Neuroactive Steroids Differ in Potency but Not in Intrinsic Efficacy at the GABAA Receptor in Vivo

Background: Propanidid is a γ-aminobutyric acid type A (GABAA) receptor agonist general anesthetic and its primary metabolite is 4-(2-[diethylamino]-2-oxoethoxy)-3-methoxy-benzeneacetic acid (DOMBA). Despite having a high water solubility at physiologic pH that might predict low-affinity GABAA receptor interactions, DOMBA is reported to have no effect on GABAA receptor currents, possibly because the DOMBA concentrations studied were simply insufficient to modulate GABAA receptors. Our objectives were to measure the propanidid and DOMBA concentration responses on GABAA receptors and to measure the behavioral responses of DOMBA in mice at concentrations that affect GABAA receptor currents in vitro. Methods: GABAA receptors were expressed in oocytes using clones for the human GABAA α1, β2 and γ2s subunits. The effects of DOMBA (0.2–10 mmol/L) and propanidid (0.001–1 mmol/L) on oocyte GABAA currents were studied using standard 2-electrode voltage clamp techniques. Based on in vitro results, 6 mice received DOMBA 32 mg intraperitoneal and were observed for occurrence of neurologic effects and DOMBA plasma concentration was measured by liquid chromatography tandem mass spectrometry. Results: DOMBA both directly activates GABAA receptors and antagonizes its GABA-mediated opening in a concentration-dependent manner at concentrations between 5–10 and 0.5–10 mmol/L respectively. In vivo, DOMBA produced rapid onset sedation at plasma concentrations that correlate with direct GABAA receptor activation. Conclusion: DOMBA modulation of GABAA receptors is associated with sedation in mice. Metabolites of propanidid analogues currently in development may similarly modulate GABAA, and impaired elimination of these metabolites could produce clinically relevant neurophysiologic effects.

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Measurement of GABAA receptor binding in vivo with [11C]Flumazenil: A test–retest study in healthy subjects

NeuroImage ◽

10.1016/j.neuroimage.2008.02.035 ◽

2008 ◽

Vol 41 (2) ◽

pp. 260-269 ◽

Cited By ~ 26

Author(s):

Elina Salmi ◽

Sargo Aalto ◽

Jussi Hirvonen ◽

Jaakko W. Långsjö ◽

Anu T. Maksimow ◽

...

Keyword(s):

Gabaa Receptor ◽

Receptor Binding ◽

Healthy Subjects

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Ethanol-induced GABAA receptor alpha4 subunit plasticity involves phosphorylation and neuroactive steroids

Molecular and Cellular Neuroscience ◽

10.1016/j.mcn.2016.01.002 ◽

2016 ◽

Vol 72 ◽

pp. 1-8 ◽

Cited By ~ 5

Author(s):

David F. Werner ◽

Patrizia Porcu ◽

Kevin N. Boyd ◽

Todd K. O'Buckley ◽

Jenna M. Carter ◽

...

Keyword(s):

Gabaa Receptor ◽

Neuroactive Steroids

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Neuroactive steroids inhibit spinal reflex potentiation by selectively enhancing specific spinal GABAA receptor subtypes

Pain ◽

10.1016/j.pain.2008.12.023 ◽

2009 ◽

Vol 143 (1) ◽

pp. 12-20 ◽

Cited By ~ 36

Author(s):

Hsien-Yu Peng ◽

Gin-Den Chen ◽

Shin-Da Lee ◽

Cheng-Yuan Lai ◽

Chun-Hsien Chiu ◽

...

Keyword(s):

Gabaa Receptor ◽

Neuroactive Steroids ◽

Spinal Reflex ◽

Receptor Subtypes ◽

Gabaa Receptor Subtypes

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GABAA receptor-mediated inhibition by ethanol of long-term potentiation in the basolateral amygdala–dentate gyrus pathway in vivo

Neuroscience ◽

10.1016/j.neuroscience.2004.01.021 ◽

2004 ◽

Vol 125 (1) ◽

pp. 113-117 ◽

Cited By ~ 5

Author(s):

K Abe ◽

Y Niikura ◽

M Misawa

Keyword(s):

Dentate Gyrus ◽

Gabaa Receptor ◽

Basolateral Amygdala ◽

Long Term Potentiation ◽

Term Potentiation

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Focus on GABAA receptor function

Nuklearmedizin ◽

10.3413/nukmed-0647-14-03 ◽

2014 ◽

Vol 53 (06) ◽

pp. 227-337 ◽

Cited By ~ 8

Author(s):

H. Hautzel ◽

H.-W. Müller ◽

S. Nikolaus

Keyword(s):

Gabaa Receptor ◽

Receptor Binding ◽

Temporal Cortex ◽

Primary Diagnosis ◽

Receptor Function ◽

Healthy Individuals ◽

Major Depressive ◽

Neuropsychiatric Diseases ◽

Pubmed Search

SummaryImpairment of GABAA receptor function is increasingly recognized to play a major role in the pathophysiology of neuropsychiatric diseases including anxiety disorder (AD), major depressive disorder (MDD) and schizophrenia (SZ). Patients, method: We conducted a PUBMED search, which provided a total of 23 in vivo investigations with PET and SPECT, in which GABAA receptor binding in patients with the primary diagnosis of AD (n = 14, 160 patients, 172 controls), MDD (n = 2, 24 patients, 28 controls) or SZ (n = 6, 77 patients, 90 controls) was compared to healthy individuals. Results: A retrospective analysis revealed that AD, MDD and SZ differed as to both site(s) and extent(s) of GABAergic impairment. Additionally, it may be stated that, while the decline of GABAA receptor binding AD involved the whole mesolimbocortical system, in SZ it was confined to the frontal and temporal cortex. Conclusion: As GABA is known to inhibit dopamine and serotonin, GABAergic dysfunction may be associated with the disturbances of dopaminergic and serotonergic neurotransmission in neuropsychiatric disorders.

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