Metabotropic glutamate receptor ligands as potential therapeutics for addiction

Abstract

There is now compelling evidence that the excitatory amino acid neurotransmitter glutamate plays a pivotal role in drug addiction and alcoholism. As a result, there has been increasing interest in developing glutamate-based therapies for the treatment of addictive disorders. Receptors for glutamate are primarily divided into two classes: ionotropic glutamate receptors (iGluRs) that mediate fast excitatory glutamate transmission, and metabotropic glutamate receptors (mGluRs), which are G-protein coupled receptors that mediate slower, modulatory glutamate transmission. Most iGluR antagonists, while showing some efficacy in animal models of addiction, exhibit serious side effects when tested in humans. mGluR ligands, on the other hand, which have been advanced to testing in clinical trials for various medical conditions, have demonstrated the ability to reduce drug reward, reinforcement, and relapse-like behaviors in animal studies. mGluR ligands that have been shown to be primarily effective are Group I (mGluR1 and mGluR5) negative allosteric modulators and Group II (mGluR2 and mGluR3) orthosteric presynaptic autoreceptor agonists. In this review, we will summarize findings from animal studies suggesting that these mGluR ligands may be of potential benefit in reducing on-going drug self-administration and may aid in the prevention of relapse. The neuroanatomical distribution of mGluR1, mGluR2/3, and mGluR5 receptors and the pharmacological properties of Group I negative allosteric modulators and Group II agonists will also be overviewed. Finally, we will discuss the current status of mGluR ligands in human clinical trials.

Fig. 1

The glutamatergic synapse. When an action potential arrives at the terminal, glutamate is released by exocytosis into the synaptic cleft where it binds to and activates iGluRs (NMDA, AMPA and KA receptors) localized on the postsynaptic neuron, which results in cation influx and subsequent activation of VGCCs that propagate the action potential. Glutamate can also be released into the extracellular space via nonexocytotic mechanisms such as cystine-glutamate-exchanger (x_c) located on glial cells. Whether released from the presynaptic terminal or neighboring glial cells, extracellular glutamate binds and activates not only iGluRs but also postsynaptic mGluRs in the perisynaptic annulus. Glutamate release from the presynaptic terminal is negatively regulated by Group II or III mGluR autoreceptors, which are negatively coupled to adenylyl cyclase (AC). On the postsynaptic neuron, there are bidirection interactions between Group I mGluRs and NMDA receptors. In glia, glutamate is converted to glutamine, which is then transported back to the presynaptic terminal and converted back to glutamate.

Fig. 2

Chemical structures of Group I mGluR NAMs and Group II orthosteric agonists. See Table 2 for chemical names and abbreviations. Note that the structures of EMQMCM, an mGluR1 antagonist, and ADX10059, a negative allosteric modulator (NAM) of mGluR5 receptors, have not been published and are therefore not shown in this figure.