprazolam; Animals; Anti-Anxiety Agents; Escape Reaction; Male; Mice; Mice, Inbred ICR; Motor Activity; Posture; Pyrrolidines; Quinolizines; Social Behavior; Social Environment; Substance Withdrawal Syndrome