title: The angiotensin converting enzyme inhibitor, captopril, prevents the hyperactivity and impulsivity of neurokinin-1 receptor gene 'knockout' mice: sex differences and implications for the treatment of attention deficit hyperactivity disorder.
abstract: Mice lacking functional neurokinin-1 receptors (NK1R-/-) display behavioural abnormalities resembling attention deficit hyperactivity disorder (ADHD): locomotor hyperactivity, impulsivity and inattentiveness. The preferred ligand for NK1R, substance P, is metabolised by angiotensin converting enzyme (ACE), which forms part of the brain renin angiotensin system (BRAS). In view of evidence that the BRAS modulates locomotor activity and cognitive performance, we tested the effects of drugs that target the BRAS on these behaviours in NK1R-/- and wildtype mice. We first tested the effects of the ACE inhibitor, captopril, on locomotor activity. Because there are well-established sex differences in both ADHD and ACE activity, we compared the effects of captopril in both male and female mice. Locomotor hyperactivity was evident in male NK1R-/- mice, only, and this was abolished by treatment with captopril. By contrast, male wildtypes and females of both genotypes were unaffected by ACE inhibition. We then investigated the effects of angiotensin AT1 (losartan) and AT2 (PD 123319) receptor antagonists on the locomotor activity of male NK1R-/- and wildtype mice. Both antagonists increased the locomotor activity of NK1R-/- mice, but neither affected the wildtypes. Finally, we tested the effects of captopril on the performance of male NK1R-/- and wildtype mice in the 5-choice serial reaction-time task (5-CSRTT) and found that ACE inhibition prevented the impulsivity of NK1R-/- mice. These results indicate that certain behaviours, disrupted in ADHD, are influenced by an interaction between the BRAS and NK1R, and suggest that ACE inhibitors could provide a novel treatment for this disorder.
authors.affiliation: Department of Neuroscience, Physiology & Pharmacology, University College London, Gower St, London WC1E 6BT, UK.
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Porter
authors.affiliation: Department of Neuroscience, Physiology & Pharmacology, University College London, Gower St, London WC1E 6BT, UK.
authors.forename: Katharine
authors.initials: K
authors.lastname: Pillidge
authors.affiliation: Department of Neuroscience, Physiology & Pharmacology, University College London, Gower St, London WC1E 6BT, UK.
authors.forename: Ewelina M
authors.initials: EM
authors.lastname: Grabowska
authors.affiliation: Department of Neuroscience, Physiology & Pharmacology, University College London, Gower St, London WC1E 6BT, UK. Electronic address: c.stanford@ucl.ac.uk.
authors.forename: S Clare
authors.initials: SC
authors.lastname: Stanford
mesh_terms: D000704:Analysis of Variance; D057912:Angiotensin II Type 2 Receptor Blockers / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics* / Q000517:prevention & control*; D002216:Captopril / Q000627:therapeutic use*; D002755:Choice Behavior / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006948:Hyperkinesis / Q000235:genetics / Q000517:prevention & control; D007093:Imidazoles / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D011725:Pyridines / Q000627:therapeutic use; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D018040:Receptors, Neurokinin-1 / Q000172:deficiency* / Q000235:genetics; D012733:Sex Differentiation
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D018040:Receptors, Neurokinin-1; C073402:PD 123319; D002216:Captopril
keywords: ADHD; Angiotensin receptor; Captopril; Hyperactivity; Impulsivity; Neurokinin-1 receptor