The behavioral effects of acute and chronic JL 13, a putative antipsychotic, in Cebus non-human primates

Rationale: Neuroleptic or antipsychotic drugs are the mainstay of treating acute and chronic psychosis. However, their efficacy is offset by a wide ar ray of side effects, especially extrapyramidal syndromes (EPS). In an attem pt to develop novel antipsychotic agents, several animal models have been d eveloped to characterize the profile of new chemical entities. Objective: T o evaluate the behavioral characteristics of JL 13, a potentially unique an tipsychotic agent, three separate studies across a wide dose range in Cebus monkeys were conducted and compared with two studies of oral and parentera l haloperidol. Methods: Twelve Cebus monkeys were tested with single i.m. d oses of JL 13 (0.1-2.5 mg/kg), single p.o. doses (1.0-50.0 mg/kg), and 35 d ays of continuous p.o. (up to 25 mg/kg) treatments and were blindly evaluat ed. The same twelve monkeys were also tested with haloperidol i.m. (0.01-0. 25 mg/kg) and nine of the monkeys also received haloperidol p.o. (0.1-5.0 m g/kg). Behaviors scored included sedation/arousal, locomotor activity, EPS of parkinsonism and dystonia, as well as reactivity. Results: JL 13 produce d mild to moderate and dose-related increased sedation and decreased locomo tor activity. Minimal decreases in eye blinking rates were also noted as a consequence of sedation. Mild dystonia and parkinsonian symptoms of slow mo vement developed at the highest dose tested of 50 mg/kg p.o. in only 6 of 1 2 monkeys. This is 50 times higher than oral doses of haloperidol that woul d be needed to produce similar EPS effects. Dose-related EPS of dystonia an d bradykinesia occurred in relation to decreased locomotor activity and rea ctivity to stimuli with haloperidol i.m. and p.o., which are features chara cteristically seen with traditional neuroleptics. Conclusions: The behavior al effects of JL 13 in non-human primates suggest this compound is well tol erated and may have a favorable antipsychotic benefit/risk ratio in the cli nic, especially if antipsychotic efficacy occurs at doses well below those that can cause EPS.