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Negative allosteric modulation of alpha 5-containing GABAA receptors engenders antidepressant-like effects and selectively prevents age-associated hyperactivity in tau-depositing mice

Abstract

Rationale

Associated with frank neuropathology, patients with Alzheimer’s disease suffer from a host of neuropsychiatric symptoms that include depression, apathy, agitation, and aggression. Negative allosteric modulators (NAMs) of α5-containing GABAA receptors have been suggested to be a novel target for antidepressant action. We hypothesized that pharmacological modulation of this target would engender increased motivation in stressful environments.

Methods

We utilized electrophysiological recordings from Xenopus oocytes and behavioral measures in mice to address this hypothesis.

Results

In the forced-swim assay in mice that detects antidepressant drugs, the α5β3γ2 GABAΑ receptor NAM, RY-080 produced a marked antidepressant phenotype. Another compound, PWZ-029, was characterized as an α5β3γ2 receptor NAM of lower intrinsic efficacy in electrophysiological studies in Xenopus oocytes. In contrast to RY-080, PWZ-029 was only moderately active in the forced-swim assay and the α5β3γ2 receptor antagonist, Xli-093, was not active at all. The effects of RY-080 were prevented by the non-selective benzodiazepine receptor antagonist flumazenil as well as by the selective ligands, PWZ-029 and Xli-093. These findings demonstrate that this effect of RY-080 is driven by negative allosteric modulation of α5βγ2 GABAA receptors. RY-080 was not active in the tail-suspension test. We also demonstrated a reduction in the age-dependent hyperactivity exhibited by transgenic mice that accumulate pathological tau (rTg4510 mice) by RY-080. The decrease in hyperactivity by RY-080 was selective for the hyperactivity of the rTg4510 mice since the locomotion of control strains of mice were not significantly affected by RY-080.

Conclusions

α5βγ2 GABAA receptor NAMs might function as a pharmacological treatment for mood, amotivational syndromes, and psychomotor agitation in patients with Alzheimer’s and other neurodegenerative disorders.

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Abbreviations

β-CCE:

3-carboethoxy-beta-carboline

L655,708:

ethyl (13aS)-7-methoxy-9-oxo-11,12,13,13a–tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate

MRK-016:

3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)-pyrazolo[1,5-d]-[1,2,4]triazine

PWZ-029:

8-chloro-3-(methoxymethyl)-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one

RO4938581:

(3-bromo-10-(difluoromethyl)-9H–benzo[f]imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]diazepine)

RY-080:

ethyl 8-ethynyl-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

XLi-093:

Bis[8-ethynyl-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid] 1,3-propanediyl ester hydrate

References

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Acknowledgments

We thank the following granting agencies for support: MH-096463 and NS-076517, as well as the Austrian Science Fund (FWF I2306). We also acknowledge UW-Milwaukee’s Shimadzu Laboratory for Advanced and Applied Analytical Chemistry and support from the Milwaukee Institute of Drug Discovery and the University of Wisconsin Research Foundation.

We are grateful for Trace Murray of the Neuroscience Discovery Group of the Lilly Research Labs for her gracious help in obtaining the rTg4510 mice. We acknowledge excellent technical assistance by Raphael Holzinger.

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Authors and Affiliations

Authors

Contributions

Participated in research design: J. M. Witkin, S. D. Gleason, T. M. Jones, R. Cerne, M, Wakulchik, and M. Ernst.

Conducted experiments: JM Witkin, SD Gleason, M, Wakulchik, and M. Treven.

Contributed new reagents or analytic tools: K. R. Methuku2, R. Cerne, J.W. Cramer, T.M. Jones, M. M. Poe, G. Li, L. A. Arnold, J. M. Schkeryantz1, and J. M. Cook2.

Performed data analysis: JM Witkin, SD Gleason, R. Cern, M. Ernst, and M. Treven.

Wrote or contributed to the writing of the manuscript: All authors.

Corresponding author

Correspondence to Jeffrey M. Witkin.

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Xu, N.Z., Ernst, M., Treven, M. et al. Negative allosteric modulation of alpha 5-containing GABAA receptors engenders antidepressant-like effects and selectively prevents age-associated hyperactivity in tau-depositing mice. Psychopharmacology 235, 1151–1161 (2018). https://doi.org/10.1007/s00213-018-4832-9

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  • DOI: https://doi.org/10.1007/s00213-018-4832-9

Keywords

  • Alpha 5-containing GABAA receptors
  • Antidepressant
  • Tau-Depositing Mice
  • Agitation
  • rTg4510 mice