Selective serotonin 5-HT_2A receptor antagonist EMD 281014 improves delayed matching performance in young and aged rhesus monkeys

Rationale: The superior cognitive effects of atypical neuroleptics over typical agents reported in the schizophrenia literature are often attributed to the more prominent antagonist activity of the atypical drugs at serotonin 5HT_2A receptors. However, atypical neuroleptics also have activity at many additional neurotransmitter receptors and few studies have specifically (and prospectively) tested the hypothesis that 5HT_2A antagonism alone results in enhanced cognitive function. Objectives: The purpose of this study was to evaluate the selective 5-HT_2A antagonist, 7-{4-[2-(4-fluoro- phenyl)-ethyl]-piperazine-1-carbonyl}-1H-indole-3-carbonitrile HCl (EMD 281014) in young and aged monkeys in a test designed to assess working memory function. Methods: Four oral doses (0.1, 1.0, 3.0, and 10.0 mg/kg) of EMD 281014 were evaluated in six young adult (mean age=9.2 years) and eight aged rhesus macaques (mean age=24.9 years) trained to perform a computer-assisted delayed matching-to-sample (DMTS) task. Results: Depending on dose, EMD 281014 improved DMTS accuracy in young and aged monkeys primarily at either the medium or long retention intervals. While the latencies associated with incorrect color selections (choices latencies) tended to be longer than those associated with correct selections (particularly in the aged subjects) under baseline conditions, there were no significant effects of EMD 281014 on either sample or choice latencies in either age group. In addition, no adverse effects were observed across the range of doses evaluated in either cohort of animals. Conclusion: These experiments, conducted in a non-human primate model, suggest that selective 5HT_2A antagonists such as EMD 281014 could offer therapeutic benefit to younger and older psychiatric patients by improving working memory function.