Using metabotropic glutamate receptors to modulate cocaine's synaptic and behavioral effects: mGluR1 finds a niche

doi:10.1016/j.conb.2013.01.009

Current Opinion in Neurobiology

Volume 23, Issue 4, August 2013, Pages 500-506

https://doi.org/10.1016/j.conb.2013.01.009 Get rights and content

Group I metabotropic glutamate receptors (mGluR) are important modulators of excitatory synaptic transmission and therefore potential targets for drug development. In several brain regions (ventral tegmental area (VTA), cerebellum, and amygdala), stimulation of mGluR1 selectively inhibits synaptic transmission mediated by calcium-permeable AMPA receptors (CP-AMPARs) and thus produces synaptic depression. The same relationship has now been demonstrated in the nucleus accumbens (NAc), a region that is critical for cocaine craving. CP-AMPAR levels in NAc synapses are normally low, but they increase after prolonged withdrawal from extended-access cocaine self-administration (SA). These CP-AMPARs mediate the intensified (‘incubated’) cue-induced cocaine craving observed under these conditions. Therefore, activation of mGluR1 with positive allosteric modulators (PAM) may reduce cue-induced relapse in abstinent cocaine addicts.

Highlights

► The review focuses on group I mGluR-based strategies for reducing cocaine craving. ► Across brain regions, mGluR1 inhibits Ca²⁺-permeable AMPAR (CP-AMPAR) function. ► CP-AMPARs accumulate in nucleus accumbens after specific types of cocaine exposure. ► Positive allosteric modulators of mGluR1 may reduce craving after such exposure. ► Cocaine history and resulting adaptations determine optimal therapeutic strategy.

Introduction

The group I metabotropic glutamate receptors (mGluR1 and mGluR5) are predominantly postsynaptic receptors that couple to the G_q-like class of G-proteins and are important in modulating neurotransmission and plasticity through their linkages with multiple signaling pathways as well as NMDA receptors [1]. Compounds that negatively or positively modulate group I mGluRs have been the focus of intense interest due to their potential to tune glutamate transmission up or down in disease states. Drug addiction has been recognized for many years as a disorder involving glutamate transmission and maladaptive plasticity [2, 3], so it is not surprising that considerable effort has been directed at evaluating group I mGluR modulators in animal models of addiction [4, 5].

This review will focus on group I mGluRs in the nucleus accumbens (NAc) and cocaine addiction. The NAc is a critical brain region for cocaine craving that expresses significant levels of both mGluR1 and mGluR5, mainly in extrasynaptic and perisynaptic regions [6, 7•, 8•, 9]. While most studies on the role of group I mGluRs in addiction have focused on negative allosteric modulators (NAM) of mGluR5, we will argue that the optimal group I mGluR-based strategy for treating cocaine addiction depends on the nature of cocaine exposure which in turn defines the nature of adaptations in the NAc. In particular, emerging evidence reviewed herein suggests that positive allosteric modulators (PAM) of mGluR1 may prevent cue-induced relapse in abstinent cocaine addicts by removing Ca²⁺-permeable AMPA receptors (CP-AMPARs) from NAc synapses.

Section snippets

Negative allosteric modulators of group I mGluRs in animal models of cocaine addiction

The focus on negative modulation of mGluR5 dates from a report in 2001 that mGluR5 knockout mice neither exhibit increased locomotor activity after cocaine injection nor learn to self-administer cocaine [10^•]. Subsequent studies extended these findings by showing that mGluR5 NAMs such as MPEP or MTEP prevented the development of cocaine conditioned place preference, reduced motivation to self-administer cocaine in progressive ratio experiments, and reduced reinstatement of cocaine seeking in

CP-AMPARs and mGluR1: a unique relationship

AMPARs are tetramers comprised of GluA1–4 subunits. In most brain regions of the adult drug-naïve rat, including the NAc [14, 15, 16••, 17], the majority of AMPARs on principal neurons contain the GluA2 subunit. However, there is a minority population that lacks GluA2. Compared to GluA2-containing receptors, this population exhibits Ca²⁺-permeability, larger single channel conductance and faster kinetics, and voltage-dependent block by intracellular polyamines resulting in inward rectification.

CP-AMPARs and mGluR1 in the NAc: regulators of cocaine craving

Our interest in the aforementioned effects of mGluR1 on CP-AMPAR transmission arose from our studies in a particular animal model of cocaine addiction called the incubation model. Incubation refers to the progressive intensification of cue-induced cocaine craving that occurs over the first two months of withdrawal from extended-access cocaine self-administration (SA); this reflects very persistent neuroadaptations, because craving remains elevated even 6 months after the last drug exposure [41,

Concluding remarks

As noted in the Introduction, many studies have found that group I mGluRs contribute to behavioral responses to cocaine and that negative modulation of group I mGluRs may therefore be useful in treating addiction [4, 5]. Contrary to this literature, our preliminary studies show that mGluR1 activation is sufficient to block the NAc CP-AMPAR transmission that mediates incubated cue-induced cocaine craving. Thus, after extended-access cocaine SA and prolonged withdrawal (the conditions that lead

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

This work was supported by National Institutes of Health grants DA009621 (M.E.W. and K.Y.T.) and postdoctoral National Research Service Award F32 DA030844 (J.A.L.). We thank Craig T. Werner for assistance with designing the figure.

References (61)

C. Lüscher et al.
Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease
Neuron
(2010)
M.E. Wolf et al.
Psychomotor stimulants and neuronal plasticity
Neuropharmacology
(2004)
M.F. Olive
Cognitive effects of Group I metabotropic glutamate receptor ligands in the context of drug addiction
Eur J Pharmacol
(2010)
D.A. Mitrano et al.
Ultrastructural relationships between cortical, thalamic, and amygdala glutamatergic inputs and group I metabotropic glutamate receptors in the rat accumbens
J Comp Neurol
(2010)
H.-K. Lee
Ca²⁺-permeable AMPA receptors in homeostatic synaptic plasticity
Front Mol Neurosci
(2012)
G.L. Gerdeman et al.
It could be habit forming: drugs of abuse and striatal synaptic plasticity
Trends Neurosci
(2003)
B.A. Grueter et al.
Group I mGluRs and long-term depression: potential roles in addiction?
Mol Neurobiol
(2007)
M.A. Ungless et al.
Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons
Nature
(2001)
C. Bellone et al.
mGluRs induce a long-term depression in the ventral tegmental area that involves a switch of the subunit composition of AMPA receptors
Eur J Neurosci
(2005)
E. Argilli et al.
Mechanism and time course of cocaine-induced long-term potentiation in the ventral tegmental area
J Neurosci
(2008)

M.E. Wolf et al.

AMPA receptor plasticity in the nucleus accumbens after repeated exposure to cocaine

Neurosci Biobehav Rev

(2010)

J.E. McCutcheon et al.

Group I mGluR activation reverses cocaine-induced accumulation of calcium-permeable AMPA receptors in nucleus accumbens synapses via a protein kinase C-dependent mechanism

J Neurosci

(2011)

S. Mangiavacchi et al.

D1 dopamine receptor stimulation increases the rate of AMPA receptor insertion onto the surface of cultured nucleus accumbens neurons through a pathway dependent on protein kinase A

J Neurochem

(2004)

K. Moussawi et al.

N-acetylcysteine reverses cocaine-induced metaplasticity

Nat Neurosci

(2009)

P.W. Kalivas

The glutamate homeostasis hypothesis of addiction

Nat Rev Neurosci

(2009)

S.E. Hyman et al.

Neural mechanisms of addiction: the role of reward-related learning and memory

Annu Rev Neurosci

(2006)

M.F. Olive

Metabotropic glutamate receptor ligands as potential therapeutics for addiction

Curr Drug Abuse Rev

(2009)

C.M. Testa et al.

Metabotropic glutamate receptor mRNA expression in the basal ganglia of the rat

J Neurosci

(1994)

D.A. Mitrano et al.

Comparative analysis of the subcellular and subsynaptic localization of mGluR1a and mGluR5 metabotropic glutamate receptors in the shell and core of the nucleus accumbens in rat and monkey

J Comp Neurol

(2007)

D.A. Mitrano et al.

Subcellular and subsynaptic localization of group I metabotropic glutamate receptors in the nucleus accumbens of cocaine-treated rats

Neuroscience

(2008)

C. Chiamulera et al.

Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice

Nat Neurosci

(2001)

X. Xie et al.

Subregion-specific role of glutamate receptors in the nucleus accumbens on drug context-induced reinstatement of cocaine-seeking behavior in rats

Addict Biol

(2012)

X. Xie et al.

Effects of mGluR1 antagonism in the dorsal hippocampus on drug context-induced reinstatement of cocaine-seeking behavior in rats

Psychopharmacology (Berl)

(2010)

O.A. Dravolina et al.

Effects of group I metabotropic glutamate receptor antagonists on the behavioral sensitization to motor effects of cocaine in rats

Psychopharmacology (Berl)

(2006)

A.C. Boudreau et al.

Cell surface AMPA receptors in the rat nucleus accumbens increase during cocaine withdrawal but internalize after cocaine challenge in association with altered activation of mitogen-activated protein kinases

J Neurosci

(2007)

S. Kourrich et al.

Cocaine experience controls bidirectional synaptic plasticity in the nucleus accumbens

J Neurosci

(2007)

K.L. Conrad et al.

Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving

Nature

(2008)

J.M. Reimers et al.

Quantitative analysis of AMPA receptor subunit composition in addiction-related brain regions

Brain Res

(2011)

S. Cull-Candy et al.

Regulation of Ca²⁺-permeable AMPA receptors: synaptic plasticity and beyond

Curr Opin Neurobiol

(2006)

J.T.R. Isaac et al.

The role of the GluR2 subunit in AMPA receptor function and synaptic plasticity

Neuron

(2007)

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Our results indicate that mGlu₁-LTD in the NAc and consequently the reduction of cue-induced seeking occur through activation of the ISR, which induces translation of oligophrenin-1. We also demonstrate CP-AMPAR accumulation and mGlu₁ reversal in female rats, as previously shown in male rats.
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The incubation of cue-induced drug craving in rodents provides a model of persistent vulnerability to craving and relapse in human addicts. After prolonged withdrawal, incubated cocaine craving depends on strengthening of nucleus accumbens (NAc) core synapses through incorporation of Ca²⁺-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (CP-AMPARs). Through metabotropic glutamate receptor 1 (mGluR1)–mediated synaptic depression, mGluR1 positive allosteric modulators remove CP-AMPARs from these synapses and thereby reduce cocaine craving. This study aimed to determine if similar plasticity accompanies incubation of methamphetamine craving.
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Citation Excerpt :
Notably, excitatory synapses in the LHb contain rectifying GluA2-lacking AMPA-Rs (Maroteaux and Mameli, 2012). A recent hypothesis posits that GluA2-lacking AMPA-R expression represents a predictive factor for a postsynaptic mGluR1-LTD requiring a subunit composition switch (Loweth et al., 2013). However, mGluR1 activation in the LHb reduces excitatory synaptic transmission while leaving the GluA2-lacking AMPA-R current-voltage relationship unchanged.
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Using metabotropic glutamate receptors to modulate cocaine's synaptic and behavioral effects: mGluR1 finds a niche

Highlights

Introduction

Section snippets

Negative allosteric modulators of group I mGluRs in animal models of cocaine addiction

CP-AMPARs and mGluR1: a unique relationship

CP-AMPARs and mGluR1 in the NAc: regulators of cocaine craving

Concluding remarks

References and recommended reading

Acknowledgements

Neuron

Neuropharmacology

Eur J Pharmacol

J Comp Neurol

Front Mol Neurosci

Trends Neurosci

Mol Neurobiol

Nature

Eur J Neurosci

J Neurosci

Neurosci Biobehav Rev

J Neurosci

J Neurochem

Nat Neurosci

Nat Rev Neurosci

Neural mechanisms of addiction: the role of reward-related learning and memory

Annu Rev Neurosci

Metabotropic glutamate receptor ligands as potential therapeutics for addiction

Curr Drug Abuse Rev

Metabotropic glutamate receptor mRNA expression in the basal ganglia of the rat

J Neurosci

Comparative analysis of the subcellular and subsynaptic localization of mGluR1a and mGluR5 metabotropic glutamate receptors in the shell and core of the nucleus accumbens in rat and monkey

J Comp Neurol

Subcellular and subsynaptic localization of group I metabotropic glutamate receptors in the nucleus accumbens of cocaine-treated rats

Neuroscience

Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice

Nat Neurosci

Subregion-specific role of glutamate receptors in the nucleus accumbens on drug context-induced reinstatement of cocaine-seeking behavior in rats

Addict Biol

Effects of mGluR1 antagonism in the dorsal hippocampus on drug context-induced reinstatement of cocaine-seeking behavior in rats

Psychopharmacology (Berl)

Effects of group I metabotropic glutamate receptor antagonists on the behavioral sensitization to motor effects of cocaine in rats

Psychopharmacology (Berl)

Cell surface AMPA receptors in the rat nucleus accumbens increase during cocaine withdrawal but internalize after cocaine challenge in association with altered activation of mitogen-activated protein kinases

J Neurosci

Cocaine experience controls bidirectional synaptic plasticity in the nucleus accumbens

J Neurosci

Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving

Nature

Quantitative analysis of AMPA receptor subunit composition in addiction-related brain regions

Brain Res

Regulation of Ca2+-permeable AMPA receptors: synaptic plasticity and beyond

Curr Opin Neurobiol

The role of the GluR2 subunit in AMPA receptor function and synaptic plasticity

Neuron

Regulation of Ca²⁺-permeable AMPA receptors: synaptic plasticity and beyond