Original Article

5-HT2C Agonists Modulate Schizophrenia-Like Behaviors in Mice

  • Neuropsychopharmacology volume 42, pages 21632177 (2017)
  • doi:10.1038/npp.2017.52
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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.

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Acknowledgements

We thank Shaina Gong, Vineet Nadkarni, Paul Skiba, Christopher Means, Liza Stephanz, Theodore Rhodes, and Aran Marati for assisting with some of the behavioral testing and Jiechun Zhou for genotyping and maintaining the mice. Some of the behavioral experiments were conducted with equipment and software purchased with a North Carolina Biotechnology Center grant. We also received the NR1 mice from Dr Amy J Ramsey (University of Toronto, Toronto, ON, Canada) and they were further backcrossed for more than 10 generations to C57BL/6 and 129X1/Sv mice as separate lines. We have no competing interests in relation to the work described herein. Dr Roth has received compensation as Deputy Editor of the Journal of Clinical Investigation and as consultant over the past 12 months from Pfizer Pharmaceuticals. Dr Roth has received research support from Merck Pharmaceuticals and Asubio Pharmaceuticals over the past 12 months. Dr Wetsel has received research support over the past 12 months from Rugen Holdings (Cayman) Limited. Dr Meltzer has received funding from Sumitomo Dainippon, Sunovion, Janssen Pharmaceuticals, Auspex, Lundbeck, and the Weisman Family Foundation. Drs Meltzer, Roth, Kozikowski, and Wetsel receive NIH funding. We are indebted to the NIMH (Grant No. R01MH99993) for financial support for this work. Some work in this manuscript from Drs Roth and Wetsel was supported by U19MH082441.

Author information

Author notes

    • Jianjun Cheng

    Current address: iHuman Institute, ShanghaiTech University, Pudong New District, Shanghai, China.

Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA

    • Vladimir M Pogorelov
    • , Ramona M Rodriguiz
    • , Claire M Schmerberg
    •  & William C Wetsel
  2. Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, USA

    • Ramona M Rodriguiz
    •  & William C Wetsel
  3. Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois, Chicago, IL, USA

    • Jianjun Cheng
    •  & Alan P Kozikowski
  4. Department of Psychiatry and Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    • Mei Huang
    •  & Herbert Y Meltzer
  5. 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

    • Bryan L Roth
  6. Departments of Cell Biology and Neurobiology, Duke University Medical Center, Durham, NC, USA

    • William C Wetsel

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Corresponding author

Correspondence to William C Wetsel.

Supplementary information

Supplementary Information accompanies the paper on the Neuropsychopharmacology website (http://www.nature.com/npp)