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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. Psychopharmacology (Berl) 2018 04;235(4):1151-1161

Date

01/28/2018

Pubmed ID

29374303

DOI

10.1007/s00213-018-4832-9

Scopus ID

2-s2.0-85041000322   14 Citations

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.

Author List

Xu NZ, Ernst M, Treven M, Cerne R, Wakulchik M, Li X, Jones TM, Gleason SD, Morrow D, Schkeryantz JM, Rahman MT, Li G, Poe MM, Cook JM, Witkin JM

Author

James M. Cook PhD University Distinguished Professor in the Chemistry and Biochemistry department at University of Wisconsin - Milwaukee




MESH terms used to index this publication - Major topics in bold

Aging
Allosteric Regulation
Animals
Antidepressive Agents
Benzodiazepines
Depressive Disorder
Dose-Response Relationship, Drug
Female
Flumazenil
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Psychomotor Agitation
Receptors, GABA-A
Xenopus laevis
tau Proteins