Send Orders for Reprints to reprints@benthamscience.net Current Pharmaceutical Design, 2014, 20, 000-000 1 1381-6128/14 $58.00+.00 © 2014 Bentham Science Publishers The Novel Object Recognition Test in Rodents in Relation to Cognitive Impairment in Schizophrenia Lakshmi Rajagopal 1 , Bill W Massey 1 , Mei Huang 1 , Yoshihiro Oyamada 1,2 and Herbert Y. Meltzer 1* 1 Dept of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine Chicago, Il 60611; 2 Dainippon Sumitomo Pharma Co., Ltd., Osaka 564-0053, Japan 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 pro- portion 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 exten- sive knowledge of its underlying circuitry, and the ease and reliability of assessment. Sub-chronic administration of an N-methyl-D- aspartate 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 re- view 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 an- tagonist 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. Keywords: NOR, PCP, schizophrenia, cognition, declarative memory, 5-HT1A, 5-HT7, lurasidone. INTRODUCTION Schizophrenia is a syndrome with three key features: cognitive impairment, positive symptoms (delusions of various types, e.g. auditory, visual, and tactile), and negative symptoms (anhedonia, anergia, avolition, and affective flattening). These are independent dimensions which show little correlation with one another in sever- ity, course, and, not surprisingly, response to treatment with antip- sychotic drugs (APDs). As reviewed elsewhere [1], the serendipi- tous discovery of the antipsychotic effects of chlorpromazine (CPZ) in 1952 was followed shortly thereafter by the discovery that its ability to relieve delusions and hallucinations in many, but not all, patients with recent onset or chronic schizophrenia, was related to blockade of dopamine (DA) D 2 receptors(R) in the meso-limbic cortical system. Increasing the availability of DA following am- phetamine administration to rodents increases locomotor activity which was prevented by CPZ, due to D 2 receptor blockade. This animal model, along with the blockade of the conditioned avoid- ance response, enabled the synthesis and development of a group of drugs which proved to be effective APDs, but also caused catalepsy in rodents and extrapyramidal side effects (EPS) in man. This group of drugs is best described as typical APDs, based upon their typical profile of combined antipsychotic action and motor impairment. These drugs minimally improve the cognitive impairment of schizophrenia (CIS) [2]. The limited effectiveness of these agents to treat the entire schizophrenia syndrome was not fully appreciated for several decades, until three developments occurred: 1) intensive study of clozapine, the first atypical APD (antipsychotics which do not produce significant catalepsy or EPS at doses effective to treat psychosis in man), showed it to be more effective than typical APDs to treat positive symptoms in refractory schizophrenia *Address correspondence to this author at the Psychiatry and Behavioral Science, Northwestern University, Feinberg School of Medicine, 303E Chicago Ave, Ward Building 12-014, Chicago, IL 60611; Tel: 312-503- 0309; Fax: 312-503-0348; E-mail: h-meltzer@northwestern.edu patients [3]; 2) the demonstration that clozapine improved some domains of cognition, including declarative memory, but the effect size was small to moderate on average, with only some patients having a robust response [4]; and 3) CIS was shown to be the major reason for poor outcome in schizophrenia [5]. The results of the Hagger et al. [4] study with clozapine have been replicated and extended to a variety of atypical APDs [2, 6] but the overall effect is weak to moderate on average, although large in some individuals. It is disputed whether the atypical APDs are more effective than typical APDs [7, 8]. The limited efficacy of the atypical APDs to improve cognition resulted in a major initia- tive, MATRICS, to identify more effective drugs for some or all domains of CIS [9]. Although there is evidence for a generalized cognitive factor which underlies CIS [10], development of treat- ments for a general cognitive factor underlying CIS could be more difficult than targeting one or more domains of CIS, because dispa- rate factors are likely to be responsible for different components of CIS. Furthermore, in a heterogeneous disorder such as schizophre- nia, there are very likely to be different etiologic factors producing the same phenotype. As an example, treatments for working mem- ory may require, for some patients, stimulation of cortical DA D 1 receptors by enhancing the release of cortical DA. This might lead to overstimulation of D 1 or other types of DA receptors in other brain regions [4, 11]. NOVEL OBJECT RECOGNITION This review will discuss the contribution of research utilizing novel object recognition (NOR) in rodents to the effort to develop more effective treatments for CIS. NOR has been a favorite target for research to develop novel treatments for CIS because: 1) it is considered the rodent equivalent of human declarative (episodic memory); 2) no training or expensive equipment is involved; and 3) acute, sub-chronic, prenatal, or perinatal treatment with an N- methyl-D-aspartate receptor (NMDAR) non-competitive antagonist, e.g. phencyclidine (PCP), dizocilpine (MK-801), or ketamine pro-