Animal models of cognitive dysfunction and negative symptoms of schizophrenia: Focus on NMDA receptor antagonism

Antidepressant activity of N-methyl-D-aspartate (NMDA) receptor antagonists and negative allosteric modulators (NAMs) has led to increased investigation of their behavioral pharmacology. NMDA antagonists, such as ketamine, impair cognition in multiple species and in multiple cognitive domains. However, studies with NR2B subtype-selective NAMs have reported mixed results in rodents including increased impulsivity, no effect on cognition, impairment or even improvement of some cognitive tasks. To date, the effects of NR2B-selective NAMs on cognitive tests have not been reported in nonhuman primates. The current study evaluated two selective NR2B NAMs, CP101,606 and BMT-108908, along with the nonselective NMDA antagonists, ketamine and AZD6765, in the nonhuman primate Cambridge Neuropsychological Test Automated Battery (CANTAB) list-based delayed match to sample (list-DMS) task. Ketamine and the two NMDA NR2B NAMs produced selective impairments in memory in the list-DMS task. AZD6765 impaired performance in a nonspecific manner. In a separate cohort, CP101,606 impaired performance of the nonhuman primate CANTAB visuo-spatial Paired Associates Learning (vsPAL) task with a selective impairment at more difficult conditions. The results of these studies clearly show that systemic administration of a selective NR2B NAM can cause transient cognitive impairment in multiple cognitive domains.

Section: Introductionmentioning

confidence: 83%

Negative Allosteric Modulators Selective for The NR2B Subtype of The NMDA Receptor Impair Cognition in Multiple Domains

Weed

Bookbinder

Polino

et al. 2015

“…Furthermore, a common preclinical model of schizophrenia involving transient blockade of N-methyl-D-aspartate receptors (NMDARs) with repeated administration of NMDAR antagonists during a critical period of adolescent development induces profound and lasting deficits in LTD at synapses from the hippocampus to PFC (Ghoshal and Conn, 2015;Thomases et al, 2014). This has been postulated to contribute to the increased activity of PFC neurons observed following phencyclidine (PCP) treatment in rodents (Katayama et al, 2007;Suzuki et al, 2002;Thomases et al, 2014;Wang et al, 2007) as well as the subsequent behavioral changes associated with negative and cognitive symptoms in the disorder (Neill et al, 2010(Neill et al, , 2014.…”

Section: Introductionmentioning

confidence: 99%

Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a Schizophrenia Mouse Model

Ghoshal

Rook

Dickerson

et al. 2015

122

Schizophrenia patients exhibit deficits in signaling of the M 1 subtype of muscarinic acetylcholine receptor (mAChR) in the prefrontal cortex (PFC) and also display impaired cortical long-term depression (LTD). We report that selective activation of the M 1 mAChR subtype induces LTD in PFC and that this response is completely lost after repeated administration of phencyclidine (PCP), a mouse model of schizophrenia. Furthermore, discovery of a novel, systemically active M 1 positive allosteric modulator (PAM), VU0453595, allowed us to evaluate the impact of selective potentiation of M 1 on induction of LTD and behavioral deficits in PCP-treated mice. Interestingly, VU0453595 fully restored impaired LTD as well as deficits in cognitive function and social interaction in these mice. These results provide critical new insights into synaptic changes that may contribute to behavioral deficits in this mouse model and support a role for selective M 1 PAMs as a novel approach for the treatment of schizophrenia.

“…PCP treatment of rodents over both acute (Ernst et al, 2012;Neill et al, 2010) and chronic (Hashimoto et al, 2005;Marquis et al, 2003;Murai et al, 2007;Qiao et al, 2001) intervals is thought to induce a psychosis-like state through blockade of N-methyl-Daspartate (NMDA) receptor activity, which results in altered levels of glutamate and increased dopamine. Alterations in glutamatergic and dopaminergic neuronal transmission in the stratium and frontal cortex have been implicated in the etiology of human SCZ, and the model was derived from observations of acute psychotomimetic effects of PCP in healthy humans and exacerbation of symptoms in chronic SCZ patients (Lahti et al, 1995;Mouri et al, 2007a).…”

Section: Introductionmentioning

confidence: 99%

A Combined Metabonomic and Proteomic Approach Identifies Frontal Cortex Changes in a Chronic Phencyclidine Rat Model in Relation to Human Schizophrenia Brain Pathology

Wesseling

Chan

Tsang

et al. 2013

Current schizophrenia (SCZ) treatments fail to treat the broad range of manifestations associated with this devastating disorder. Thus, new translational models that reproduce the core pathological features are urgently needed to facilitate novel drug discovery efforts. Here, we report findings from the first comprehensive label-free liquid-mass spectrometry proteomic-and proton nuclear magnetic resonance-based metabonomic profiling of the rat frontal cortex after chronic phencyclidine (PCP) intervention, which induces SCZ-like symptoms. The findings were compared with results from a proteomic profiling of post-mortem prefrontal cortex from SCZ patients and with relevant findings in the literature. Through this approach, we identified proteomic alterations in glutamate-mediated Ca 2 þ signaling (Ca 2 þ /calmodulin-dependent protein kinase II, PPP3CA, and VISL1), mitochondrial function (GOT2 and PKLR), and cytoskeletal remodeling (ARP3). Metabonomic profiling revealed changes in the levels of glutamate, glutamine, glycine, pyruvate, and the Ca 2 þ regulator taurine. Effects on similar pathways were also identified in the prefrontal cortex tissue from human SCZ subjects. The discovery of similar but not identical proteomic and metabonomic alterations in the chronic PCP rat model and human brain indicates that this model recapitulates only some of the molecular alterations of the disease. This knowledge may be helpful in understanding mechanisms underlying psychosis, which, in turn, can facilitate improved therapy and drug discovery for SCZ and other psychiatric diseases. Most importantly, these molecular findings suggest that the combined use of multiple models may be required for more effective translation to studies of human SCZ.