Figure 4.

Basmisanil improved cognition in rodents and non-human primates at plasma concentrations which did not show anxiogenic or proconvulsant effects. (a) Basmisanil reversed the diazepam-induced spatial learning impairment of rats in the Morris water maze. Basmisanil (3 and 10 mg/kg p.o. as indicated below the abscissa) and diazepam (6 mg/kg i.p.) were administered to male Lister Hooded rats 30 min before the test. Data are presented as mean ± SEM (n = 10 per dose group). Statistics: *Significant difference between vehicle and diazepam-treated groups on percent time in platform quadrant (unpaired t-test); § significant difference between percent time spent in platform quadrant versus left, right and opposite quadrants (post hoc Newman-Keuls test). Total plasma concentrations (ng/mL) for each dose are shown above each bar and were collected in parallel to the experiment (n = 4 per dose). The range shows the concentrations at 30 and 100 min post-administration which are equivalent to the beginning and end of testing. (b) Basmisanil improved executive function in adult cynomolgus macaques. The effect of basmisanil administered at 1, 3, 10 and 30 mg/kg p.o. on percent correct (first reaches) during difficult trials of the object retrieval task. Data are presented as mean ± SEM (n = 12/dose; within-subjects design). Statistics: *Significant difference versus vehicle-treated group (post hoc Dunnett’s test). Total plasma concentrations (ng/mL) for each dose are shown above each bar. Samples were collected at 180 min for the same three subjects. (c) Effect of basmisanil and the positive control (PC), FG7142, on the percent of male or female rats with tonic convulsions following administration of a threshold dose of PTZ (n = 8 per treatment group). *Significant difference versus vehicle group (Pearson Chi-Square test). Plasma samples were collected either immediately following tonic convulsions or 30 min following PTZ, i.e., approximately 60–90 min (males) or 180–210 min (females) post administration of basmisanil (n = 8 per dose). (d) Effect of basmisanil administered p.o. 1 h prior to testing and the positive control (PC), Ro 19-4603 administered p.o. 30 min prior to testing, in the social approach avoidance test in male F-344 rats (n = 10 per treatment group). Data are expressed as mean ± SEM. *Significant difference versus vehicle group (unpaired t-test). Total plasma concentrations (ng/mL) for each dose are shown above each bar. Plasma samples were collected immediately after testing i.e., approximately 75 min post administration of basmisanil (n = 4 per dose).