Kisspeptin restores pulsatile LH secretion in patients with neurokinin B signaling deficiencies: physiological, pathophysiological and therapeutic implications.

Pulsatile gonadotropin-releasing hormone (GnRH) is crucial to normal reproductive function and abnormalities in pulse frequency give rise to reproductive dysfunction. Kisspeptin and neurokinin B (NKB), neuropeptides secreted by the same neuronal population in the ventral hypothalamus, have emerged recently as critical central regulators of GnRH and thus gonadotropin secretion. Patients with mutations resulting in loss of signaling by either of these neuroendocrine peptides fail to advance through puberty but the mechanisms mediating this remain unresolved. We report here that continuous kisspeptin infusion restores gonadotropin pulsatility in patients with loss-of-function mutations in NKB (TAC3) or its receptor (TAC3R), indicating that kisspeptin on its own is sufficient to stimulate pulsatile GnRH secretion. Moreover, our findings suggest that NKB action is proximal to kisspeptin in the reproductive neuroendocrine cascade regulating GnRH secretion, and may act as an autocrine modulator of kisspeptin secretion. The ability of continuous kisspeptin infusion to induce pulsatile gonadotropin secretion further indicates that GnRH neurons are able to set up pulsatile secretion in the absence of pulsatile exogenous kisspeptin.

Pharmacological characterization of senktide-induced tail whips.

The tachykinin NK(3) receptor shows promise as a novel target for antipsychotics, but knowledge of downstream activity following tachykinin NK(3) receptor activation is lacking. To determine the practical utility of senktide-induced tail whips in mice as a tool for determining and characterizing downstream activity following tachykinin NK(3) receptor activation, mice were injected with 0.05 nmol of senktide i.c.v. and the number of tail whip bouts was counted for 20 min. Strain differences were observed, with NMRI mice showing a stronger tail whip response than C57Bl/6J mice. Tachykinin NK(3) receptor specificity was confirmed by the absence of the senktide-induced tail whip response in tachykinin NK(3) receptor knockout mice. Effects of tachykinin receptor pharmacological agents were tested by pretreatment with tachykinin NK(3) receptor antagonists (SB222200, talnetant and osanetant), which attenuated senktide-induced tail whips, and the tachykinin NK(1) receptor antagonist MK869, which had no effect on senktide-induced tail whips. Pharmacological interactions with other neurotransmitter systems were determined by pretreatment with dopamine D(1), D(2), and D(3) receptor antagonists, atypical antipsychotics, serotonin 5HT(1a) receptor antagonists, serotonin 5HT(2a/c) receptor antagonists, benzodiazepine and putative anxiolytics, antidepressants, and an anticholinergic. Senktide-induced tail whips were attenuated by dopamine D(2) receptor antagonists, atypical antipsychotics, serotonin 5HT(2a/c) antagonists, and benzodiazepine anxiolytics, but unaffected by drugs from other classes. Thus, the senktide-induced tail whip response is easily quantifiable, specific to the tachykinin NK(3) receptor, and provides valuable information on the downstream pharmacology of tachykinin NK(3) receptor activation.

Disruption of the neurokinin-3 receptor (NK3) in mice leads to cognitive deficits.

RATIONALE: The structurally related neuropeptides, substance P, neurokinin A, and neurokinin B, belong to a family of molecules termed tachykinins and are widely distributed in the central and peripheral nervous systems. These peptides mediate their effects through three G protein coupled receptor subtypes, the neurokinin-1, neurokinin-2 and neurokinin-3 receptors, respectively. OBJECTIVE: To study the physiological functions of NK3, a line of NK3 knockout mice were generated and characterized in a broad spectrum of well-established behavioral tests. RESULTS: In several tests, including spontaneous locomotor activity, elevated plus maze, forced swim, and hot plate, wild-type and knockout mice performed similarly. However, in several cognition tests, including passive avoidance, acquisition of conditioned avoidance responding (CAR), and the Morris water maze, NK3 knockout mice displayed deficits compared to wild-type mice. Although NK3 wild-type and knockout mice performed similarly in the training phase of the passive avoidance test, knockout mice had shorter latencies to enter the dark compartment on days 3 and 4, suggesting impaired retention. In the acquisition phase of the conditioned avoidance responding assay, NK3 knockout mice acquired the CAR task at a slower rate than wild-type mice. Once the CAR test was acquired, both NK3 wild-type and knockout mice responded similarly to clozapine and risperidone, drugs which suppress responding in this test. In the Morris water maze, NK3 knockout mice showed increased latencies to find the escape platform on day 3 of training, suggesting a modest, but significant delay in acquisition compared to wild-type mice. CONCLUSION: These studies suggest a role for NK3 in learning and memory in mice.

Tachykinin NK3-receptor deficiency does not inhibit pulmonary eosinophilia in allergic mice.

Tachykinins are important in the development of pulmonary inflammation in mice but the tachykinin receptor subtype mediating this response has not been defined. To elucidate the role of tachykinin NK3-receptors on allergen-induced pulmonary inflammation, studies were performed on ovalbumin (OVA) sensitized and challenged mice with genetic disruption of the tachykinin NK3-receptor (NK3-/-). Aerosol OVA (0.5%) challenge produced eosinophil influx into the bronchoalveolar lavage fluid and lung tissue, goblet cell hyperplasia and damage to the airway epithelium of both NK3-/- mice and in wild type control mice (NK3+/+). There was no difference in the magnitude of these allergic inflammatory pulmonary responses between NK3-/- and NK3+/+ mice. These results find no role for tachykinin NK3-receptors on the pulmonary eosinophilia and lung damage after antigen challenge in mice.