Antagonism of L-type Ca(v) channels with nifedipine differentially affects performance of wildtype and NK1R-/- mice in the 5-Choice Serial Reaction-Time Task.

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 Ca(v) 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 Ca(v) 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'.

Behavioural and neurochemical abnormalities in mice lacking functional tachykinin-1 (NK1) receptors: a model of attention deficit hyperactivity disorder.

In rodent behavioural screens, such as the forced swim or resident/intruder tests, the behaviour of mice that lack functional substance P-preferring, tachykinin-1 receptors ((NK1R) either through drug antagonism or gene ablation) mimics that of wildtype mice that have been treated with an antidepressant drug. All antidepressants modify the function of monoamine-releasing neurones in the brain. Our intention was to investigate whether monoaminergic transmission in NK1R-/- mice resembles that of wildtypes given an antidepressant. In the course of this work, we discovered that NK1R-/- mice express locomotor hyperactivity that is prevented by psychostimulants (d-amphetamine or methylphenidate). Moreover, hyperactivity is induced in wildtypes by treating them with an NK1R antagonist (at doses that have no effect on the behaviour of NK1R-/- mice): this hyperactivity is prevented by d-amphetamine, as in NK1R-/- mice. The mutant mice display several other abnormalities, which affect their behaviour and central monoaminergic transmission. These include: increased release of noradrenaline and a deficit in dopaminergic transmission in the prefrontal cortex ('hypofrontality'); a lack of an increase in dopamine efflux in the dorsal striatum following systemic administration of d-amphetamine; and a lack of development of d-amphetamine or morphine-induced conditioned place preference. Collectively, these findings strongly parallel abnormalities expressed by patients with Attention Deficit Hyperactivity Disorder (ADHD) and suggest that NK1R-/- mice offer a novel model of this disorder. We propose that mutations in the NK1R gene (tacr1 in humans) could contribute to this disorder, and that drugs that activate NK1R could offer therapeutic relief.