Effects of the metabotropic glutamate receptor 5 positive allosteric modulator CDPPB on rats tested with the paired associates learning task in touchscreen-equipped operant conditioning chambers

Lins, Brittney R.; Howland, John G.

doi:10.1016/j.bbr.2015.12.029

Cited by 14 publications

(9 citation statements)

References 48 publications

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“…In rodents, acute MK-801 treatment demonstrates face validity as a model of schizophrenia as its administration produces behavioral changes similar to those observed in the disease (Nestler and Hyman 2010). The acute administration of MK-801 results in locomotor hyperactivity (Howland et al 2012;Mahmood et al 2016), reduced sociability (Morales and Spear 2014), and performance deficits on touchscreen-based (Kumar et al 2015b;Kumar et al 2015a;Lins et al 2015;Lins and Howland 2016) and working memory (Homayoun et al 2004;Galizio et al 2012) tasks. One published study has explored the changes following acute MK-801 (0.05 mg/kg) administration in the TUNL task (Kumar et al 2015a).…”

Section: Discussionmentioning

confidence: 95%

“…The present study is the first to analyze the effects of MK-801 on correction trials. Previous studies utilizing touchscreen tasks in rodents have identified correction trials as a measure of perseveration (Lins et al 2015;Lins and Howland 2016), a behavior frequently observed in patients with schizophrenia (Szoke et al 2008;Ortuño et al 2009). We observed MK-801 treatment increased the number of correction trials completed by the rats, suggesting MK-801 hindered the ability to inhibit incorrect response selection.…”

Section: Discussionmentioning

confidence: 99%

“…In our study, MK-801 reduced overall accuracy and detailed analysis showed that working memory and pattern separating abilities were impaired. Further, MK-801 reduced latency measures and increased the number of correction trials completed, which may be indicative of impulsivity and perseveration respectively (Lins et al 2015;Lins and Howland 2016). By antagonising NMDA receptors, MK-801 reduced NMDA receptor function.…”

Section: Mk-801-induced Impairmentsmentioning

confidence: 96%

“…Similarly, non-competitive NMDA receptor antagonism in rodents produces behaviors analogous to the positive, negative, and cognitive symptoms of schizophrenia (Moghaddam and Krystal 2012). For example, locomotor hyperactivity (Manahan-Vaughan et al 2008;Howland et al 2012;Zemanova et al 2013;Mahmood et al 2016), reduced sociability (Morales and Spear 2014), and performance deficits on visual learning and working memory tasks (Brown et al 2013;Zemanova et al 2013;Kumar et al 2015b;Kumar et al 2015a;Lins and Howland 2016) are observed following MK-801 administration, mirroring the positive, negative, and cognitive symptoms respectively. Beyond its direct effect on NMDA receptors, MK-801 administration indirectly mimics other pathophysiological features of the disease (Lewis et al 2005).…”

Section: Nmda Receptor Hypofunction As a Model Of Schizophreniamentioning

confidence: 99%

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MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

et al. 2016

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The cognitive symptoms observed in schizophrenia are highly prevalent and predictive of patient functional outcome but are not usually alleviated by conventional antipsychotics. In a recent pilot study, sodium nitroprusside (SNP), a nitric oxide donor, was identified as a promising adjunct treatment to reduce the working memory impairments experienced by schizophrenia patients.Adjunctive SNP has also been reported to decrease the positive and negative symptoms experienced by patients for weeks following a single administration. The mechanisms underlying these changes and the areas of cognition affected remain largely unknown.Therefore, it is of interest to examine the effects of SNP using a rodent model of schizophrenia that has demonstrated predictive validity. The aim of the present experiment was to explore the effects of SNP on the acute MK-801 rodent model of schizophrenia using a highly translatable task in order to establish its validity. Working memory and pattern separation were measured using the trial-unique, delayed nonmatching-to-location (TUNL) task in touchscreen-equipped operant conditioning chambers. Acute MK-801 administration 25 minutes prior to task initiation impaired both areas of cognition. When SNP and MK-801 were administered within 5 minutes of each other, no interaction was observed. Interestingly, SNP improved performance on trials with difficult to discriminate patterns (p=0.058). Previous rodent studies using the ketamine model of schizophrenia and the novel object preference task observed a preventative effect of SNP administration. When we administered SNP nearly 4 hours prior to MK-801, no cognitive improvements were observed. Our results suggest that SNP may have intrinsic cognitive enhancing properties but is not capable of reducing MK-801-induced working memory and pattern separation impairments in the TUNL task. This study failed to mirror the results of the human pilot study that observed improved working memory following SNP administration.iii Further, it did not replicate previous animal studies using ketamine. Ultimately, the findings suggest that the effects of MK-801 in the TUNL task may not hold the predictive validity needed for its use in the study of SNP. In order to advance the understanding of SNP, future studies should investigate other translatable paradigms to establish validity. iv ACKNOWLDGEMENTSFirst and foremost, I would like to thank my supervisor Dr. John Howland, for his guidance and encouragement over the past three years. He believed in my abilities before I had proven them to myself and pushed me to be the best scientist and student I could be. John has provided me with countless opportunities to grow as a researcher and selflessly helped me make decisions about my future. I would not be where I am today without him and will always be grateful to have had such an incredible mentor in my life.I would like to thank my committee members, Dr.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Mk-801-induced Impairmentsmentioning

confidence: 96%

Section: Nmda Receptor Hypofunction As a Model Of Schizophreniamentioning

confidence: 99%

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MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

et al. 2016

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“…These novel treatments reverse deficits on tasks, including paired associates learning and trial-unique, delayed nonmatchingto-location tasks. [105][106][107][108] NMDA receptor activation results in the production of neuronal nitric oxide (NO). Bujas-Bobanovic and colleagues 109 studied this relationship and found that PCPinduced effects in rats were blocked by the NO donor SNP.…”

Section: Drug-induced Modelsmentioning

confidence: 99%

An Overview of Animal Models Related to Schizophrenia

et al. 2018

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Schizophrenia is a heterogeneous psychiatric disorder that is poorly treated with current therapies. In this brief review, we provide an update regarding the use of animal models to study schizophrenia in an attempt to understand its aetiology and develop novel therapeutic strategies. Tremendous progress has been made developing and validating rodent models that replicate the aetiologies, brain pathologies, and behavioural abnormalities associated with schizophrenia in humans. Here, models are grouped into 3 categories-developmental, drug induced, and genetic-to reflect the heterogeneous risk factors associated with schizophrenia. Each of these models is associated with varied but overlapping pathophysiology, endophenotypes, behavioural abnormalities, and cognitive impairments. Studying schizophrenia using multiple models will permit an understanding of the core features of the disease, thereby facilitating preclinical research aimed at the development and validation of better pharmacotherapies to alter the progression of schizophrenia or alleviate its debilitating symptoms.

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Effects of the T-type calcium channel antagonist Z944 on paired associates learning and locomotor activity in rats treated with the NMDA receptor antagonist MK-801

et al. 2018

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Effects of the metabotropic glutamate receptor 5 positive allosteric modulator CDPPB on rats tested with the paired associates learning task in touchscreen-equipped operant conditioning chambers

Cited by 14 publications

References 48 publications

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

An Overview of Animal Models Related to Schizophrenia

Effects of the T-type calcium channel antagonist Z944 on paired associates learning and locomotor activity in rats treated with the NMDA receptor antagonist MK-801

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