Interaction of hallucinogenic rapid-acting antidepressants with mGlu2/3 receptor ligands as a window for more effective therapies.

The desire to find a gold-standard therapy for depression is still ongoing. Developing one universal and effective pharmacotherapy remains troublesome due to the high complexity and variety of symptoms. Over the last decades, the understanding of the mechanism of pathophysiology of depression and its key consequences for brain functioning have undergone significant changes, referring to the monoaminergic theory of the disease. After the breakthrough discovery of ketamine, research began to focus on the modulation of glutamatergic transmission as a new pharmacological target. Glutamate is a crucial player in mechanisms of a novel class of antidepressants, including hallucinogens such as ketamine. The role of glutamatergic transmission is also suggested in the antidepressant (AD) action of scopolamine and psilocybin. Despite fast, robust, and sustained AD action hallucinogens belonging to a group of rapid-acting antidepressants (RAA) exert significant undesired effects, which hamper their use in the clinic. Thus, the synergistic action of more than one substance in lower doses instead of monotherapy may alleviate the likelihood of adverse effects while improving therapeutic outcomes. In this review, we explore AD-like behavioral, synaptic, and molecular action of RAAs such as ketamine, scopolamine, and psilocybin, in combination with mGlu2/3 receptor antagonists.

Blunted type-5 metabotropic glutamate receptor-mediated polyphosphoinositide hydrolysis in two mouse models of monogenic autism.

The involvement of the mGlu5 receptors in the pathophysiology of several forms of monogenic autism has been supported by numerous studies following the seminal observation that mGlu5 receptor-dependent long-term depression was enhanced in the hippocampus of mice modeling the fragile-X syndrome (FXS). Surprisingly, there are no studies examining the canonical signal transduction pathway activated by mGlu5 receptors (i.e. polyphosphoinositide - PI - hydrolysis) in mouse models of autism. We have developed a method for in vivo assessment of PI hydrolysis based on systemic injection of lithium chloride followed by treatment with the selective mGlu5 receptor PAM, VU0360172, and measurement of endogenous inositolmonophosphate (InsP) in brain tissue. Here, we report that mGlu5 receptor-mediated PI hydrolysis was blunted in the cerebral cortex, hippocampus, and corpus striatum of Ube3am-/p+ mice modeling Angelman syndrome (AS), and in the cerebral cortex and hippocampus of Fmr1 knockout mice modeling FXS. In vivo mGlu5 receptor-mediated stimulation of Akt on threonine 308 was also blunted in the hippocampus of FXS mice. These changes were associated with a significant increase in cortical and striatal Homer1 levels and striatal mGlu5 receptor and Gαq levels in AS mice, and with a reduction in cortical mGlu5 receptor and hippocampal Gαq levels, and an increase in cortical phospholipase-Cß and hippocampal Homer1 levels in FXS mice. This is the first evidence that the canonical transduction pathway activated by mGlu5 receptors is down-regulated in brain regions of mice modeling monogenic autism.

Where do we go next in antidepressant drug discovery? A new generation of antidepressants: a pivotal role of AMPA receptor potentiation and mGlu2/3 receptor antagonism.

INTRODUCTION: Major depressive disorder remains a prevalent world-wide health problem. Currently available antidepressant medications take weeks of dosing, do not produce antidepressant response in all patients, and have undesirable ancillary effects. AREAS COVERED: The present opinion piece focuses on the major inroads to the creation of new antidepressants. These include N-methyl-D-aspartate (NMDA) receptor antagonists and related compounds like ketamine, psychedelic drugs like psilocybin, and muscarinic receptor antagonists like scopolamine. The preclinical and clinical pharmacological profile of these new-age antidepressant drugs is discussed. EXPERT OPINION: Preclinical and clinical data have accumulated to predict a next generation of antidepressant medicines. In contrast to the current standard of care antidepressant drugs, these compounds differ in that they demonstrate rapid activity, often after a single dose, and effects that outlive their presence in brain. These compounds also can provide efficacy for treatment-resistant depressed patients. The mechanism of action of these compounds suggests a strong glutamatergic component that involves the facilitation of AMPA receptor function. Antagonism of mGlu2/3 receptors is also relevant to the antidepressant pharmacology of this new class of drugs. Based upon the ongoing efforts to develop these new-age antidepressants, new drug approvals are predicted in the near future.