title: Dopamine D1 receptor activation improves PCP-induced performance disruption in the 5C-CPT by reducing inappropriate responding.
abstract: Attentional deficits contribute significantly to the functional disability of schizophrenia patients. The 5-choice continuous performance test (5C-CPT) measures attention in mice, rats, and humans, requiring the discrimination of trial types that either require a response or the inhibition of a response. The 5C-CPT, one version of human continuous performance tests (CPT), enables attentional testing in rodents in a manner consistent with humans. Augmenting the prefrontal cortical dopaminergic system has been proposed as a therapeutic target to attenuate the cognitive disturbances associated with schizophrenia. Using translational behavioural tasks in conjunction with inducing conditions relevant to schizophrenia pathophysiology enable the assessment of pro-attentive properties of compounds that augment dopaminergic activity. Here, using a repeated phencyclidine (PCP) treatment regimen and the 5C-CPT paradigm, we assess the pro-attentive properties of SKF 38393, a dopamine D1 receptor agonist, in rats. We show that repeated PCP treatment induces robust deficits in 5C-CPT performance indicative of impaired attention. Pre-treatment with SKF 38393 partially attenuates the PCP-induced deficits in 5C-CPT performance by reducing false alarm responding and increasing response accuracy. Impaired target detection was still evident in SKF 38393-treated rats however. Thus, augmentation of the dopamine D1 system improves PCP-induces deficits in 5C-CPT performance by selectively reducing aspects of inappropriate responding. These findings provide evidence to support the hypothesis that novel therapies targeting the dopamine D1 receptor system could improve aspects of attentional deficits in schizophrenia patients.
authors.affiliation: Department of Psychiatry, University of California San Diego, CA, USA. Electronic address: sabarnes@ucsd.edu.
authors.forename: S A
authors.initials: SA
authors.lastname: Barnes
authors.affiliation: Department of Psychiatry, University of California San Diego, CA, USA; Research Service, VA San Diego Healthcare System, San Diego, CA, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Young
authors.affiliation: Statistical Sciences Europe, GlaxoSmithKline Pharmaceuticals, Stevenage SG1 2NY, UK.
authors.forename: S T
authors.initials: ST
authors.lastname: Bate
authors.affiliation: Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK.
authors.forename: J C
authors.initials: JC
authors.lastname: Neill
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology*; D000818:Animals; D001288:Attention / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology*; D005260:Female; D007266:Inhibition, Psychological; D009483:Neuropsychological Tests; D010622:Phencyclidine; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D011619:Psychotropic Drugs / Q000494:pharmacology*; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000378:metabolism; D012565:Schizophrenic Psychology; D016896:Treatment Outcome
chemical_list: D018491:Dopamine Agonists; D011619:Psychotropic Drugs; D017447:Receptors, Dopamine D1; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D010622:Phencyclidine
keywords: Attention; Cognition; Dopamine D1 receptors; Phencyclidine; Schizophrenia