Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders

Abstract

Mood disorders are common, chronic, recurrent mental illnesses that affect the lives of millions of individuals worldwide. To date, the monoaminergic systems (serotonergic, noradrenergic and dopaminergic) in the brain have received the greatest attention in neurobiological studies of mood disorders, and most therapeutics target these systems. However, there is growing evidence that the glutamatergic system is central to the neurobiology and treatment of these disorders. Here, we review data supporting the involvement of the glutamatergic system in mood-disorder pathophysiology as well as the efficacy of glutamatergic agents in mood disorders. We also discuss exciting new prospects for the development of improved therapeutics for these devastating disorders.

Ocimum basilicum leaf essential oil and (-)-linalool reduce orofacial nociception in rodents: a behavioral and electrophysiological approach

“…AMPA receptors mediate most fast synapses, and are responsible for responses to glutamate in the synapses. Its activation opens the channels for sodium ions, resulting in neuronal membrane for polarization (Sanacora et al, 2008;. AMPA receptors play an integral role in brain function.…”

“…Glutamatergic AMPA receptors are considered targets to suppress epileptic crisis as they have the property to modulate transmission induced by glutamate (Porto et al, 2007). The kainate receptors are associated with channels voltage-dependent actions and mediate excitatory direct and indirect modulation (Sanacora et al, 2008). NMDA receptors are normally blocked under resting conditions by the obstructing effects of Mg 2+ ions.…”

“…Thus, NMDA receptor activation serves as a functional marker of converging excitatory input and produces excitation over longer periods of time. Synaptic NMDA receptors activate mitogen-activated protein kinase (MAPK) and the transcription factor cyclic AMP-Ca 2+ response elementbinding protein (CREB); induce expression of the gene that encodes brain-derived neurotrophic factor (BDNF); and promote neuronal survival (Sanacora et al, 2008).…”

“…NMDA receptors, located in extrasynaptic space, act in an opposite manner, propagating signals that promote cell death (Sanacora et al, 2008). Glutamatergic system changes have been reported in plasma, serum, cerebrospinal fluid and brain tissue of affected individuals with mood disorders (Sanacora et al, 2008).…”

Population Pharmacokinetic and Exposure–dizziness Modeling for a Metabotropic Glutamate Receptor Subtype 5 Negative Allosteric Modulator in Major Depressive Disorder Patients

“…Response rates for initial treatment are estimated to be about 50%, while remission, considered to be the goal of treatment, ranges from 15–40% 1. The metabotropic glutamate receptor 5 (mGlu5) receptor has emerged as an attractive target for the treatment of anxiety and depressive disorders based on its expression pattern in the brain and the efficacy of mGlu5 antagonists in various animal models 2, 3. Glutamate is the main excitatory neurotransmitter that mediates its effects via ionotropic glutamate receptors (i.e., N‐methyl‐D‐aspartate (NMDA), α‐amino‐3‐hydroxy‐5‐methylisoazol‐4‐priopionate (AMPA) or kainate receptors) and G‐protein‐coupled receptors (e.g., mGlu receptors).…”