Original Research
Long-term Treatment of Insulin-insensitive Mares with Cabergoline: Effects on Prolactin and Melanocyte Stimulating Hormone Responses to Sulpiride and on Indices of Insulin Sensitivity

https://doi.org/10.1016/j.jevs.2013.12.015Get rights and content

Abstract

The main experiment assessed whether the inhibitory effects of the dopamine agonist, cabergoline, on prolactin and α-melanocyte stimulating hormone (MSH) concentrations would persist throughout a longer-term administration (65 days). The possible effect of cabergoline on insulin sensitivity was also studied. Ten mares known to be insulin insensitive were allotted to two groups (treated vs. control). An insulin challenge, a glucose tolerance test, and a sulpiride challenge were administered before treatment. On day 0, treated mares (n = 5) received an injection of 5 mg cabergoline in slow-release vehicle; control mares (n = 5) received an equivalent vehicle injection. Injections were repeated every 10 days for a total of seven injections. Sulpiride challenges were done 1 day before each cabergoline treatment to assess possible refractoriness to the treatment. Behavior and hair coat density were also monitored. Plasma prolactin was suppressed (P < .01) to undetectable levels in mares receiving cabergoline; control mares had robust prolactin responses to each sulpiride injection. There was no indication of refractoriness to cabergoline over time. Plasma MSH concentrations after sulpiride were also suppressed (P < .05) by cabergoline. After treatment, neither the glucose response to insulin nor the insulin response to glucose differed (P > .1) between groups. No behavioral changes were noted because of treatment. Weight of hair samples indicated that cabergoline perturbed (P < .05) winter coat growth. It is concluded that 5 mg of cabergoline in slow-release vehicle administered every 10 days is an effective way of delivering dopaminergic activity to mares that results in no noticeable detrimental effects and no refractoriness to the drug.

Introduction

Recent research by Hebert et al [1] indicated that the long-acting dopamine agonist, cabergoline, in a slow-release formulation suppressed plasma prolactin secretion in mares for at least 10 days after a single intramuscular injection. Moreover, the suppression was complete, even in the face of low-dose sulpiride challenges [1], which, in the absence of cabergoline, caused relatively consistent elevations in prolactin secretion in both mares and estrogen-treated geldings [1], [2]. Similarly, injections of pergolide in slow-release vehicle suppressed prolactin secretion, but for a much shorter period of time [1]. Because only one injection of cabergoline was tested in the experiment of Hebert et al [1], the possibility of long-term detrimental effects or refractoriness could not be assessed.

Hebert et al [1] suggested that the dopaminergic effects of cabergoline observed for prolactin secretion would likely be similar for melanotrope hormonal output, primarily α-melanocyte stimulating hormone (MSH) and perhaps adrenocorticotropin in pituitary pars intermedia dysfunction (PPID), because of the similar physiologic control by dopamine (via the portal blood for lactotropes and via neural input for melanotropes [3], [4]). Hebert et al [1] did not include plasma MSH concentrations in their report, thus we are providing those data herein as a prelude to the main experiment. Recently, we have reported that mares displaying hyperleptinemia, hyperinsulinemia, and a diminished response to injected insulin also have exaggerated MSH responses to sulpiride and thyrotropin releasing hormone [5], similar to, but not as great a magnitude of, horses displaying symptoms of PPID [6], [7]. Currently, horses and ponies diagnosed with PPID are treated with pergolide mesylate, a dopamine agonist known by its trade name Prascend. Although it has been reported to have good success rate, the medication needs to be fed daily for the duration of the horse's life [8].

The present (main) experiment was designed primarily to test the long-term effects of repeated cabergoline injections (every 10 days for a total of seven injections) on prolactin and MSH concentrations. Insulin-insensitive mares were monitored for any overt detrimental effects to cabergoline injection (e.g., behavioral changes), for any sign of refractoriness to cabergoline, and for any changes in hair coat that might be predicted from previous reports in which inadvertent immunization of pony mares against prolactin in the winter-delayed hair shedding, later in the spring [9]. In addition, given the similarity in MSH response to secretagogue [5] between the insulin-insensitive horses, first described by Gentry et al [10] and subsequently characterized by Cartmill et al [11] and Caltabilota et al [12], and horses either displaying or testing positive for PPID, we also evaluated whether cabergoline injections would improve the insulin sensitivity (i.e., increase the glucose response to insulin or reduce the insulin response to glucose infusion) in these insulin-insensitive mares as part of our ongoing study of their characteristics.

Section snippets

Materials and Methods

Procedures used in these experiments were approved by the Institutional Animal Care and Use Committee of the Louisiana State University Agricultural Center.

Preliminary Experiment

Mean concentrations of MSH in control mares and in mares treated with cabergoline are presented in Figure 1. All mares had a robust MSH response in the first 10 minutes after injection of sulpiride on day −1, before vehicle or cabergoline injection, as did the control mares on day 10 after vehicle injection (time effect; P < .01). In contrast, mares receiving 5 mg of cabergoline 10 days earlier had little to no response to the injected sulpiride (differed from controls at times 10 and

Discussion

Hebert et al [1] was the first to report the efficacy of cabergoline in slow-release vehicle for the suppression of prolactin secretion in horses. In the first experiment in that report, a single intramuscular injection of 5 mg of cabergoline reduced basal (i.e., unstimulated) plasma prolactin concentrations for at least 5 days in geldings, and in a second experiment, the same injection suppressed basal and sulpiride-stimulated prolactin concentrations within 30 minutes and for at least

Acknowledgments

The authors thank A. F. Parlow and the National Institute of Diabetes and Digestive and Kidney Diseases, National Hormone and Pituitary Program, Harbor-University of California Los Angeles Medical Center, Torrance, CA, for reagents.

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    Approved for publication by the Director of the Louisiana Agricultural Experiment Station as manuscript number 2013-230-9526.

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