title: The effect of reduced dopamine D4 receptor expression in the 5-choice continuous performance task: Separating response inhibition from premature responding.
abstract: Impairments in attention/vigilance and response disinhibition are commonly observed in several neuropsychiatric disorders. Validating animal models could help in developing therapeutics for cognitive deficits and improving functional outcomes in such disorders. The 5-choice continuous performance test (5C-CPT) in mice offers the opportunity to assess vigilance and two forms of impulsivity. Since reduced dopamine D4 receptor (DRD4) function is implicated in several disorders, DRD4 is a potential therapeutic target for cognition enhancement. We trained wildtype (WT), heterozygous (HT), and knockout (KO) mice of the murine Drd4 to perform the 5C-CPT under baseline and variable stimulus duration conditions. To dissect motor impulsivity (premature responding) from behavioral disinhibition (false alarms), we administered the 5-HT(2C) antagonist SB242084 during an extended inter-trial-interval session. We also examined the preattentive and exploratory profile of these mice in prepulse inhibition (PPI) and the Behavioral Pattern Monitor (BPM). Reduced Drd4 expression in HT mice, as confirmed by quantitative RT-PCR, resulted in response disinhibition and impaired 5C-CPT performance, while premature responding was unaffected. Conversely, SB242084 increased premature responding without affecting response inhibition or attentional measures. No genotypic differences were observed in PPI or BPM behavior. Thus, reduced Drd4 expression impairs attentional performance, but not other behaviors associated with neuropsychiatric disorders. Moreover, the use of signal and non-signal stimuli in the 5C-CPT enabled the differentiation of response disinhibition from motor impulsivity in a vigilance task.
authors: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804, United States. jaredyoung@ucsd.edu
authors: Jared W
authors: JW
authors: Young
authors: Susan B
authors: SB
authors: Powell
authors: Christine N
authors: CN
authors: Scott
authors: Xianjin
authors: X
authors: Zhou
authors: Mark A
authors: MA
authors: Geyer
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001143:Arousal / Q000235:genetics; D001288:Attention / Q000502:physiology*; D002755:Choice Behavior / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D015870:Gene Expression / Q000235:genetics / Q000502:physiology*; D005838:Genotype; D007211:Indoles / Q000494:pharmacology; D007266:Inhibition, Psychological; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009483:Neuropsychological Tests; D012333:RNA, Messenger / Q000378:metabolism; D011930:Reaction Time / Q000502:physiology; D050638:Receptors, Dopamine D4 / Q000172:deficiency* / Q000235:genetics; D013216:Reflex, Startle / Q000187:drug effects / Q000235:genetics; D055139:Sensory Gating / Q000187:drug effects / Q000235:genetics; D012702:Serotonin Antagonists / Q000494:pharmacology; D013223:Statistics as Topic; D013997:Time Factors
chemical_list: C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; C493600:Drd4 protein, mouse; D007211:Indoles; D012333:RNA, Messenger; D012702:Serotonin Antagonists; D050638:Receptors, Dopamine D4