The Novel Object Recognition Test in Rodents in Relation to Cognitive Impairment in Schizophrenia

Abstract

Novel object recognition (NOR) in rodents is analogous in some ways to human declarative (episodic) memory, one of the seven cognitive domains which are abnormal in schizophrenia. Cognitive impairment in schizophrenia (CIS) accounts for the largest proportion of the poor functional outcomes in this complex syndrome, with psychosis and negative symptoms accounting for much of the rest. Current atypical antipsychotic drugs (APDs) e.g. amisulpride, aripiprazole, clozapine, lurasidone, olanzapine and risperidone, and typical APDs as well, significantly improve some, but not all aspects of CIS, including declarative memory, but not in all patients, and rarely restore normal function. Thus, finding new ways to prevent or treat CIS is a major goal of current schizophrenia research, with animal models as an essential tool. NOR in rodents is valuable in this regard because of its relationship to declarative memory, the extensive knowledge of its underlying circuitry, and the ease and reliability of assessment. Sub-chronic administration of an N-methyl-Daspartate receptor (NMDAR) non-competitive antagonist, e.g. phencyclidine (PCP), dizocilpine (MK-801) or ketamine, is a favored means to study NOR as a model of CIS, because it produces deficient glutamatergic and GABAergic function, both of which have been implicated in the development of CIS. Transgenic mice and anti-cholinergic-induced deficits in NOR have received less attention. We review here NOR studies in rodents that bear upon CIS, including the evidence that atypical, but not typical APDs, as well as specific ligands, e.g. 5-HT1A partial agonists, 5-HT7 antagonists, D1 agonists, among others, can restore NOR following sub-chronic NMDAR antagonist treatment, and can also prevent the impairment in NOR produced by sub-chronic NMDAR antagonists. We discuss how well these findings translate to the bedside.

Distinct cortical and striatal actions of a β-arrestin–biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties

“…Brain imaging studies in schizophrenia patients have shown that AMPH-induced DA release is enhanced in the STR (78) (hyperdopaminergia), whereas a recent study has shown, for the first time, cortical hypodopaminergia in schizophrenia patients (79). Partial agonists, such as ARI, were originally developed to counteract these opposite phenomena but have largely been unsuccessful in correcting cortical dysfunction (80,81). Our behavioral and electrophysiological data show that the ARI-derived βarr2-biased D2R ligand, 94A, can act as a D2R-βarr2 agonist in the PFC but a D2R-βarr2 antagonist on striatal D2 MSNs, highlighting the feasibility of a pharmacological approach, where a drug could potentially simultaneously counteract both the cortical hypodopaminergia with D2R-βarr2 agonism and striatal hyperdopaminergia with D2R-βarr2 antagonism in schizophrenia.…”

Agmatine-attenuated cognitive and social deficits in subchronic MK-801 model of schizophrenia in rats

“…It has been thought that perirhinal cortex and hippocampus have primer roles for mediating cognitive functions in NORT [37]. Therefore, the decreased discrimination ratio of novel and familiar objects in NORT due to the subchronic administration of MK-801 and PCP is one of the repeatable data to assess visual recognition memory in schizophrenia models [38,39]. In this study, we showed that subchronic MK-801 impaired visual recognition memory even after seven days of the washout period and both agmatine and risperidone attenuated this effect of MK-801 in NORT.…”

Oxytocin Receptor <b><i>(OXTR)</i></b> Methylation and Cognition in Psychotic Disorders

“…Additionally, the use of peripheral blood DNA methylation can have significant biomarker value regardless of it not being from the tissue of interest. Nevertheless, preclinical models of cognition in schizophrenia are available [80] and may enable translational studies that can be used to support epigenetic findings in the peripheral blood from humans.…”