Mouse pharmacological models of cognitive disruption relevant to schizophrenia

Abstract

Schizophrenia is a debilitating cognitive disorder. The link between cognitive debilitation and functional outcome in patients with schizophrenia has prompted research to develop procognitive therapies. It is hoped that by improving cognition in these patients, their functional outcome will also improve. Although no established treatments exist as yet, progress has been made toward understanding how to evaluate putative compounds in the clinic. Genetic mouse models and pharmacological rat models of cognitive disruption are being developed that may help to evaluate these putative compounds preclinically. Considering the increased number of genetic mouse models relevant to schizophrenia, there is a need to evaluate pharmacological manipulations on cognition in mice. Here we review the current literature on mouse pharmacological models relevant to schizophrenia. In this review, we discuss where different pharmacological effects between rats and mice on cognitive tasks are observed and assess the validity offered by these models. We conclude that the predictive validity of these models is currently difficult to assess and that much more needs to be done to develop useful mouse pharmacological models of cognitive disruption in schizophrenia.

Pharmacogenetic associations of the type-3 metabotropic glutamate receptor (GRM3) gene with working memory and clinical symptom response to antipsychotics in first-episode schizophrenia

“…In animal studies, metabotropic glutamate antagonism, agonism, and D2 antagonism appear to have differential beneficial and adverse effects on cognition depending on the model studied and cognitive domain assessed (Amitai and Markou 2010; Young et al 2012). Rodent studies have helped to highlight important mGluR-antipsychotic interactions in cognition whereby antipsychotics reverse phencyclidine (PCP) effects on certain memory tasks, but that pretreatment with an mGluR2/3 antagonist (LY341495) blocks the benefits of antipsychotic treatment (Grayson et al 2007; Horiguchi et al 2011).…”

Inhibition of phosphodiesterase 10A has differential effects on dopamine D1 and D2 receptor modulation of sensorimotor gating

“…Compounds with mixed D1 agonist/D2 antagonist profiles have also been suggested as potential antipsychotics effective in treating a broader range of symptoms of schizophrenia (Natesan et al 2008), including negative symptoms (e.g. anhedonia, asociality, blunted affect) and/or cognitive disruptions, which are not well treated by current antipsychotic medications (Young et al 2012). Evidence suggests that PDE10A inhibition, via pharmacological or genetic manipulations, may in fact be effective in increasing sociality in animals (Sano et al 2008; Grauer et al 2009).…”

Clozapine and glycinamide prevent MK-801-induced deficits in the novel object recognition (NOR) test in the domestic rabbit (Oryctolagus cuniculus)

“…1, 2 and 5) -was not negatively affected by this drug. However, as alluded to by others [69], since cognitive and negative symptoms are minimally responsive to clozapine in clinical studies, the fact that clozapine often completely prevents acute PCP-or MK-801-induced deficits NOR task in this model as well as in rodent models, argues against these deficits being completely equivalent to cognitive or negative symptoms. Indeed, in schizophrenic subjects, acute ketamine treatment reportedly increased positive (thought disturbance) and negative (withdrawal-retardation) symptoms, but only the positive symptoms were reduced by concurrent clozapine treatment [40,41].…”

“…Second, based on the relatively rapid decay time of the memory trace in the rabbit NOR test (novel object discrimination is not reliably present after delays of 20 min; [22]) and its dependence primarily on tactile cues, we have argued that novel object recognition in this paradigm is based on the short-term habituation to tactile object characteristics, and a sensitized response to novel tactile characteristics of the unfamiliar object ("sensitization"; [22,23]). We argue that this mechanism may be distinct from the case of the rodent NOR test, where slowly decaying (up to 24 h) episodic-like memory appears to operate [14] (but for alternative interpretations, see [69]). A model that potentially involves alterations in primary sensory processing could be useful for modeling deficits in "bottom-up" processes that have been described in schizophrenics, including deficits in habituation and automatic responses to novelty [10,27,43,45,65].…”

“…Thus, NMDA receptor antagonists acutely provoke hyper-locomotion and deficits in memory tasks, which arguably demonstrate good face and predictive validity as models for positive and cognitive symptoms [29,37,51] (but for a more critical view, see [69]). One test of short-term memory that has been used in this context is the Novel Object Recognition (NOR) test.…”