Comparison of the hypothalamic–pituitary–adrenal axis in MDR1-1Δ and MDR1 wildtype dogs

Authors

  • Katrina L. Mealey DVM, PhD, DACVIM, DACVCP,

    1. Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA.
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  • John M. Gay DVM, PhD, DACVPM,

    1. Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA.
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  • Linda G. Martin DVM, MS, DACVECC,

    1. Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA.
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  • Denise K. Waiting LVT

    1. Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA.
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Address correspondence and reprint requests to:
Katrina L. Mealey, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99164-6610.
E-mail: kmealey@vetmed.wsu.edu

Abstract

Objective: To evaluate the hypothalamic–pituitary–adrenal (HPA) axis in MDR1-1Δ (dogs with the MDR1 mutation associated with ivermectin sensitivity) and MDR1 wildtype dogs.

Design: Prospective study.

Setting: Institutional vivarium.

Animals: Seven healthy Collie dogs.

Measurements: MDR1 genotyping was used for allocation of dogs to 1 of 2 groups: dogs homozygous for the wildtype MDR1 allele (MDR1 wildtype) and those homozygous for the MDR1-1Δ mutation (MDR1 mutant). Blood samples were obtained for determination of cortisol and adrenocorticotropin hormone (ACTH) concentrations under basal conditions, before and after ACTH administration, and before and after dexamethasone administration.

Main results: Significant differences were identified between the MDR1 mutant and MDR1 wildtype groups. Basal plasma cortisol concentrations and cortisol concentrations after ACTH administration were significantly lower in MDR1 mutant dogs as compared with MDR1 wildtype dogs. Plasma ACTH concentrations after dexamethasone administration were significantly lower in MDR1 mutant dogs as compared with MDR1 wildtype dogs.

Conclusions: Results suggest that P-glycoprotein (P-gp) plays a role in regulation of the HPA axis. Furthermore, it appears that the HPA axis in MDR1 mutant dogs that lack P-gp is suppressed compared with MDR1 wildtype dogs. This finding may explain some clinical observations in breeds known to harbor the MDR1 mutation including Collies, Shelties, Australian Shepherds, and others. There is a clinical impression that many of these dogs have worse outcomes in response to stress and, at times, respond poorly to appropriate therapy. HPA axis suppression, secondary to the MDR1 mutation, could result in a relative adrenal insufficiency (RAI) state during times of stress or illness. Further studies are required to determine the relationship between the MDR1 genotype and RAI.

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