MGlu2/3 Receptor Antagonists as Novel Antidepressants. (June 2017)

• Record Type: Journal Article
• Authors: Chaki, Shigeyuki
• Is Part Of: Trends in pharmacological sciences. Volume 38:Number 6(2017)
• Page Start: 569
• Page End: 580
• Publication Date: 2017-06
• Subjects: mGlu2/3 receptor antagonist -- ketamine -- antidepressant -- AMPA receptor -- neuroplasticity; Pharmacology -- Periodicals; Pharmacology -- trends -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Electronic journals; Periodicals; 615.1
• DOI: 10.1016/j.tips.2017.03.008
• Languages: English
• ISSNs: 0165-6147

Abstract

Abstract : 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. Trends: Data suggest that the glutamatergic system is an attractive target for the development of novel antidepressants. Preclinical evidence suggests that metabotropic glutamate (mGlu) 2/3 receptor antagonists exert rapid and sustained antidepressant effects, even in models with depression refractory to treatment with conventional antidepressants. Increased synaptogenesis, increased activity of certain serotonergic pathways, and increased mesolimbic dopaminergic neuronal signaling, which are all triggered by AMPA receptor stimulation, may also be involved in the antidepressant effects of mGlu2/3 receptor antagonists. All of these synaptic and neural mechanisms underlying the antidepressant effects of mGlu2/3 receptor antagonists are shared by ketamine. mGlu2/3 receptor antagonists additionally exert anxiolytic and pro-cognitive effects in animal models, both of which are beneficial for the treatment of depression.