1 In the conscious rat, three tachykinin NK 3 receptor antagonists, namely SR142801 ((S)-(N)- (1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl)propyl)-4-phenylpiperidin-4-yl)-N-methylacetamide), R820 (3-indolylcarbonyl-Hyp-Phg-N(Me)-Bzl) and R486 (H-Asp-Ser-Phe-Trp-b-Ala-Leu-Met-NH 2 ) were assessed against the intracerebroventricular (i.c.v.) e ects induced by senktide, a selective NK 3 receptor agonist, on mean arterial blood pressure (MAP), heart rate (HR) and motor behaviour. 2 Senktide (10 ± 650 pmol per animal; i.c.v; n=4 ± 16) at the lowest dose caused a signi®cant fall in MAP (710+6 mmHg), while at the highest doses (100 and 650 pmol), senktide caused a rise in MAP (9+3 and 12+1 mmHg, respectively) when compared to vehicle. The intermediate doses (25 and 65 pmol) had no e ect on MAP. The highest two doses caused a tachycardia of 62+15 and 88+8 beats min 71 , respectively. The dose of 65 pmol had a biphasic e ect on HR, an initial bradycardia of 47+12 beats min 71 followed by a tachycardia of 46+14 beats min 71 . The lowest doses caused either a rise of 52+10 beats min 71 (25 pmol) or no e ect (10 pmol) on HR. All doses of senktide caused similar increases in face washing, sni ng and wet dog shakes except at the dose of 100 pmol, when wet dog shakes were more than double those observed with the other doses. 3 The antagonist SR142801 (100 pmol ± 65 nmol per animal; i.c.v.; n=6 ± 8) caused increases in MAP at the highest two doses (6.5 and 65 nmol) while HR, dose-dependently, increased (23+6 to 118+26 beats min 71 ) and the onset dose-dependently decreased. The (R)-enantiomer, SR142806 (100 pmol ± 65 nmol per animal; i.c.v.; n=6 ± 8) only caused rises in MAP (13+2 mmHg) and HR (69+11 beats min 71 ) at the highest dose. These drugs had no apparent e ect on behaviour, except for the highest dose of SR142801 which increased sni ng. The antagonist R820 (650 pmol ± 6.5 nmol per animal; i.c.v.; n=6) had no e ect on MAP or HR and only increased sni ng behaviour at 6.5 nmol. At 650 pmol (n=6), R486 had no e ect on any variable, but at 3.25 nmol, i.c.v. (n=4) a delayed tachycardia and a signi®cant increase in all behavioural variables were observed. 4 The cardiovascular responses induced by 6.5 nmol SR142801 and 25 pmol senktide were inhibited by R820 (6.5 nmol, 5 min earlier i.c.v.). In contrast, R820 failed to a ect the central cardiovascular and behavioural responses induced by 10 pmol [Sar 9 , Met(O 2 ) 11 ]substance P, a NK 1 receptor selective agonist. The senktide-induced behavioural changes were not inhibited by R820 (6.5 nmol, i.c.v.) while R486 (650 pmol, i.c.v.) blocked both the cardiovascular and behavioural responses to 25 pmol senktide. A mixture of antagonists for NK 1 (RP67580; 6.5 nmol) and NK 2 (SR48968; 6.5 nmol) receptors injected i.c.v. did not a ect the cardiovascular response to SR142801. Cross-desensitization was shown between the central responses to SR142801 and senktide, but not between SR142801 and [Sar 9 , Met(O 2 ) 11 ]substance P. 5 The antagonists SR142801 and SR142806 (6.5 ± 6...