Skip to main content

Slow-release delivery enhances the pharmacological properties of oral 5-hydroxytryptophan: mouse proof-of-concept.

Publication ,  Journal Article
Jacobsen, JPR; Oh, A; Bangle, R; Roberts, WL; Royer, EL; Modesto, N; Windermere, SA; Yi, Z; Vernon, R; Cajina, M; Urs, NM; Snyder, JC ...
Published in: Neuropsychopharmacology
November 2019

5-hydroxytryptophan (5-HTP) has shown therapeutic promise in a range of human CNS disorders. But native 5-HTP immediate release (IR) is poorly druggable, as rapid absorption causes rapid onset of adverse events, and rapid elimination causes fluctuating exposure. Recently, we reported that 5-HTP delivered as slow-release (SR) in mice augmented the brain pro-serotonergic effect of selective serotonin reuptake inhibitors (SSRIs), without the usual adverse events associated with 5-HTP IR. However, our previous study entailed translational limitations, in terms of route, dose, and duration. Here we modeled oral 5-HTP SR in mice by administering 5-HTP via the food. We modeled oral SSRI treatment via fluoxetine in the water, in a regimen recapitulating clinical pharmacokinetics and pharmacodynamics. 5-HTP SR produced plasma 5-HTP levels well within the range enhancing brain 5-HT function in humans. 5-HTP SR robustly increased brain 5-HT synthesis and levels. When administered with an SSRI, 5-HTP SR enhanced 5-HT-sensitive behaviors and neurotrophic mRNA expression. 5-HTP SR's pro-serotonergic effects were stronger in mice with endogenous brain 5-HT deficiency. In a comprehensive screen, 5-HTP SR was devoid of overt toxicological effects. The present preclinical data, appreciated in the context of published 5-HTP clinical data, suggest that 5-HTP SR could represent a new therapeutic approach to the plethora of CNS disorders potentially treatable with a pro-serotonergic drug. 5-HTP SR might in particular be therapeutically relevant when brain 5-HT deficiency is pathogenic and as an adjunctive augmentation therapy to SSRI therapy.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Neuropsychopharmacology

DOI

EISSN

1740-634X

Publication Date

November 2019

Volume

44

Issue

12

Start / End Page

2082 / 2090

Location

England

Related Subject Headings

  • Selective Serotonin Reuptake Inhibitors
  • Psychiatry
  • Proof of Concept Study
  • Mice, Transgenic
  • Male
  • Fluoxetine
  • Female
  • Brain Chemistry
  • Behavior, Animal
  • Animals
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Jacobsen, J. P. R., Oh, A., Bangle, R., Roberts, W. L., Royer, E. L., Modesto, N., … Caron, M. G. (2019). Slow-release delivery enhances the pharmacological properties of oral 5-hydroxytryptophan: mouse proof-of-concept. Neuropsychopharmacology, 44(12), 2082–2090. https://doi.org/10.1038/s41386-019-0400-1
Jacobsen, Jacob P. R., Adrianna Oh, Rachel Bangle, Wendy L. Roberts, Elizabeth L. Royer, Nathan Modesto, Sonora A. Windermere, et al. “Slow-release delivery enhances the pharmacological properties of oral 5-hydroxytryptophan: mouse proof-of-concept.Neuropsychopharmacology 44, no. 12 (November 2019): 2082–90. https://doi.org/10.1038/s41386-019-0400-1.
Jacobsen JPR, Oh A, Bangle R, Roberts WL, Royer EL, Modesto N, et al. Slow-release delivery enhances the pharmacological properties of oral 5-hydroxytryptophan: mouse proof-of-concept. Neuropsychopharmacology. 2019 Nov;44(12):2082–90.
Jacobsen, Jacob P. R., et al. “Slow-release delivery enhances the pharmacological properties of oral 5-hydroxytryptophan: mouse proof-of-concept.Neuropsychopharmacology, vol. 44, no. 12, Nov. 2019, pp. 2082–90. Pubmed, doi:10.1038/s41386-019-0400-1.
Jacobsen JPR, Oh A, Bangle R, Roberts WL, Royer EL, Modesto N, Windermere SA, Yi Z, Vernon R, Cajina M, Urs NM, Snyder JC, Nicholls PJ, Sachs BD, Caron MG. Slow-release delivery enhances the pharmacological properties of oral 5-hydroxytryptophan: mouse proof-of-concept. Neuropsychopharmacology. 2019 Nov;44(12):2082–2090.

Published In

Neuropsychopharmacology

DOI

EISSN

1740-634X

Publication Date

November 2019

Volume

44

Issue

12

Start / End Page

2082 / 2090

Location

England

Related Subject Headings

  • Selective Serotonin Reuptake Inhibitors
  • Psychiatry
  • Proof of Concept Study
  • Mice, Transgenic
  • Male
  • Fluoxetine
  • Female
  • Brain Chemistry
  • Behavior, Animal
  • Animals