Abstract

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 (GABAA a4ß3d, GABAA a5ß2?2, and GABAB B1/B2) and antagonist (GABAA a6ß2?2) activity while (R)-4APA showed weak agonist activity only with GABAA a5ß2?2. Both 4APA enantiomers (100 mg/kg IP) were detected in mouse brain 10 min after injection, and by one hour had reached concentrations that were stable over six hours; both enantiomers were cleared rapidly from mouse serum over six hours. Two-month old mice had no mortality following 100 to 900 mg/kg IP of each 4APA enantiomer but ded have similar dose-dependent reduction in distance moved in a novel cage. Neither enantiomer at 30 or 100 mg/kg impacted outcomes in twenty-three measures of well-being, activity chamber, or withdrawal from hotplate. 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.

View details for DOI 10.1111/jnc.15474

View details for PubMedID 34273193