Endocrine Abstracts

Introduction: Kisspeptins, the products of the Kiss1 gene that act via the receptor, GPR54 (or Kiss1R), are pivotal elements in the neuroendocrine control of GnRH neurons and, thereby, gonadotropin secretion. Extensive efforts have been devoted recently to elucidate the pharmacological effects and major putative regulators of the kisspeptin system. Yet, our knowledge on the potential interactions of kisspeptins with other key neurotransmitters involved in the central regulation of the gonadotropic axis remains superficial.

Design: We present herein a series of hormonal analyses addressing the impact of pharmacological manipulations (either activation or inactivation by the use of suitable agonists or antagonists) of major central aminoacidergic (glutamate, GABA) and neuro-peptidergic (neurokinin-B, dynorphin) pathways on the patterns of gonadotropin responses to kisspeptin-10 (Kp-10) in peripubertal male rats.

Results: Blockade of ionotropic glutamate receptors decreased (to a variable extent) LH responses to a sub-maximal dose of Kp-10, whereas activation of both ionotropic and metabotropic receptors, which enhanced LH release per se, failed to evoke further increases in LH responses to Kp-10. Conversely, selective activation of GABA-A receptors decreased Kp-evoked LH secretion, while central inhibition of GABA-A transmission elicited robust LH secretory peaks, and protracted responses to Kp-10 when combined with GABA-B receptor blockade. In addition, antagonization of dynorphin (κ-opiod) receptors enhanced LH responses to Kp-10, while activation of dynorphin or NKB signaling evoked mild inhibitory effects in peripubertal male rats.

Conclusion: Our present data document the roles of glutamate-, GABA-, dynorphin- and NKB-neurotransmission as putative modifiers of gonadotropic responses to kisspeptin. These studies, together with on-going analyses of gonadotropin secretory profiles following activation or inactivation of aminoacidergic and neuropeptidergic pathways in models of genetic or pharmacological blockade of kisspeptin signaling, will aid to dissect out the central interactions and eventual hierarchy of different neuroendocrine pathways with key functions in the control of the gonadotropic axis.