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mGlu5 Signaling: A Target for Addiction Therapeutics?

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mGLU Receptors

Part of the book series: The Receptors ((REC,volume 31))

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Abstract

The role of metabotropic glutamate 5 (mGlu5) receptors in substance abuse disorders has been a focus of research for over a decade. In animal models, mGlu5 antagonists not only decrease drug taking but also drug seeking. It follows that mGlu5 antagonists are promising potential pharmacotherapeutic agents for the treatment of substance abuse. More recently, however, evidence has emerged that such compounds may in fact interfere with cognitive behavioral strategies for treatment of such disorders. mGlu5 receptors are linked to N-methyl-D-aspartate (NMDA) receptors via scaffold proteins and consequently are critical for NMDA receptor-dependent neural plasticity, giving them a prominent role in learning and memory. This is important because these processes are critical for rehabilitation treatment during recovery from substance abuse disorders. Therefore, although an antagonist or negative allosteric modulator (NAM) for mGlu5 may serve to decrease the reinforcing value of drugs such as cocaine or methamphetamine, it may also interfere with the process of behavioral change during treatment. Conversely, mGlu5 stimulation may actually serve to enhance this process. This chapter will follow the line of evidence supporting the idea that compounds that enhance mGlu5 receptor function may serve as useful adjuncts to behavioral therapy for substance abuse. We will also discuss the effects of chronic drug use on mGlu5 expression and function. We propose that mGlu5 PAMs in fact show promise as short-term adjuncts to behavioral therapy and could improve the long-term prognosis of such strategies.

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Abbreviations

CDPPB:

3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide

CET:

cue exposure therapy

LTD:

long-term depression

LTP:

long-term potentiation

mGlu5:

metabotropic glutamate 5

MPEP:

2-Methyl-6-(phenylethynyl)pyridine

MSN:

medium spiny neuron

MTEP:

3-((2-Methyl-4-thiazolyl)ethynyl)pyridine

NAM:

negative allosteric modulator

NMDA:

N-Methyl-D-aspartate

PAM:

positive allosteric modulator

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Acknowledgments

AJL is a Principal Research Fellow of the National Health and Medical Research Council (NHMRC) of Australia, and CJP is supported by NHMRC project grant number 1022201. These authors acknowledge support from the Victorian Government’s Operational Infrastructure Support Program. MFO wishes to acknowledge the support of the US National Institute of Health grants DA024355, DA025606, DA037741, and AA013852.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Authors and Affiliations

  1. Behavioural Neuroscience Division, Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC, 3052, Australia

    Christina J. Perry Ph.D. & Andrew J. Lawrence Ph.D., FBPhS

  2. Behavioral Neuroscience Area, Department of Psychology, Arizona State University, Tempe, AZ, USA

    M. Foster Olive Ph.D.

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  1. Christina J. Perry Ph.D.
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  2. M. Foster Olive Ph.D.
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  3. Andrew J. Lawrence Ph.D., FBPhS
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Correspondence to Christina J. Perry Ph.D. .

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Editors and Affiliations

  1. Neuropharmacology Unit I.N.M. Neuromed, I.N.M. Neuromed, Pozzilli, Isernia, Italy

    Richard Teke Ngomba

  2. Department of Physiology and Biochemistry, University of Malta, Malta, Italy

    Giuseppe Di Giovanni

  3. Neuropharmacology Unit, I.N.M. Neuromed, Pozzilli, Isernia, Italy

    Giuseppe Battaglia

  4. Dipartimento di Fisiologia Umana, Università di Roma, Roma, Italy

    Ferdinando Nicoletti

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Perry, C.J., Olive, M.F., Lawrence, A.J. (2017). mGlu5 Signaling: A Target for Addiction Therapeutics?. In: Ngomba, R., Di Giovanni, G., Battaglia, G., Nicoletti, F. (eds) mGLU Receptors. The Receptors, vol 31. Humana Press, Cham. https://doi.org/10.1007/978-3-319-56170-7_1

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