The tachykinin NK3 receptor agonist senktide induces locomotor activity in male Mongolian gerbils

The tachykinin family of receptors has been of strong interest recently due to the potential of the tachykinin NK3 receptor antagonism in treatment of schizophrenia. However, critical differences in the tachykinin NK3 receptor between rats, mice and humans make rats and mice less acceptable species for testing tachykinin NK3 receptor antagonism. This has led to testing of tachykinin NK3 receptor activity in gerbils and guinea pigs. As these species are much less common laboratory animals than rats and mice, there is a relative paucity of in vivo testing models for tachykinin NK3 receptor activation. In the present study, locomotor activity induced by the tachykinin NK3 receptor agonist senktide was characterized. Injection of senktide i.c.v. was found to dose-dependently induce hyperlocomotion from a dose of 0.06 nmol to the maximal dose tested, 0.6 nmol. Locomotion induced by 0.1 nmol of senktide could be blocked by injection of the tachykinin NK3 receptor antagonists SB222200 (10 and 30 mg/kg i.p.) and talnetant (SB223412; 10 and 30 mg/kg i.p.), as well as by osanetant (SR142801; 10 and 30 mg/kg i.p.) when administered in a vehicle containing vitamin E and glycofurol. Senktide-induced activity was also reversed by the antipsychotics haloperidol (0.3 and 1 mg/kg p.o.) and risperidone (1 mg/kg p.o.), but not by the serotonin 5HT2a/c receptor antagonist MDL100907 (tested at 0.1, 0.3 and 1 mg/kg p.o.). Hyperlocomotion induced by 0.03 nmol of senktide was potentiated by antagonism of the tachykinin NK1 receptor with aprepitant (1, 3 and 10 mg/kg, p.o.). Thus, hyperlocomotion induced by senktide in gerbils is a tachykinin NK3 receptor-mediated behavior that is appropriate for use in testing tachykinin NK3 receptor activity of novel compounds.