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