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Enantiomers of 4‐aminopentanoic acid act as false GABAergic neurotransmitters and impact mouse behavior
Author(s) -
Wawro Adam M.,
Gajera Chandresh R.,
Baker Steven A.,
Leśniak Robert K.,
Montine Kathleen S.,
Fischer Curt R.,
Saw Nay L.,
Shamloo Mehrdad,
Montine Thomas J.
Publication year - 2021
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.15474
Subject(s) - enantiomer , gabaa receptor , chemistry , agonist , pharmacology , antagonist , gabab receptor , neurotransmission , excitatory postsynaptic potential , gabaergic , synaptosome , intrinsic activity , endocrinology , medicine , biochemistry , biology , receptor , stereochemistry , in vitro
Imbalance in the metabolic pathway linking excitatory and inhibitory neurotransmission has been implicated in multiple psychiatric and neurologic disorders. Recently, we described enantiomer‐specific effects of 2‐methylglutamate, which is not decarboxylated to the corresponding methyl analogue of gamma‐aminobutyric acid (GABA): 4‐aminopentanoic acid (4APA). Here, we tested the hypothesis that 4APA also has enantiomer‐specific actions in brain. Mouse cerebral synaptosome uptake (nmol/mg protein over 30 min) of ( R )‐4APA or ( S )‐4APA was time and temperature dependent; however, the R enantiomer had greater uptake, reduction of endogenous GABA concentration, and release following membrane depolarization than did the S enantiomer. ( S )‐4APA exhibited some weak agonist (GABA A α4β3δ, GABA A α5β2γ2, and GABA B B1/B2) and antagonist (GABA A α6β2γ2) activity while ( R )‐4APA showed weak agonist activity only with GABAA α5β2γ2. Both 4APA enantiomers (100 mg/kg IP) were detected in mouse brain 10 min after injection, and by 1 hr had reached concentrations that were stable over 6 hr; both enantiomers were cleared rapidly from mouse serum over 6 hr. Two‐month‐old mice had no mortality following 100–900 mg/kg IP of each 4APA enantiomer but did have similar dose‐dependent reduction in distance moved in a novel cage. Neither enantiomer at 30 or 100 mg/kg impacted outcomes in 23 measures of well‐being, activity chamber, or withdrawal from hot plate. Our results suggest that enantiomers of 4APA are active in mouse brain, and that ( R )‐4APA may act as a novel false neurotransmitter of GABA. Future work will focus on disease models and on possible applications as neuroimaging agents.