Although the Dat1-cocaine insensitive mice exhibit hyperactivity, their locomotor activity and responses to amphetamine are dependent
on their genetic background [24], suggesting a crucial role of gene–gene interactions for these phenotypes. Other phenotypes relating to attention and impulsivity in these mice have not been documented. Although genes encoding DA receptors are classic candidates for ADHD, experimental evidence from Drd1, Drd2, Drd3, Drd4, and Drd5 KO mice for these genes affecting ADHD-relevant endophenotypes is weak [25•]. Interesting results were reported for Drd4-heterozygous mice [26]. Young et al. applied a 5-choice continuous performance test (5C-CPT), which is a modification of the 5-choice serial reaction time test (5CSRTT) [27] that may more closely correspond to the CPT used in humans [28]. In the 5C-CPT, rodents must continue to respond to signal stimuli (illumination of any 1 of 5 holes), Belnacasan ic50 and must also inhibit their response to non-signal stimuli (simultaneous illumination of all 5 holes). Heterozygous but not homozygous Drd4-KO mice
exhibited attention deficits in the 5C-CPT [26]. High impulsivity was also measured by false alarms but not by premature responses. The mice showed no deficits in AZD2014 PPI or spontaneous exploratory behavior. It is plausible that the complete lack of D4 receptors leads to a robust compensatory system(s) at the molecular and/or neural circuit levels. Interactions of the gene with
other genetic or environmental factors require further evaluation. Recent works for catechol-O-methyltransferase (COMT)-KO mice support the notion that gene–environment interactions and gene–gene interactions are involved in attention and impulsivity domains 29•• and 30••]. COMT methylates and inactivates DA. In the 5CSRTT, male and female COMT+/+,+/− and COMT−/− mice equally acquire the task. Interestingly, environmental factors induced genotype-sex interactions in the task. For example, a mild stress (15 min exposure in an empty cage at ∼800 lx before test) increased impulsive premature responses in COMT+/− however and −/− males, but not in females [29••]. In contrast, females, but not males, exhibited genotype differences in perseverative responses. COMT−/− females showed perseverative responses at a lower rate compared to other genotypes [29••]. Differential effects of various stimuli are consistent with the sex difference in ADHD prevalence [1]. DTNBP1 (dysbindin) is a molecule that has a role in homeostasis of excitatory synapses [31]. C57BL6/J congenic COMT+/− and −/− males and C57BL6/J congenic Dtnbp1+/− and −/− males learn the T-maze working memory task, which demands a high level of attention, faster than wild-type mice. In contrast, double mutants (double heterozygotes and homozygotes) learn slower than wild-types [30••]. Although Papaleo et al.