5-HT2C Agonists Modulate Schizophrenia-Like Behaviors in Mice

Vladimir M. Pogorelov, Ramona M. Rodriguiz, Jianjun Cheng, Mei Huang, Claire M. Schmerberg, Herbert Y. Meltzer, Bryan L. Roth, Alan P. Kozikowski, William C. Wetsel

Research output: Research - peer-reviewArticle

  • 2 Citations

Abstract

All FDA-approved antipsychotic drugs (APDs) target primarily dopamine D2 or 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-HT2C 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-HT2C agonists is that most ligands also possess 5-HT2B and/or 5-HT2A activities. We have developed selective 5-HT2C 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-HT2C agonist with potent 5-HT2B and 5-HT2A 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-HT2C receptors are suitable drug targets with fewer side effects, greater therapeutic selectivity, and enhanced efficacy for treating schizophrenia and related disorders than current APDs.Neuropsychopharmacology advance online publication, 12 April 2017; doi:10.1038/npp.2017.52.

LanguageEnglish (US)
JournalNeuropsychopharmacology
DOIs
StateAccepted/In press - Apr 12 2017

Fingerprint

Serotonin
Schizophrenia
Antipsychotic Agents
Dopamine
Amphetamine
Ligands
lorcaserin
Reversal Learning
Catalepsy
Drug Receptors
Neurobehavioral Manifestations
Dizocilpine Maleate
Social Behavior
Microdialysis
Therapeutic Uses
Publications
Motivation
Weight Loss
Obesity
Pharmacology

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Cite this

Pogorelov, V. M., Rodriguiz, R. M., Cheng, J., Huang, M., Schmerberg, C. M., Meltzer, H. Y., ... Wetsel, W. C. (2017). 5-HT2C Agonists Modulate Schizophrenia-Like Behaviors in Mice. Neuropsychopharmacology. DOI: 10.1038/npp.2017.52

5-HT2C Agonists Modulate Schizophrenia-Like Behaviors in Mice. / Pogorelov, Vladimir M.; Rodriguiz, Ramona M.; Cheng, Jianjun; Huang, Mei; Schmerberg, Claire M.; Meltzer, Herbert Y.; Roth, Bryan L.; Kozikowski, Alan P.; Wetsel, William C.

In: Neuropsychopharmacology, 12.04.2017.

Research output: Research - peer-reviewArticle

Pogorelov, VM, Rodriguiz, RM, Cheng, J, Huang, M, Schmerberg, CM, Meltzer, HY, Roth, BL, Kozikowski, AP & Wetsel, WC 2017, '5-HT2C Agonists Modulate Schizophrenia-Like Behaviors in Mice' Neuropsychopharmacology. DOI: 10.1038/npp.2017.52
Pogorelov VM, Rodriguiz RM, Cheng J, Huang M, Schmerberg CM, Meltzer HY et al. 5-HT2C Agonists Modulate Schizophrenia-Like Behaviors in Mice. Neuropsychopharmacology. 2017 Apr 12. Available from, DOI: 10.1038/npp.2017.52
Pogorelov, Vladimir M. ; Rodriguiz, Ramona M. ; Cheng, Jianjun ; Huang, Mei ; Schmerberg, Claire M. ; Meltzer, Herbert Y. ; Roth, Bryan L. ; Kozikowski, Alan P. ; Wetsel, William C./ 5-HT2C Agonists Modulate Schizophrenia-Like Behaviors in Mice. In: Neuropsychopharmacology. 2017
@article{3d64f3561d4c4246ade6bf5ea0ee1218,
title = "5-HT2C Agonists Modulate Schizophrenia-Like Behaviors in Mice",
abstract = "All FDA-approved antipsychotic drugs (APDs) target primarily dopamine D2 or 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-HT2C 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-HT2C agonists is that most ligands also possess 5-HT2B and/or 5-HT2A activities. We have developed selective 5-HT2C 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-HT2C agonist with potent 5-HT2B and 5-HT2A 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-HT2C receptors are suitable drug targets with fewer side effects, greater therapeutic selectivity, and enhanced efficacy for treating schizophrenia and related disorders than current APDs.Neuropsychopharmacology advance online publication, 12 April 2017; doi:10.1038/npp.2017.52.",
author = "Pogorelov, {Vladimir M.} and Rodriguiz, {Ramona M.} and Jianjun Cheng and Mei Huang and Schmerberg, {Claire M.} and Meltzer, {Herbert Y.} and Roth, {Bryan L.} and Kozikowski, {Alan P.} and Wetsel, {William C.}",
year = "2017",
month = "4",
doi = "10.1038/npp.2017.52",
journal = "Neuropsychopharmacology",
issn = "0893-133X",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - 5-HT2C Agonists Modulate Schizophrenia-Like Behaviors in Mice

AU - Pogorelov,Vladimir M.

AU - Rodriguiz,Ramona M.

AU - Cheng,Jianjun

AU - Huang,Mei

AU - Schmerberg,Claire M.

AU - Meltzer,Herbert Y.

AU - Roth,Bryan L.

AU - Kozikowski,Alan P.

AU - Wetsel,William C.

PY - 2017/4/12

Y1 - 2017/4/12

N2 - All FDA-approved antipsychotic drugs (APDs) target primarily dopamine D2 or 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-HT2C 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-HT2C agonists is that most ligands also possess 5-HT2B and/or 5-HT2A activities. We have developed selective 5-HT2C 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-HT2C agonist with potent 5-HT2B and 5-HT2A 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-HT2C receptors are suitable drug targets with fewer side effects, greater therapeutic selectivity, and enhanced efficacy for treating schizophrenia and related disorders than current APDs.Neuropsychopharmacology advance online publication, 12 April 2017; doi:10.1038/npp.2017.52.

AB - All FDA-approved antipsychotic drugs (APDs) target primarily dopamine D2 or 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-HT2C 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-HT2C agonists is that most ligands also possess 5-HT2B and/or 5-HT2A activities. We have developed selective 5-HT2C 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-HT2C agonist with potent 5-HT2B and 5-HT2A 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-HT2C receptors are suitable drug targets with fewer side effects, greater therapeutic selectivity, and enhanced efficacy for treating schizophrenia and related disorders than current APDs.Neuropsychopharmacology advance online publication, 12 April 2017; doi:10.1038/npp.2017.52.

UR - http://www.scopus.com/inward/record.url?scp=85017456469&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85017456469&partnerID=8YFLogxK

U2 - 10.1038/npp.2017.52

DO - 10.1038/npp.2017.52

M3 - Article

JO - Neuropsychopharmacology

T2 - Neuropsychopharmacology

JF - Neuropsychopharmacology

SN - 0893-133X

ER -