Differential modulation of thresholds for intracranial self-stimulation by mGlu5 positive and negative allosteric modulators: implications for effects on drug self-administration

Richard M Cleva

doi:10.3389/fphar.2011.00093

Abstract

Pharmacological manipulation of the type 5 metabotropic glutamate (mGlu5) receptor alters various addiction related behaviors such as drug self-administration and the extinction and reinstatement of drug-seeking behavior. However, the effects of pharmacological modulation of mGlu5 receptors on brain reward function have not been widely investigated. We examined the effects of acute administration of positive and negative allosteric modulators (PAMs and NAMs, respectively) on brain reward function by assessing thresholds for intracranial self-stimulation (ICSS). In addition, when acute effects were observed, we examined changes in ICSS thresholds following repeated administration. Male Sprague-Dawley rats were implanted with bipolar electrodes into the medial forebrain bundle and trained to respond for ICSS, followed by assessment of effects of mGlu5 ligands on ICSS thresholds using a discrete trials current–intensity threshold determination procedure. Acute administration of the selective mGlu5 NAMs MTEP (0, 0.3, 1, or 3 mg/kg) and fenobam (0, 3, 10, or 30 mg/kg) dose-dependently increased ICSS thresholds (∼70% at the highest dose tested), suggesting a deficit in brain reward function. Acute administration of the mGlu5 PAMs CDPPB (0, 10, 30, and 60 mg/kg) or ADX47273 (0, 10, 30, and 60 mg/kg) was without effect at any dose tested. When administered once daily for five consecutive days, the development of tolerance to the ability of threshold-elevating doses of MTEP and fenobam to increase ICSS thresholds was observed. We conclude that mGlu5 PAMs and NAMs differentially affect brain reward function, and that tolerance to the ability of mGlu5 NAMs to reduce brain reward function develops with repeated administration. These brain reward deficits should be taken into consideration when interpreting acute effects of mGlu5 NAMs on drug self-administration, and repeated administration of these ligands may be an effective method to reduce these deficits.

Highlights

The type 5 metabotropic glutamate receptor has been implicated in numerous CNS functions including synaptic plasticity, learning and memory, cognition, nociception, affect regulation, and motivated behaviors (Niswender and Conn, 2010). mGlu5 receptors are involved in numerous CNS diseases such as depression, anxiety, schizophrenia, epilepsy, chronic pain, Fragile X syndrome, and drug addiction (Spooren et al, 2001; Bird and Lawrence, 2009a,b; Krystal et al, 2010; Niswender and Conn, 2010)
Acute administration of the mGlu5 positive allosteric modulators (PAMs) CDPPB and ADX47273 are without effect on intracranial self-stimulation (ICSS) thresholds, suggesting an absence of alteration in brain reward function
In contrast to the lack of observed effects of acute administration of mGlu5 PAMs, acute administration of the mGlu5 negative allosteric modulator (NAM) MTEP and fenobam dose-dependently increased ICSS thresholds, which is reflective of decreased brain reward function (Kornetsky and Esposito, 1979; Kornetsky and Bain, 1992; Markou and Koob, 1992)

Summary

Introduction

The type 5 metabotropic glutamate (mGlu5) receptor has been implicated in numerous CNS functions including synaptic plasticity, learning and memory, cognition, nociception, affect regulation, and motivated behaviors (Niswender and Conn, 2010). mGlu receptors are involved in numerous CNS diseases such as depression, anxiety, schizophrenia, epilepsy, chronic pain, Fragile X syndrome, and drug addiction (Spooren et al, 2001; Bird and Lawrence, 2009a,b; Krystal et al, 2010; Niswender and Conn, 2010). Antagonism of mGlu receptors with the negative allosteric modulator (NAM) 2-methyl6-(phenylethynyl) pyridine (MPEP) was first demonstrated to www.frontiersin.org mGlu modulation of brain reward reduce thresholds for ICSS by Harrison et al (2002). These findings were subsequently replicated by Kenny et al (2003, 2005) who advanced the hypothesis that inhibition of mGlu receptor function may reduce cocaine self-administration by reducing brain reward function. MGlu receptor NAMs that exhibit increased selectivity for mGlu receptors with fewer off-target effects have been developed, including 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (MTEP; Cosford et al, 2003) and 1-(3-chlorophenyl)-3-(3-methyl-5-oxo-4H-imidazol2-yl)urea (fenobam; Porter et al, 2005; Montana et al, 2009)

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