A metabotropic glutamate 2/3 receptor antagonist, MGS0039, increases extracellular dopamine levels in the nucleus accumbens shell

doi:10.1016/j.neulet.2005.09.058

Neuroscience Letters

Volume 393, Issues 2–3, 30 January 2006, Pages 127-130

https://doi.org/10.1016/j.neulet.2005.09.058 Get rights and content

Abstract

(1R,2R,3R,5R,6R)-2-Amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039), a potent and selective metabotropic glutamate 2/3 (mGlu 2/3) receptor antagonist, exhibits antidepressant-like activities in some animal models. In the present study, we examined the effect of MGS0039 on extracellular dopamine levels in the rat nucleus accumbens (NAc) shell using in vivo microdialysis evaluation because accumbal dopamine has been implicated in depression. Local application of MGS0039 into the NAc shell at 10 μM significantly increased extracellular dopamine levels in the NAc shell in freely moving rats. In contrast, local application of 10 μM of LY354740, an mGlu 2/3 receptor agonist, significantly decreased extracellular dopamine levels in the same brain region. These findings suggest that dopamine release in the NAc shell is regulated by mGlu 2/3 receptors, and that the effect on dopamine levels in the NAc shell may partially explain the antidepressant-like properties of mGlu 2/3 receptor antagonists.

References (21)

E.E. Brown et al.
Chronic desipramine enhances the effect of locally applied amphetamine on interstitial concentrations of dopamine in the nucleus accumbens
Eur. J. Pharmacol.
(1991)
S. Chaki et al.
MGS0039: a potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity
Neuropharmacology
(2004)
G. Di Chiara et al.
Reciprocal changes in prefrontal and limbic dopamine responsiveness to aversive and rewarding stimuli after chronic mild stress: implications for the psychobiology of depression
Biol. Psychiatry
(1999)
R.G. Greenslade et al.
Selective action of (–)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), a Group II metabotropic glutamate receptor agonist, on basal and phencyclidine-induced dopamine release in the nucleus accumbens shell
Neuropharmacology
(2004)
P.W. Kalivas et al.
GABA and enkephalin projection from the nucleus accumbens and ventral palladium to VTA
Neuroscience
(1993)
H. Ohishi et al.
Distribution of the messenger RNA for a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat
Neuroscience
(1993)
Z.L. Rossetti et al.
Depletion of mesolimbic dopamine during behavioral despair: partial reversal by chronic imipramine
Eur. J. Pharmacol.
(1993)
G. Segovia et al.
Involvement of NMDA and AMPA/kainate receptors in the effects of endogenous glutamate on extracellular concentrations of dopamine and GABA in the nucleus accumbens of the awake rat
Brain Res. Bull.
(2001)
T. Shimazaki et al.
Anxiolytic-like activity of MGS0039, a potent group II metabotropic glutamate receptor antagonist, in marble-burying behavior test
Eur. J. Pharmacol.
(2004)
C.M. Andrews et al.
Effects of cocaine on extracellular dopamine and serotonin levels in the nucleus accumbens
Psychopharmacology
(2001)

There are more references available in the full text version of this article.

Cited by (68)

Targeting mGluR2/3 for treatment of neurodegenerative and neuropsychiatric diseases
2022, Pharmacology and Therapeutics
Glutamate is the primary excitatory neurotransmitter in the brain and plays critical roles in all aspects of neuronal function. Disruption of normal glutamate transmission has been implicated in a variety of neurodegenerative and neuropsychiatric diseases. Glutamate exerts its effect through ionotropic and metabotropic glutamate receptors (mGluRs). mGluR2 and mGluR3 are members of the Group II mGluR family and their activation leads to the inhibition of glutamate release from presynaptic nerve terminals and is also poised upstream of a myriad of signaling pathways in postsynaptic nerve terminals and neuroglia. Therefore, mGluR2 and mGluR3 have been considered as potential drug targets for the treatment of many neurological conditions and several compounds targeting these receptors have been developed. In this review, we discuss what is currently known regarding the contribution of mGluR2 and mGluR3 to the pathophysiology of some neurodegenerative and neuropsychiatric diseases including Amyotrophic lateral sclerosis, Alzheimer’s disease, Huntington’s disease, Parkinson’s diseases, schizophrenia and depression as well as drug addiction. We then highlight the evidence supporting the use of various drugs including orthosteric and allosteric ligands acting on either mGluR2, mGluR3 or both for the management of these brain disorders.
mGlu2/3 receptor antagonism: A mechanism to induce rapid antidepressant effects without ketamine-associated side-effects
2020, Pharmacology Biochemistry and Behavior
The consensus that ketamine can produce rapid-onset antidepressant effects in patients combined with the recent approval of S(+)-ketamine (esketamine, Spravato) as an antidepressant, has fueled the search for other compounds that might recapitulate the remarkable therapeutic benefits of ketamine. At the same time, discovery efforts have been additionally directed toward minimization of the tolerability, side-effect, and safety issues associated with ketamine. The history of thought on the viability of metabotropic 2/3 (mGlu2/3) receptor antagonism as a potential mechanism for inducing rapid-acting antidepressant effects is reviewed here. The biological basis for predicting antidepressant efficacy of mGlu2/3 receptor antagonists in depressed patients is also presented. This prediction is based upon convergent biochemical, neurochemical, electrophysiological, and behavioral data that indicate a striking homology in the substrates that underlie the effects of mGlu2/3 receptor antagonists and the known antidepressant ketamine. The data reviewed to date also demonstrate that the preclinical side-effect/tolerability and toxicology profile of mGlu2/3 receptor antagonists are not concerning. Finally, preclinical data on a relatively new mGlu2/3 receptor antagonist, LY3020371, and its orally-bioavailable prodrug, LY3027788, are reviewed. The data on this mechanism provides optimism for successful translation of the mGlu2/3 receptor antagonist hypothesis into therapeutics for those suffering from depression.
mGlu2/3 receptor as a novel target for rapid acting antidepressants
2020, Advances in Pharmacology
Given that ketamine, a noncompetitive N-methyl-d-aspartate receptor antagonist that exerts rapid antidepressant effects in patients with treatment-resistant depression, also has undesirable adverse effects, agents that can be used as alternatives to ketamine have been actively pursued. Group II metabotropic glutamate (mGlu) receptors, consisting of mGlu2 and mGlu3 receptors, have emerged as one of the most promising targets in the development of ketamine-like antidepressants. Indeed, mGlu2/3 receptor antagonists have been demonstrated to exert rapid antidepressant effects in animal models and to be efficacious in animal models refractory to conventional antidepressants. Moreover, there are striking similarities between mGlu2/3 receptor antagonists and ketamine in terms of not only their antidepressant profiles, but also the underlying mechanisms of their antidepressant effects. Nonetheless, studies in rodents have shown that mGlu2/3 receptor antagonists do not cause ketamine-like adverse events, such as psychotomimetic-like behavior, abuse potential or neurotoxicity, supporting the usefulness of mGlu2/3 receptor antagonists as alternatives to ketamine. In this chapter, the past and recent research on the antidepressant effects of mGlu2/3 receptor antagonists will be reviewed. In particular, the potential of mGlu2/3 receptor antagonists as novel ketamine-like antidepressants will be emphasized.
Rapid-acting antidepressants
2019, Advances in Pharmacology
Conventional antidepressants (biogenic amine mechanisms) are not fully efficacious (e.g., symptoms remain after treatment, not all patients respond), produce effects only after weeks of daily dosing, and do not impact all disease symptoms. In contrast, a new class of antidepressants has been emerging since 2006 that has demonstrated rapid onset, large effect size, activity after only a single or few dose applications, and positive impact in treatment refractory patients and against some treatment-resistant symptoms (e.g., anhedonia). Rapid-acting antidepressant drug action has been demonstrated in controlled clinical studies for ketamine, a few other NMDA receptor antagonists, and scopolamine. Less clinical data are currently available for psychedelic drugs such as psilocybin, lysergic acid diethylamide, and ayahuasca. The mechanisms of action of rapid-acting antidepressants are not fully understood. However, a general triggering mechanism appears to involve the potentiation of AMPA receptor function. Although the durability of antidepressant effects of ketamine and scopolamine is limited, psychedelic drugs have been reported to produce effects for many months. The primary impediment to generating a medicine of this type for depressed patients is side effects and the lack of methods to ensure enduring antidepressant effects. Thus, further exploration of drug possibilities continues. Esketamine ((S)-ketamine) was recently FDA approved. Compounds currently in clinical development include the NMDA receptor antagonist (R)-ketamine, the NMDA receptor modulator, GLYX-13 (Rapastinel), and the AMPA receptor potentiator TAK-653. Additional pharmacological classes have produced effects in the preclinical laboratory to suggest their potential as rapid-acting agents. These include mGlu2/3 receptor antagonists, AMPA receptor potentiators, and negative allosteric modulators of GABA_A(α5) receptors. In all cases, molecules exist that could be used to provide clinical proof of concept testing.
Metabotropic Glutamate Receptors 2 and 3 as Targets for Treating Nicotine Addiction
2018, Biological Psychiatry
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.
mGlu2/3 Receptor Antagonists as Novel Antidepressants
2017, Trends in Pharmacological Sciences
Citation Excerpt :
Ketamine was reported to reverse suppression of the VTA dopaminergic neuronal activity associated with learned helplessness behaviors, and this was accompanied by reversal of the helplessness behavior [52]. It was previously reported that local injection of mGlu2/3 receptor antagonists increased the extracellular dopamine level in the nucleus accumbens (NAc) shell via AMPA receptor stimulation [53,54]. It was confirmed subsequently that systemic administration of LY341495 or LY3020371 increased the number of spontaneously active dopaminergic neurons in the VTA via AMPA receptor stimulation, and increased the extracellular dopamine level in the medial PFC (mPFC) and NAc [29,55].
Based on the discovery of the robust antidepressant effects of ketamine in patients with depression, including those with treatment-resistant depression, agents acting on the glutamatergic system have drawn much attention as potential novel antidepressants. Among the agents acting on the glutamatergic system, preclinical data have indicated that the group II metabotropic glutamate (mGlu) receptors, mGlu2 and mGlu3, are attractive targets for the development of novel antidepressants. The antidepressant effects of mGlu2/3 receptor antagonists have been demonstrated in rodent models, and the synaptic and neural mechanisms underlying the antidepressant effects of these compounds have been investigated. Furthermore, these findings have indicated the similarities of the antidepressant effects and of the mechanisms underlying these effects between mGlu2/3 receptor antagonists and ketamine. Based on the results obtained hitherto, here I discuss the potential for mGlu2/3 receptor antagonists to be developed as next-generation antidepressants.

View all citing articles on Scopus

View full text

A metabotropic glutamate 2/3 receptor antagonist, MGS0039, increases extracellular dopamine levels in the nucleus accumbens shell

Abstract

Eur. J. Pharmacol.

Neuropharmacology

Biol. Psychiatry

Neuropharmacology

Neuroscience

Neuroscience

Eur. J. Pharmacol.

Brain Res. Bull.

Eur. J. Pharmacol.

Effects of cocaine on extracellular dopamine and serotonin levels in the nucleus accumbens

Psychopharmacology