5-HT_2C Agonists Modulate Schizophrenia-Like Behaviors in Mice

All FDA-approved antipsychotic drugs (APDs) target primarily dopamine D₂ or serotonin (5-HT_2A) receptors, or both; however, these medications are not universally effective, they may produce undesirable side effects, and provide only partial amelioration of negative and cognitive symptoms. The heterogeneity of pharmacological responses in schizophrenic patients suggests that additional drug targets may be effective in improving aspects of this syndrome. Recent evidence suggests that 5-HT_2C receptors may be a promising target for schizophrenia since their activation reduces mesolimbic nigrostriatal dopamine release (which conveys antipsychotic action), they are expressed almost exclusively in CNS, and have weight-loss-promoting capabilities. A difficulty in developing 5-HT_2C agonists is that most ligands also possess 5-HT_2B and/or 5-HT_2A activities. We have developed selective 5-HT_2C ligands and herein describe their preclinical effectiveness for treating schizophrenia-like behaviors. JJ-3-45, JJ-3-42, and JJ-5-34 reduced amphetamine-stimulated hyperlocomotion, restored amphetamine-disrupted prepulse inhibition, improved social behavior, and novel object recognition memory in NMDA receptor hypofunctioning NR1-knockdown mice, and were essentially devoid of catalepsy. However, they decreased motivation in a breakpoint assay and did not promote reversal learning in MK-801-treated mice. Somewhat similar effects were observed with lorcaserin, a 5-HT_2C agonist with potent 5-HT_2B and 5-HT_2A agonist activities, which is approved for treating obesity. Microdialysis studies revealed that both JJ-3-42 and lorcaserin reduced dopamine efflux in the infralimbic cortex, while only JJ-3-42 decreased it in striatum. Collectively, these results provide additional evidence that 5-HT_2C receptors are suitable drug targets with fewer side effects, greater therapeutic selectivity, and enhanced efficacy for treating schizophrenia and related disorders than current APDs.