5-HT2C receptor agonist anorectic efficacy potentiated by 5-HT1B receptor agonist coapplication: an effect mediated via increased proportion of pro-opiomelanocortin neurons activated

Barbora Doslikova, Alastair S. Garfield, Jill Shaw, Mark L. Evans, Denis Burdakov, Brian Billups, Lora K. Heisler*

*Corresponding author for this work

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

An essential component of the neural network regulating ingestive behavior is the brain 5-hydroxytryptamine2C receptor (5-HT2CR), agonists of which suppress food intake and were recently approved for obesity treatment by the US Food and Drug Administration. 5-HT2CR-regulated appetite is mediated primarily through activation of hypothalamic arcuate nucleus (ARC) pro-opiomelanocortin (POMC) neurons, which are also disinhibited through a 5-HT1BR-mediated suppression of local inhibitory inputs. Here we investigated whether 5-HT2CR agonist anorectic potency could be significantly enhanced by coadministration of a 5-HT1BR agonist and whether this was associated with augmented POMC neuron activation on the population and/or single-cell level. The combined administration of subanorectic concentrations of 5-HT2CR and 5-HT1BR agonists produced a 45% reduction in food intake and significantly greater in vivo ARC neuron activation in mice. The chemical phenotype of activated ARC neurons was assessed by monitoring agonist-induced cellular activity via calcium imaging in mouse POMC-EGFP brain slices, which revealed that combined agonists activated significantly more POMC neurons (46%) compared with either drug alone (similar to 25% each). Single-cell electrophysiological analysis demonstrated that 5-HT2CR/5-HT1BR agonist coadministration did not significantly potentiate the firing frequency of individual ARC POMC-EGFP cells compared with agonists alone. These data indicate a functional heterogeneity ofARCPOMCneurons by revealing distinct subpopulations of POMC cells activated by 5-HT(2C)Rs and disinhibited by 5-HT(1B)Rs. Therefore, coadministration of a 5-HT1BR agonist potentiates the anorectic efficacy of 5-HT2CR compounds by increasing the number, but not the magnitude, of activated ARC POMC neurons and is of therapeutic relevance to obesity treatment.

Original languageEnglish
Pages (from-to)9800-9804
Number of pages5
JournalJournal of Neuroscience
Volume33
Issue number23
DOIs
Publication statusPublished - 5 Jun 2013

Keywords

  • food-intake
  • energy-balance
  • POMC neurons
  • serotonin
  • fenfluramine
  • hypothalamus
  • population
  • hypophagia
  • pathways
  • anorexia

Cite this

5-HT2C receptor agonist anorectic efficacy potentiated by 5-HT1B receptor agonist coapplication : an effect mediated via increased proportion of pro-opiomelanocortin neurons activated. / Doslikova, Barbora; Garfield, Alastair S.; Shaw, Jill; Evans, Mark L.; Burdakov, Denis; Billups, Brian; Heisler, Lora K.

In: Journal of Neuroscience, Vol. 33, No. 23, 05.06.2013, p. 9800-9804.

Research output: Contribution to journalArticle

Doslikova, Barbora ; Garfield, Alastair S. ; Shaw, Jill ; Evans, Mark L. ; Burdakov, Denis ; Billups, Brian ; Heisler, Lora K. / 5-HT2C receptor agonist anorectic efficacy potentiated by 5-HT1B receptor agonist coapplication : an effect mediated via increased proportion of pro-opiomelanocortin neurons activated. In: Journal of Neuroscience. 2013 ; Vol. 33, No. 23. pp. 9800-9804.
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abstract = "An essential component of the neural network regulating ingestive behavior is the brain 5-hydroxytryptamine2C receptor (5-HT2CR), agonists of which suppress food intake and were recently approved for obesity treatment by the US Food and Drug Administration. 5-HT2CR-regulated appetite is mediated primarily through activation of hypothalamic arcuate nucleus (ARC) pro-opiomelanocortin (POMC) neurons, which are also disinhibited through a 5-HT1BR-mediated suppression of local inhibitory inputs. Here we investigated whether 5-HT2CR agonist anorectic potency could be significantly enhanced by coadministration of a 5-HT1BR agonist and whether this was associated with augmented POMC neuron activation on the population and/or single-cell level. The combined administration of subanorectic concentrations of 5-HT2CR and 5-HT1BR agonists produced a 45{\%} reduction in food intake and significantly greater in vivo ARC neuron activation in mice. The chemical phenotype of activated ARC neurons was assessed by monitoring agonist-induced cellular activity via calcium imaging in mouse POMC-EGFP brain slices, which revealed that combined agonists activated significantly more POMC neurons (46{\%}) compared with either drug alone (similar to 25{\%} each). Single-cell electrophysiological analysis demonstrated that 5-HT2CR/5-HT1BR agonist coadministration did not significantly potentiate the firing frequency of individual ARC POMC-EGFP cells compared with agonists alone. These data indicate a functional heterogeneity ofARCPOMCneurons by revealing distinct subpopulations of POMC cells activated by 5-HT(2C)Rs and disinhibited by 5-HT(1B)Rs. Therefore, coadministration of a 5-HT1BR agonist potentiates the anorectic efficacy of 5-HT2CR compounds by increasing the number, but not the magnitude, of activated ARC POMC neurons and is of therapeutic relevance to obesity treatment.",
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T2 - an effect mediated via increased proportion of pro-opiomelanocortin neurons activated

AU - Doslikova, Barbora

AU - Garfield, Alastair S.

AU - Shaw, Jill

AU - Evans, Mark L.

AU - Burdakov, Denis

AU - Billups, Brian

AU - Heisler, Lora K.

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AB - An essential component of the neural network regulating ingestive behavior is the brain 5-hydroxytryptamine2C receptor (5-HT2CR), agonists of which suppress food intake and were recently approved for obesity treatment by the US Food and Drug Administration. 5-HT2CR-regulated appetite is mediated primarily through activation of hypothalamic arcuate nucleus (ARC) pro-opiomelanocortin (POMC) neurons, which are also disinhibited through a 5-HT1BR-mediated suppression of local inhibitory inputs. Here we investigated whether 5-HT2CR agonist anorectic potency could be significantly enhanced by coadministration of a 5-HT1BR agonist and whether this was associated with augmented POMC neuron activation on the population and/or single-cell level. The combined administration of subanorectic concentrations of 5-HT2CR and 5-HT1BR agonists produced a 45% reduction in food intake and significantly greater in vivo ARC neuron activation in mice. The chemical phenotype of activated ARC neurons was assessed by monitoring agonist-induced cellular activity via calcium imaging in mouse POMC-EGFP brain slices, which revealed that combined agonists activated significantly more POMC neurons (46%) compared with either drug alone (similar to 25% each). Single-cell electrophysiological analysis demonstrated that 5-HT2CR/5-HT1BR agonist coadministration did not significantly potentiate the firing frequency of individual ARC POMC-EGFP cells compared with agonists alone. These data indicate a functional heterogeneity ofARCPOMCneurons by revealing distinct subpopulations of POMC cells activated by 5-HT(2C)Rs and disinhibited by 5-HT(1B)Rs. Therefore, coadministration of a 5-HT1BR agonist potentiates the anorectic efficacy of 5-HT2CR compounds by increasing the number, but not the magnitude, of activated ARC POMC neurons and is of therapeutic relevance to obesity treatment.

KW - food-intake

KW - energy-balance

KW - POMC neurons

KW - serotonin

KW - fenfluramine

KW - hypothalamus

KW - population

KW - hypophagia

KW - pathways

KW - anorexia

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DO - 10.1523/JNEUROSCI.4326-12.2013

M3 - Article

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EP - 9804

JO - Journal of Neuroscience

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