Metabotropic glutamatergic receptors and their ligands in drug addiction

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Abstract

Glutamatergic excitatory transmission is implicated in physiological and pathological conditions like learning, memory, neuronal plasticity and emotions, while glutamatergic abnormalities are reported in numerous neurological and psychiatric disorders, including neurodegenerative diseases, epilepsy, stroke, traumatic brain injury, depression, anxiety, schizophrenia and pain. Also, several lines of evidence have accumulated indicating a pivotal role for glutamatergic neurotransmission in mediating addictive behaviors. Among the proteins regulating glutamatergic transmission, the metabotropic glutamate receptors (mGluR) are being developed as pharmacological targets for treating many neuropsychiatric disorders, including drug addiction. In this review we describe the molecular structure of mGluRs and their distribution, physiology and pharmacology in the central nervous system, as well as their use as targets in preclinical studies of drug addiction.

Introduction

Glutamate (Glu) is the primary excitatory neurotransmitter and mediates nearly 70% of synaptic transmission within the central nervous system (CNS). Glu acts through three types of ionotropic (iGlu) receptors (e.g. NMDA, AMPA and kainate) and eight metabotropic (mGlu) glutamatergic receptors that are localized in almost all brain areas. The localization of Glu receptors and their expression in a typical glutamatergic synapse are shown in Fig. 1 and in the Table 1. iGlu receptors are ion channels, responsible for fast synaptic neurotransmission. Pharmacological agonists and antagonists of iGlu receptors are not primarily targeted in the search for new drugs because their activation leads to toxic damage neurons, while their inhibition induces strong psychomimetic effects, impairment of cognitive function and neuronal toxicity (Kew & Kemp, 2005). mGlu receptors, on the other hand, have become important targets for medication development because of their more modulatory role on transmission at glutamatergic and other synapses (Kew & Kemp, 2005). In this review we describe in detail the structure, distribution, functional effects in the CNS of mGlu receptors and potential usefulness of their ligands in psychiatric disorders with drug addiction being a topic of focus.

Drug addiction is a chronic disease characterized by compulsive drug use and loss of control over intake. Impairment evoked by abuse of addictive drugs begins in the brain areas responsible for processing reward, whereas long-term drug intake disrupts brain physiology, and leads to dysfunctions in emotion, motivation, learning, memory, executive control and cognitive awareness. These functions are executed by the amygdala and hippocampus (memory and learning), the dorsal striatum (habit forming learning) and the prefrontal cortex (motivation and compulsive behaviors, salience attribution, inhibitory control) (Volkow et al., 2003). All of the above behavioral functions are under control of Glu neurotransmission (Tzschentke and Schmidt, 2003, Volkow et al., 2003, Kalivas, 2004), which by itself is a cellular mediator of synaptic plasticity, as well as learning and memory processes.

Drugs of abuse belonging to different chemical classes (psychostimulants, opioids, cannabinoids, nicotine) do not reinforce behavior via pharmacological actions directly on Glu transmission (Sizemore et al., 2000, McFarland et al., 2003, Madayag et al., 2007, Miguens et al., 2008, Lominac et al., 2012, Wydra et al., 2013). Ethanol, as the exception, does directly inhibiting neuronal NMDA receptor function via a non-competitive mechanism that induces the phosphorylation and internalization of the NR2 receptor subunits (for review see Gass & Olive, 2008). However, this action is not thought to be directly related to ethanol's reinforcing properties. It was established that both the development and expression of behaviors modeling aspects of drug addiction (sensitization, reinstatement of drug seeking) promote Glu release from the corticofugal and allocortical glutamatergic projections from the prefrontal cortex and amygdala to the ventral tegmental area and to the core of the nucleus accumbens. The most prominent changes in the Glu system are reported during withdrawal from chronic treatment with cocaine, methamphetamine, heroin, nicotine or alcohol, and during drug-induced relapse. Early (6 h) withdrawal from acute cocaine administration induces emerging changes in the accumbal number of Glu synapses and spine density associated with a deteriorating actin cytoskeleton and a reduction in Glu signaling-related proteins (Shen et al., 2009). Withdrawal from psychostimulant or nicotine self-administration in rodents results in reduced basal accumbal extracellular Glu (Miguens et al., 2008, Kalivas, 2009, Lominac et al., 2012, Wydra et al., 2013), together with changes in mechanisms responsible for Glu clearance. The most significant reduction is noted for the membrane level of the cystine–Glu antiporter (system xc-) (Madayag et al., 2007, Pendyam et al., 2009); this antiporter mediates the exchange of extracellular l-cystine and intracellular Glu across the cellular plasma membrane (McBean & Flynn, 2001). A reduction of the astrocytic membrane expression of EAAT2 (GLT1) due to chronic cocaine, alcohol and nicotine self-administration is found, too (Knackstedt et al., 2010, Sari et al., 2011, Gipson, Kupchik, et al., 2013, Gipson, Reissner, et al., 2013). The changes in extracellular Glu during drug withdrawal are critically involved in relapse-like behavior because pharmacological activation of system xc- or EAAT2 by N-acetylcysteine or ceftriaxone reverses changes in basal and relapse associated changes in extracellular Glu level, and inhibits drug seeking and relapse (Baker et al., 2003, Moran et al., 2005, Zhou and Kalivas, 2008, Moussawi et al., 2009, Sari et al., 2009, Knackstedt et al., 2010). On the other hand, the release of Glu during drug seeking (Miguens et al., 2008, Kalivas, 2009, Lominac et al., 2012) elicits rapid postsynaptic changes in proteins regulating Glu signaling and surface spine morphology (McFarland et al., 2003, Brebner et al., 2005, Gipson, Reissner, et al., 2013), while attenuation of Glu transmission reduces drug reinforcement and relapse-like behavior. The potentiation of Glu transmission, from prefrontal glutamatergic neurons to the accumbal core during drug seeking behaviors is also critical to drug-associated memories (Kalivas, 2009). Altered synaptic Glu content following repeated exposure to drugs of abuse contributes to significant adaptations in iGlu receptors (for review see: Gass and Olive, 2008, Kalivas, 2009, Schmidt and Pierce, 2010, Wolf, 2010; see also recent findings by Wolf and Ferrario, 2010, Yamamoto and Zahniser, 2012, Gipson, Kupchik, et al., 2013, Gipson, Reissner, et al., 2013) and mGlu receptors (see below) in cortical and subcortical brain areas.

Section snippets

Metabotropic glutamatergic receptors

mGlu receptors are composed of 872–912 amino acids and the number of amino acids exceeds other metabotropic receptors, which contain no more than 590 amino acids. mGlu receptors are a family of G-protein–coupled receptors, and consist of seven closely located hydrophobic segments separated by three extracellular and three intracellular loops. A relatively large N-terminal extracellular domain contains the Glu-binding site and cysteine-rich region (19 cysteines), whereas the intracellular

Final conclusions

Although clinical exploration of mGlu receptor ligands has focused on disorders outside of addiction-related disorders, the widespread mGlu receptor localization in the brain areas linked to drug reward and seeking indicates that mGlu receptor ligands should be evaluated for pharmacological properties associated with drug addiction. Supporting this approach, several preclinical studies in the last decade implicate the importance of mGlu1, mGlu2/3, mGlu5 and mGlu7 receptors in the control of the

Acknowledgments

This study was supported by the grant NN40 545340 from the Ministry of Science and Higher Education (Warszawa, Poland), the Department of Toxicology, Faculty of Pharmacy Jagiellonian University (Kraków, Poland) and the Institute of Pharmacology (Kraków, Poland).

Conflict of interest statement

The authors declare that there are no conflicts of interest.

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