Neuronal death/apoptosis induced by intracellular zinc deficiency associated with changes in amino-acid neurotransmitters and glutamate receptor subtypes

Neurons isolated from the medial subnuclei of nucleus tractus solitarius in adult guinea pigs were studied for responses to the excitatory amino acid glutamate and its analogues using the whole cell tight-seal voltage clamp technique. In 80% of the cells studied (n = 60) 100 microM glutamate produced inward currents at negative voltages. To further characterize the glutamate response, the agonists for three glutamate receptor subtypes, N-methyl-D-aspartate (NMDA), kainate, and quisqualate, were examined for their effects on membrane conductance. NMDA (25-250 microM) activated currents in 85% of the neurons tested (n = 30). NMDA currents were generally very small in amplitude. Of the neurons tested, 84% responded to kainate (10-30 microM, n = 19) and only 50% to quisqualate (25-50 microM, n = 26). The conductance activated by NMDA was outwardly rectifying. The conductance activated by kainate was voltage independent, while that activated by quisqualate showed varying degrees of outward rectification. Responses to NMDA were specifically antagonized by DL-2-amino-5-phosphonovaleric acid (AP-5, 50-100 microM). Kainate responses were blocked by kynurenate at concentrations (0.5-1.5 mM) ineffective on quisqualate-induced current. Glutamic acid diethyl ester (GDEE, 2-15 mM) was effective in reducing quisqualate responses at concentrations that had no effect on kainate responses. This characterization of the glutamate receptor subtypes and effective antagonists provides a basis for future determination of the specific receptor of glutamate responsible for mediation of the excitatory postsynaptic potentials produced by activation of the baroreceptor input.

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Effect of 5,7 DHT lesion on glutamate receptor subtypes in the rat brain: autoradiographic evaluation

Neurochemistry International ◽

10.1016/0197-0186(90)90322-k ◽

1990 ◽

Vol 16 ◽

pp. 55

Keyword(s):

Rat Brain ◽

Glutamate Receptor ◽

Receptor Subtypes

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Emerging Therapeutics Based on the Amino Acid Neurotransmitter System: An Update on the Pharmaceutical Pipeline for Mood Disorders

Chronic Stress ◽

10.1177/24705470211020446 ◽

2021 ◽

Vol 5 ◽

pp. 247054702110204

Author(s):

Julia Hecking ◽

Pasha A. Davoudian ◽

Samuel T. Wilkinson

Keyword(s):

Amino Acid ◽

Mood Disorders ◽

Phase Iii ◽

Public Health Issue ◽

Complex Nature ◽

Novel Therapies ◽

Amino Acid Neurotransmitters ◽

Neurotransmitter System ◽

Phase Iii Clinical Trials ◽

The World

Mood disorders represent a pressing public health issue and significant source of disability throughout the world. The classical monoamine hypothesis, while useful in developing improved understanding and clinical treatments, has not fully captured the complex nature underlying mood disorders. Despite these shortcomings, the monoamine hypothesis continues to dominate the conceptual framework when approaching mood disorders. However, recent advances in basic and clinical research have led to a greater appreciation for the role that amino acid neurotransmitters play in the pathophysiology of mood disorders and as potential targets for novel therapies. In this article we review progress of compounds that focus on these systems. We cover both glutamate-targeting drugs such as: esketamine, AVP-786, REL-1017, AXS-05, rapastinel (GLYX-13), AV-101, NRX-101; as well as GABA-targeting drugs such as: brexanolone (SAGE-547), ganaxolone, zuranolone (SAGE-217), and PRAX-114. We focus the review on phase-II and phase-III clinical trials and evaluate the extant data and progress of these compounds.

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