Elsevier

Biological Psychiatry

Volume 83, Issue 11, 1 June 2018, Pages 947-954
Biological Psychiatry

Review
Metabotropic Glutamate Receptors 2 and 3 as Targets for Treating Nicotine Addiction

https://doi.org/10.1016/j.biopsych.2017.11.021Get rights and content

Abstract

Tobacco smoking, driven by the addictive properties of nicotine, continues to be a worldwide health problem. Based on the well-established role of glutamatergic neurotransmission in drug addiction, novel medication development strategies seek to halt nicotine consumption and prevent relapse to tobacco smoking by modulating glutamate transmission. The presynaptic inhibitory metabotropic glutamate receptors 2 and 3 (mGluR2/3) are key autoreceptors on glutamatergic terminals that maintain glutamate homeostasis. Accumulating evidence suggests the critical role of mGluR2/3 in different aspects of nicotine addiction, including acquisition and maintenance of nicotine taking, nicotine withdrawal, and persistent nicotine seeking even after prolonged abstinence. The involvement of mGluR2/3 in other neuropsychiatric conditions, such as anxiety, depression, schizophrenia, Alzheimer’s disease, Parkinson’s disease, and pain, provides convincing evidence suggesting that mGluR2/3 may provide an effective therapeutic approach for comorbidity of smoking and these conditions. This focused review article highlights that mGluR2/3 provide a promising target in the search for smoking cessation medication with novel mechanisms of actions that differ from those of currently U.S. Food and Drug Administration–approved pharmacotherapies.

Section snippets

Neurobiology of mGluR2/3

Protein and messenger RNA expression studies reveal mGluR2/3 to be distributed in brain regions and circuits associated with neuropsychiatric disorders, including drug addiction. High density of mGluR2/3 has been identified in brain areas related to processing of reward, motivated behaviors, learning, memory, and emotion, including the nucleus accumbens (NAc), dorsal striatum, hippocampus, amygdala, prefrontal cortex (PFC), thalamus, and olfactory bulb 24, 25, 26. Although the distributions of

mGluR2/3 and Nicotine Reward

Nicotine addiction is characterized by the persistence of compulsive nicotine taking, the emergence of aversive withdrawal symptoms on abstinence from smoking (e.g., anhedonia, anxiety, craving, and irritability), and relapse to tobacco smoking even after periods of abstinence (37). Tobacco smoking or nicotine administration produces mild euphoria, increased arousal, relaxation, and decreased fatigue in humans. The rewarding effects and conditioned reinforcement of nicotine drive the

mGluR2/3 and Nicotine Withdrawal

In humans, nicotine withdrawal is associated with negative affective symptoms, such as anxiety, depression, and irritability (37). In contrast to the somatic signs that are primarily peripherally mediated, the centrally mediated negative affective withdrawal signs are hypothesized to critically contribute to the persistence of nicotine taking and relapse to smoking after abstinence 61, 64, 65, 66, 67, 68. Hence, amelioration of these affective signs of early nicotine withdrawal may prevent

mGluR2/3 and Reinstatement of Nicotine Seeking

A high rate of relapse to smoking is a major hurdle to long-term quitting. Maintenance of tobacco smoking is largely driven by conditioned motivational effects of environmental stimuli (e.g., the sight and smell of a lit cigarette or contexts within which smoking occurs) previously associated with smoking 93, 94. These conditioned cues also play an important role in relapse to smoking in humans 95, 96, 97. Smokers report strong urges to smoke after being exposed to specific environments in

mGluR2/3 and Smoking-Associated Psychiatric Disorders

As the primary excitatory neurotransmitter in the brain, glutamate is implicated in a wide range of brain functions. In addition to drug addiction, imbalances in glutamate neurotransmission have been implicated in the pathophysiology of different neurological and psychiatric conditions, such as anxiety disorders, major depression, schizophrenia, and chronic pain. As the key regulators of glutamate homeostasis, mGluR2/3 appear to be critically involved in these conditions and have been

Medication Development Targeting mGluR2/3

Owing to the high level of conservation within the extracellular orthosteric binding site of mGluR2 and mGluR3 (117), all the well-validated compounds currently commercially available bind with similar affinity to both receptors, making it impossible to distinguish the function of each receptor with these pharmacological tools. In recent years, selective mGluR2 PAMs that act on less well-conserved allosteric receptor sites within transmembrane spanning domains have been synthesized 40, 41, 118.

Acknowledgments and Disclosures

This work was supported by the National Institute on Drug Abuse Grant Nos. R56DA011946 (to AM) and R21DA040195 (to XL), Tobacco-Related Disease Research Program, University of California, Grant Nos. 20KT-0046 (to XL) and 24RT-0034 (to XL), AstraZeneca (AM), and National Institute on Drug Abuse and Department of Veterans Affairs Cooperative Studies Program Grant Nos. 032 and 1033 (to RA).

AJC and XL report no biomedical financial interests or potential conflicts of interest. RA provides

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      Citation Excerpt :

      mGluRs are primarily presynaptic inhibitory receptors suppressing Glu excitability. One study has demonstrated that activation of mGluRs 2/3 in the terminals of glutamatergic neurons inhibited glutamate release [85], resulting in impulsive nicotine-seeking behavior [86]. Sevoflurane anesthesia impaired the inhibitory function of mGluR through upregulating small conductance calcium-activated potassium type 2 channels [87].

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      The long-term effects of adolescent nicotine exposure on mGluR down-regulation in the PFC, VTA, and NAc, and the resulting behavioral and cognitive deficits are also of interest (Counotte et al., 2011). The mGluR2/3 subtype is most often implicated in nicotine addiction and self-administration (Counotte et al., 2011; Cross, Anthenelli, & Li, 2018; Liechti, Lhuillier, Kaupmann, & Markou, 2007). Lower adulthood mGluR2 expression in the rat PFC following adolescent, but not adult, nicotine exposure is also thought to underlie lasting attentional deficits (Counotte et al., 2011).

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      A list of allosteric modulators used in preclinical investigations of AUD and other substance use disorders (SUDs) can be found in Table 1. Although it is outside the scope of this chapter, there is extensive literature detailing preclinical investigations of mGlu receptor orthosteric and allosteric ligands on reward, consumption, and seeking of other psychoactive drugs, and we refer readers to several recent reviews that address these topics (Barnes, Sheffler, Semenova, Cosford, & Bespalov, 2018; Caprioli, Justinova, Venniro, & Shaham, 2018; Cross, Anthenelli, & Li, 2018; Joffe, Centanni, Jaramillo, Winder, & Conn, 2018; Johnson & Lovinger, 2016; Li & Markou, 2015; Scofield et al., 2016). A variety of organisms and behavioral paradigms have been used to examine the actions of acute and chronic ethanol that are thought to contribute to drinking.

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