Antagonism of L-type Cav channels with nifedipine differentially affects performance of wildtype and NK1R−/− mice in the 5-Choice Serial Reaction-Time Task

• Published in: Neuropharmacology 2013-01, Vol.64, p.329-336
• Main Authors: Dudley, Julia A., Weir, Ruth K., Yan, Ting C., Grabowska, Ewelina M., Grimmé, Ashley J., Amini, Susana, Stephens, David N., Hunt, Stephen P., Stanford, S. Clare
• Format: Article
• Language: English
• Subjects: 5-Choice Serial Reaction-Time Task; Attention Deficit Hyperactivity Disorder; Impulsivity; Inattentiveness; L-type Cav-channel; NK1R−/− ‘knockout’ mouse
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2012.06.056

Mice with functional ablation of the substance P-preferring receptor gene (‘Nk1r’ in mice (‘NK1R−/−’), ‘TACR1’ in humans) display deficits in cognitive performance that resemble those seen in patients with Attention Deficit Hyperactivity Disorder (ADHD): namely, inattentiveness, impulsivity and perseveration. A recent report suggested that the L-type Cav channel blocker, nifedipine, can ameliorate behavioral abnormalities of this type in humans. In light of evidence that NK1R antagonists modulate the opening of these L-type channels, we investigated whether nifedipine modifies %premature responses (impulsivity), perseveration or %omissions (inattentiveness) in the 5-Choice Serial Reaction-Time Task (5-CSRTT) and whether the response differs in NK1R−/− and wildtype mice. %Premature responses and perseveration were reduced in both genotypes, although wildtype mice were more sensitive to the effects of nifedipine than NK1R−/− mice. By contrast, nifedipine greatly increased %omissions but, again, was more potent in wildtypes. %Accuracy and locomotor activity were unaffected in either genotype. We infer that behavior of mice in the 5-CSRTT depends on the regulation of striato-cortical networks by L-type Cav channels and NK1R. We further suggest that disruption of NK1R signaling in patients with ADHD, especially those with polymorphisms of the TACR1 gene, could lead to compensatory changes in the activity of L-type channels that underlie or exacerbate their problems. This article is part of a Special Issue entitled ‘Cognitive Enhancers’. ► We compared the behavior of nifedipine-treated wildtype and NK1R−/− mice in the 5-CSRTT. ► Impulsivity and perseveration were reduced and inattentiveness was increased in both genotypes. ► Nifedipine was more potent in wildtypes than NK1R−/− mice. ► Accuracy was unaffected in either genotype. ► Functional coupling between NK1R and L-type channels affects cognitive performance.