Central nervous system characterization of the new cholecystokininB antagonist LY288513

The activity of LY288513, an investigational cholecystokinin (CCK)B antagonist, was evaluated in a wide range of pharmacological tests in mice and rats. The anxiolytic benzodiazepine, diazepam, served as a reference standard for LY288513 in many of the tests. In the elevated plus-maze, LY288513 (3, 10 mg/kg, IP; 10, 30 mg/kg, PO) produced an anxiolytic-like action in mice with a magnitude of effect similar to that of diazepam. However, unlike diazepam, LY288513 produced no overt clinical signs and did not affect muscle tone, neuromuscular coordination, or sensorimotor reactivity. Also, in contrast to diazepam, LY288513 did not produce changes in the thresholds for electroshock- or pentylenetetrazol-induced convulsions. High doses of LY288513 (1000 mg/kg, PO) were required to reduce spontaneous activity levels, decrease body temperature, or potentiate the CNS-depressant effects of hexobarbital. LY288513 had no analgesic activity in mouse writhing or tail-flick tests. Electrophysiological studies in anesthetized rats showed that acute administration of LY288513 decreased the number of spontaneously active dopamine neurons in the substantia nigra and ventral tegmental area. However, LY288513 did not produce catalepsy. These data indicate that LY288513 possess both anxiolytic and antipsychotic potential.