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mGluR5 positive allosteric modulation and its effects on MK-801 induced set-shifting impairments in a rat operant delayed matching/non-matching-to-sample task

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Abstract

Rationale

Positive allosteric modulators (PAMs) of type 5 metabotropic glutamate receptors (mGluR5) exert pro-cognitive effects in animal models of various neuropsychiatric diseases. However, few studies to date have examined ability of mGluR5 PAMs to reverse cognitive deficits in operant delayed matching/non-matching-to-sample (DMS/DNMS) tasks.

Objectives

This study aims to determine the ability of the mGluR5 PAM 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) to reverse set-shifting deficits induced by the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801.

Methods

Male Sprague-Dawley rats were initially trained to lever press for sucrose reinforcement under either DMS or DNMS conditions. Following successful acquisition of the task, reinforcement conditions were reversed (DNMS → DMS or DMS → DNMS). In Experiment 1, rats were treated daily prior to each session with vehicle/vehicle, vehicle/MK-801 (0.06 mg/kg) simultaneously, CDPPB (20 mg/kg)/MK-801 simultaneously, or CDPPB 30 min prior to MK-801. In Experiment 2, rats were treated with either vehicle/vehicle, vehicle/MK-801, or CDPPB 30 min prior to MK-801 only prior to sessions that followed task reversal.

Results

In Experiment 1, no group differences in initial task acquisition were observed. Rats treated with vehicle/MK-801 showed significant set-shifting impairments following task reversal, which were partially attenuated by simultaneous administration of CDPPB/MK-801 and completely precluded by administration of CDPPB 30 min prior to MK-801. In Experiment 2, MK-801 did not impair reversal learning, and no other group differences were observed.

Conclusions

MK-801-induced deficits in operant set-shifting ability were prevented by pretreatment with CDPPB. MK-801 did not produce deficits in task learning when treatment was initiated following task reversal.

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Acknowledgments

This work was funded by NIH grant DA024355 to MFO.

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Authors and Affiliations

  1. Department of Psychology, Arizona State University, Tempe, AZ, USA

    Amber L. LaCrosse, Brian T. Burrows, Rachel M. Angulo, Phoebe R. Conrad, Sarah M. Himes, Nordia Mathews, Scott A. Wegner, Sara B. Taylor & M. Foster Olive

  2. Interdisciplinary Graduate Program in Neuroscience, Arizona State University, Tempe, AZ, USA

    M. Foster Olive

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  1. Amber L. LaCrosse
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  2. Brian T. Burrows
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Correspondence to Amber L. LaCrosse.

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LaCrosse, A.L., Burrows, B.T., Angulo, R.M. et al. mGluR5 positive allosteric modulation and its effects on MK-801 induced set-shifting impairments in a rat operant delayed matching/non-matching-to-sample task. Psychopharmacology 232, 251–258 (2015). https://doi.org/10.1007/s00213-014-3653-8

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