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.
Highlights
Male mice with functional ablation of the Nk1r gene, which encodes the substance P-preferring NK1 receptor (NK1RÀ /À ), express locomotor hyperactivity in several experimental contexts (Fisher et al, 2007; Herpfer et al, 2005; Yan et al, 2010)
The first aim of this study was to establish whether the locomotor hyperactivity of male NK1RÀ/À mice, which we have reported previously
To the best of our knowledge, the results of this study offer the first evidence that the brain renin angiotensin system (BRAS) influences premature responses and that this abnormal behaviour is diminished by captopril, and possibly other angiotensin converting enzyme (ACE) inhibitors
Summary
Male mice with functional ablation of the Nk1r gene, which encodes the substance P-preferring NK1 receptor (NK1RÀ /À ), express locomotor hyperactivity in several experimental contexts (Fisher et al, 2007; Herpfer et al, 2005; Yan et al, 2010). Hyperactivity, inattentiveness and impulsivity are diagnostic criteria for attention deficit hyperactivity disorder (ADHD) On this basis, and supported by evidence from human genetic studies (Sharp et al, 2014), we have proposed that polymorphism(s) of the TACR1 gene (the human equivalent of the mouse Nk1r gene) could be associated with increased risk of developing ADHD. Histochemical markers indicate that the BRAS is distributed across neuronal networks that have been strongly implicated in ADHD and motor control. Both ACE and angiotensin (AT) receptors are densely expressed within the basal ganglia, in regions such as the dorsal striatum, globus pallidus and substantia nigra (Strittmatter et al, 1984; Chai et al, 1987; Allen et al, 1992)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
