title: 5-HT2CAgonists Modulate Schizophrenia-Like Behaviors in Mice.
abstract: All FDA-approved antipsychotic drugs (APDs) target primarily dopamine D2or serotonin (5-HT2A) 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-HT2Creceptors 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-HT2Cagonists is that most ligands also possess 5-HT2Band/or 5-HT2Aactivities. We have developed selective 5-HT2Cligands 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-HT2Cagonist with potent 5-HT2Band 5-HT2Aagonist 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-HT2Creceptors are suitable drug targets with fewer side effects, greater therapeutic selectivity, and enhanced efficacy for treating schizophrenia and related disorders than current APDs.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.
authors.forename: Vladimir M
authors.initials: VM
authors.lastname: Pogorelov
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.|Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, USA.
authors.forename: Ramona M
authors.initials: RM
authors.lastname: Rodriguiz
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois, Chicago, IL, USA.
authors.forename: Jianjun
authors.identifier: http://orcid.org/0000-0001-6065-2682
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Psychiatry and Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Schmerberg
authors.affiliation: Department of Psychiatry and Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
authors.affiliation: National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, NC, USA.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois, Chicago, IL, USA.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.|Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, USA.|Departments of Cell Biology and Neurobiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
mesh_terms: D000161:Acoustic Stimulation / Q000009:adverse effects; D000661:Amphetamine / Q000633:toxicity; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002375:Catalepsy / Q000188:drug therapy / Q000209:etiology; D004193:Discrimination Learning / Q000187:drug effects; D004195:Disease Models, Animal; D004347:Drug Interactions; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009042:Motivation / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D065808:Prepulse Inhibition / Q000187:drug effects*; D021641:Recognition, Psychology / Q000187:drug effects; D012559:Schizophrenia / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000737:chemistry / Q000627:therapeutic use*; D012919:Social Behavior
chemical_list: D001552:Benzazepines; D018377:Neurotransmitter Agents; D058826:Serotonin 5-HT2 Receptor Agonists; C506658:lorcaserin; D000661:Amphetamine