The regulation of stress-induced vocalisations by central NK 1 receptors was investigated using pharmacological antagonists in guinea-pigs, a species with human-like NK 1 receptors, and transgenic NK1R−/− mice. In guinea-pigs, i.c.v. infusion of the selective substance P agonist GR73632 (0.1 nmol) elicited a pronounced vocalisation response that was blocked enantioselectively by the NK 1 receptor antagonists CP-99,994 and L-733,060 (0.1–10 mg/kg). GR73632-induced vocalisations were also markedly attenuated by the antidepressant drugs imipramine and fluoxetine (30 mg/kg), but not by the benzodiazepine anxiolytic diazepam (3 mg/kg) or the 5-HT 1A agonist buspirone (10 mg/kg). Similarly, vocalisations in guinea-pig pups separated from their mothers were blocked enantioselectively by the highly brain-penetrant NK 1 receptor antagonists L-733,060 and GR205171 (ID 50 3 mg/kg), but not by the poorly brain-penetrant compounds LY303870 and CGP49823 (30 mg/kg). Separation-induced vocalisations were also blocked by the anxiolytic drugs diazepam, chlordiazepoxide and buspirone (ID 50 0.5–1 mg/kg), and by the antidepressant drugs phenelzine, imipramine, fluoxetine and venlafaxine (ID 50 3–8 mg/kg). In normal mouse pups, GR205171 attenuated neonatal vocalisations when administered at a high dose (30 mg/kg) only, consistent with its lower affinity for the rat than the guinea-pig NK 1 receptor. Ultrasound calls in NK1R−/− mouse pups were markedly reduced compared with those in WT pups, confirming the specific involvement of NK 1 receptors in the regulation of vocalisation. These observations suggest that centrally-acting NK 1 receptor antagonists may have clinical utility in the treatment of a range of anxiety and mood disorders.
Neuropharmacology – Elsevier
Published: Jul 1, 2000
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