Neurosteroid allopregnanolone inhibits glutamate release from rat cerebrocortical nerve terminals

Abstract

Allopregnanolone, an active metabolite of progesterone, has been reported to exhibit neuroprotective activity in several preclinical models. Considering that the excitotoxicity caused by excessive glutamate is implicated in many brain disorders, the effect of allopregnanolone on glutamate release in rat cerebrocortical nerve terminals and possible underlying mechanism were investigated. We observed that allopregnanolone inhibited 4‐aminopyridine (4‐AP)‐evoked glutamate release, and this inhibition was prevented by chelating the extracellular Ca2+ ions and the vesicular transporter inhibitor. Allopregnanolone reduced the elevation of 4‐AP‐evoked intrasynaptosomal Ca2+ levels, but did not affect the synaptosomal membrane potential. In the presence of N‐, P/Q‐, and R‐type channel blockers, allopregnanolone‐mediated inhibition of 4‐AP‐evoked glutamate release was markedly reduced; however, the intracellular Ca2+‐release inhibitors did not affect the allopregnanolone effect. Furthermore, allopregnanolone‐mediated inhibition of 4‐AP‐evoked glutamate release was completely abolished in the synaptosomes pretreated with inhibitors of Ca2+/calmodulin, adenylate cyclase, and protein kinase A (PKA), namely calmidazolium, MDL12330A, and H89, respectively. Additionally, the allopregnanolone effect on evoked glutamate release was antagonized by the GABAA receptor antagonist SR95531. Our data are the first to suggest that allopregnanolone reduce the Ca2+ influx through N‐, P/Q‐, and R‐type Ca2+ channels, through the activation of GABAA receptors present on cerebrocortical nerve terminals, subsequently suppressing the Ca2+‐calmodulin/PKA cascade and decreasing 4‐AP‐evoked glutamate release.

Sex Hormones, Neurosteroids, and Glutamatergic Neurotransmission: A Review of the Literature

“…Allopregnanolone appears to interact with glutamate release, but data are conflicting, with some research showing an inhibitory effect on release, and other research showing a role for allopregnanolone in the induction of glutamate release [32, 33]. Allopregnanolone action in the peripheral nervous system may also have a role in modifying glutamate uptake [34].…”

Prospective Investigation of Glutamate Levels and Percentage Gray Matter in the Medial Prefrontal Cortex in Females at Risk for Postpartum Depression

“…Animal studies have shown that ALLO administration decreases Glu release in specific brain areas [ 46 ]. For example, Hu and colleagues found that ALLO inhibits the release of Glu in rat MPFC, which is our voxel of interest [ 47 ].…”

Efficacy of Olanzapine in Anxiety Dimension of Schizophrenia: A Systematic Review of Randomized Controlled Trials

“…It is known that the dysfunction of the glutamatergic system is associated with numerous psychiatric conditions, including schizophrenia, depression and anxiety disorders [ 57 ]. Long term administration of olanzapine increases allopregnanolone (that can reduce the release of glutamate) in the rat cerebral cortex and hippocampus [ 58 , 59 ], increases D-aspartate and extracellular L-glutamate in the prefrontal cortex of the mouse [ 60 ], induces a down-regulation of N-methyl-D-aspartate (NMDA) receptors in the caudate and medial and lateral putamen (CPu) and an increase in a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in the same areas and a reduction of NMDA receptors in the hippocampal regions CA1 and CA3 [ 61 ]. On the clinical side, the improvement in anxiety symptoms given by olanzapine could be mediated either by a direct anxiolytic effect or indirectly by its efficacy on nuclear symptoms of schizophrenia.…”