A novel agent for induced spawning using a combination of GnRH analog and an FDA-approved dopamine receptor antagonist

Abstract

In certain fish species, endogenous dopamine has a significant inhibitory effect on LH release and spawning induced by externally applied GnRH. Preovulatory LH surge and spawning in these fish species are caused by the simultaneous release of GnRH and exclusion of the dopaminergic inhibition. To induce spawning, a potent dopamine D2 receptor (DRD2) antagonist and a GnRH analog are concomitantly applied to fish with solid dopaminergic inhibition. However, the currently used dopamine antagonists are not approved by the FDA for veterinary use. This project was conducted in order to find a novel FDA-approved dopamine antagonist that will be efficient in spawning induction in fish species and will not be lethal to the fish. First, we studied the inhibitory effect of the novel dopamine antagonist, azaperone, on tilapia DRD2, transiently expressed in COS-7 cell line. Azaperone was more effective than metoclopramide in antagonizing the effect of quinpirole on taDRD2 both in terms of EC50 and maximal response. Next, we tested the ability of the combination of the dopamine antagonist and sGnRHa on GTH secretion, in adult tilapia. The novel dopamine antagonist significantly increased the GnRH-stimulated LH release in vivo, on both LH release and gene expression. We next aimed to test the novel combination in carp. The combination of the novel dopamine antagonist together with GnRHa, increased the release of estradiol and LH, in a dose-dependent manner. A higher hatching rate and spawning efficiency were observed than in the positive control that contained metoclopramide as a dopamine antagonist.