RU-33965

An operant task for the measurement of sustained attention or vigilance in rats was characterized. The task requires the animals to respond to the presentation of visual signals (presented for 25, 50, or 500 ms) by operating one lever ("hits") and to the absence of a signal by operating the opposite lever ("correct rejection"). Incorrect responses ("misses" and "false alarms", respectively) were not rewarded. Performance in this task is a function of signal length, i.e., the shorter the signals the higher the number of misses. An increase in "background noise" by flashing the chamber houselight (at 0.5 Hz) impaired the animals' ability to discriminate between signal and non-signal events. Also flashing the houselight augmented the vigilance decrement observed for shortest signals. An increase in the event-rate also resulted in a vigilance decrement. Finally, the inability of the animals to time signals was examined by testing the effects of an increase in event asynchrony. In a second experiment, the performance of differently aged rats (6- and 20 month-old male BNNia/F344 rats) was studied. Compared to young animals, 20-month-old rats showed a decrease in their ability to discriminate between shortest signals (25 ms) and non-signal events but did not differ in their ability to correctly reject non-signal trials. Administration of the benzodiazepine receptor (BZR) agonist chlordiazepoxide (CDP; 3, 5, 8 mg/kg) resulted in an impairment of the animals' ability to discriminate between signal and non-signal events and, similar to the effects of age, this effect was exclusively due to an increase in the number of misses. CDP generally produced potent effects while affecting the aged animals to a greater degree. BZR-ligands with weak or "selective" inverse agonist properties (ZK 93426; beta-CCtB) did not affect vigilance performance. The BZR partial inverse agonist RU 33965 (0.1, 0.5 mg/kg) dose-dependently impaired vigilance performance. The administration of amphetamine (0.4, 0.8 mg/kg) also impaired performance, but these impairments were possibly based on effects unrelated to attentional mechanisms. The finding that performance in this task revealed the interactions between the effects of age and BZR agonists on attentional abilities further supports the validity of measures of performance generated by this task.

1. Two 3-cyclopropyl carbonyl imidazobenzodiazepines, RU 33965 and RU 34030, were tested for their ability to modulate GABAA synaptic transmission in rat cerebellar slices. The action of the full benzodiazepine agonist RU 32007 and the inverse agonist Ro19-4603 were tested for comparison. 2. Extracellular recordings were made from the Purkinje cell layer of the cerebellar slices and inhibition induced by just threshold electrical stimulation of the parallel fibres was bicuculline sensitive. 3. The major effect of RU 32007 when examined at 100 nM and 1 microM was to increase the GABAA mediated inhibition in the slice. 4. In contrast the major effect of the inverse agonist Ro19-4603 was to reduce the period of inhibition. 5. RU 33965 and RU 34030 at 10 and 1 microM respectively either had little effect on GABAA mediated inhibition or decreased it slightly. 6. RU 34030, 1 microM, abolished the agonist effect of RU 32007, 1 microM. 7. The effects of RU 32007 and Ro19-4603 were abolished by the benzodiazepine antagonist flumazenil. 8. It is concluded that both RU 33965 and RU 34030 have marginal inverse agonist properties.