Inhibition of Oestradiol‐induced Prolactin Release in a Dual‐Cannulated Ovariectomized Rat Model by Carmoxirole, a Peripherally Restricted Dopamine Agonist

Abstract

Centrally acting dopamine agonists (e.g. bromocriptine) and dopamine transport inhibitors (e.g. GBR12909) are known to inhibit oestradiol-induced prolactin release. The capacity of peripherally restricted compounds to do likewise, however, is unknown. Here, the effects of the peripherally restricted dopamine receptor agonist carmoxirole on oestradiol-induced prolactin release were investigated. Dual-cannulated ovariectomized rats were used, so that a robust, reproducible response to exogenous oestrogen could be induced and sequential blood samples were taken with minimal stress. Carmoxirole (15 mg/kg) inhibited oestradiol-induced prolactin release, similar to bromocriptine and GBR12909. However, carmoxirole also induced a rapid, transient, oestradiol-independent release of prolactin. These data show that peripherally restricted dopamine receptor agonists are sufficient to inhibit oestradiol-induced prolactin release. Like centrally acting compounds, they may therefore be expected to affect the incidence of prolactin-dependent tumours in rat carcinogenesis studies without inducing central-mediated side effects.Understanding the relevance or translation of pre-clinical drug effects to the clinic is critical for accurate human risk assessment for new pharmaceutical agents. In particular, accurate identification of specific mechanisms of serious toxicities observed in non-clinical species, and translation of specific mechanism in human beings can provide a scientific basis with which to evaluate specific risk in human beings. For example, it is known that some endocrine modulators can affect the incidence of particular tumours in life-time rat carcinogenicity bioassays, but not in human beings [1]. More specifically, the centrally active dopamine (D2) receptor agonist, bromocriptine, can induce hypoprolactinaemia in rats and human beings, but increases the incidence of hyperplastic proliferative endometrial lesions and benign and malignant uterine tumours only in rats [2], which has been postulated to be due to a lesser impact of prolactin on ovarian steroidogenesis in human beings [3].Prolactin is a peptide hormone spontaneously produced and secreted by lactotrophs in the anterior lobe of the pituitary gland under control by hypothalamic factors. In the rat, three dopaminergic systems [tuberoinfundibular (TIDA), tuberohypophyseal and periventricular hypophyseal dopaminergic neurons] regulate prolactin release, with the relative contribution varying between reproductive, physiological and pathological stages [4]. Hypothalamic dopaminergic neurons play a central role in the regulation of prolactin release by exerting an effect on the lactotrophs via the D2 receptor [5,6]. However, dopamine can also affect prolactin secretion by acting in the hypothalamus [7,8]. The pituitary lactotroph population is not entirely homogenous; mammosomatotropes, which are particularly common in neonatal rats, are differentiated into lactotrophs under the influence by oestrogens and secrete both prolactin and growth hormone [9]...

A peripherally restricted P2Y 12 receptor antagonist altered rat tumor incidences with no human relevance: Mode of action consistent with dopamine agonism

“…Dopamine from hypothalamic dopaminergic neurons decreases prolactin release by exerting an inhibiting effect on the lactotrophs via the dopamine (D 2 ) receptor [31] . Dopaminergic compounds known to inhibit estradiol-induced prolactin release [24] such as the centrally-acting D 2 agonist bromocriptine are known to alter tumor incidences in female rats with a profile similar to Ticagrelor [26] , [34] . More specifically, bromocriptine can induce hypoprolactinemia in rats and humans, but increases uterine and decreases mammary tumors only in rats, which is postulated to be due to a direct prolactin impact on rat ovarian steroidogenesis in aged rats [34] , [35] .…”

“…However, the QWBA study did demonstrate Ticagrelor levels in the pituitary gland, with the anterior pituitary being outside of the blood brain barrier. Other peripherally-restricted compounds such as the dopamine receptor agonist carmoxirole impacting dopaminergic regulation of prolactin release would be active at this hypophyseal end of the axis [24] . Therefore, it is reasonable to hypothesize that Ticagrelor exerts its effect at the level of the anterior pituitary gland, outside the blood brain barrier and due to peripheral exposure.…”

“…The rat ovariectomized in vivo assay was a modification of Brott et al [24] , in that Ticagrelor was (1) dosed orally once a day for 4 days and (2) on Day 4, Ticagrelor treatment was considered as t = 0 h and the rats dosed with estradiol (2 μg/rat) at t = 1 h with blood collected at various time points for prolactin analysis.…”

Scientific and Regulatory Policy Committee (SRPC) Paper

“…PRL in female rodents is under positive regulation by E2, and overiectomized rats and mice thus have low concentrations of PRL. In ovariectomized animals, an E2 injection will cause a marked release of PRL (after a delay of several hours), and any inhibitory effect on this system can be studied by remote sampling in cannulated animals or by blood sampling following decapitation (Brott et al 2012;Murai and Ben-Jonathan 1990).…”