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Dissociable effects of mGluR5 allosteric modulation on distinct forms of impulsivity in rats: interaction with NMDA receptor antagonism

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Abstract

Rationale

Impaired N-methyl-d-aspartate (NMDA) receptor signalling underlies several psychiatric disorders that express high levels of impulsivity. Although synergistic interactions exist between NMDA receptors and metabotropic glutamate receptor 5 (mGluR5), the significance of this interaction for impulsivity is unknown.

Objective

This study aims to investigate the effects of negative and positive allosteric mGluR5 modulation (NAM/PAM) on trait impulsivity and impulsivity evoked by NMDA receptor antagonism in rats.

Methods

Motor and choice impulsivity were assessed using the five-choice serial reaction time task (5-CSRTT) and delayed-discounting task (DDT), respectively. The effects of RO4917523 and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) (NAMs) and ADX47273 (PAM) were investigated in non-impulsive rats and in trait high- and low-impulsive rats. The effects of these compounds on impulsivity induced by NMDA receptor antagonism (MK801) in the 5-CSRTT were also investigated.

Results

RO4917523 (0.1–1 mg/kg) decreased premature responding and increased omissions but had no effect on locomotor activity up to 0.1 mg/kg. MTEP significantly increased omissions, decreased accuracy and slowed responding but had no effect on premature responding. ADX47273 decreased premature responding at doses that had no effect on locomotor activity. MK801 increased premature responding and impaired attentional accuracy; these deficits were dose dependently rescued by ADX47273 pre-treatment. Allosteric modulation of mGluR5 had no significant effect on choice impulsivity, nor did it modulate general task performance.

Conclusions

These findings demonstrate that mGluR5 allosteric modulation selectively dissociates motor and choice impulsivity. We further show that mGluR5 PAMs may have therapeutic utility in selectively targeting specific aspects of impulsivity and executive dysfunction.

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Acknowledgements

This research was supported by a Medical Research Council (MRC) grant to JWD (G0701500) and a grant from Boehringer Ingelheim Pharma GmbH & Co. KG. This work was carried out in the Behavioural and Clinical Neuroscience Institute (BCNI) at Cambridge University with joint support from the MRC (G1000183) and Wellcome Trust (093875/Z/10/Z) and at Boehringer Ingelheim Pharma GmbH & Co. KG, Germany. We thank David Theobald, Johannes Freudenreich, Peter Schorn, Alfie Wearn and Benjamin Jaehnke for technical support and Gert Kramer, Dr. Holger Rosenbrock and Dr. Cornelia Dorner-Ciossek for helpful scientific discussions. The authors declare that the experiments performed in this manuscript followed the principles of laboratory animal care and are in compliance with the current laws of the UK and Germany.

Conflict of interest

The authors declare no conflict of interest.

Sarah Isherwood, Anton Pekcec and Janet Nicholson are employees of Boehringer Ingelheim Pharma GmbH & Co. KG

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Authors and Affiliations

  1. Boehringer Ingelheim Pharma GmbH & Co. KG, Div. Research Germany, Birkendorfer Strasse 65, 88397, Biberach an der Riss, Germany

    Sarah N. Isherwood, Anton Pekcec & Janet R. Nicholson

  2. Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK

    Sarah N. Isherwood, Trevor W. Robbins & Jeffrey W. Dalley

  3. Department of Psychiatry, University of Cambridge, Downing Street, Cambridge, CB2 2QQ, UK

    Jeffrey W. Dalley

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  1. Sarah N. Isherwood
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  2. Anton Pekcec
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Correspondence to Anton Pekcec.

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Isherwood, S.N., Pekcec, A., Nicholson, J.R. et al. Dissociable effects of mGluR5 allosteric modulation on distinct forms of impulsivity in rats: interaction with NMDA receptor antagonism. Psychopharmacology 232, 3327–3344 (2015). https://doi.org/10.1007/s00213-015-3984-0

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