Potentiation of metabotropic GABAB receptors by L-amino acids and dipeptides in rat neocortex

Selected neutral l-α-amino acids, and their dipeptides, were reversible, stereospecific, potentiators of GABA_B receptor-mediated hyperpolarizing responses to baclofen (3-100 μM) in rat neocortical slices. These responses were sensitive to the GABA_B receptor antagonist (+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid (Sch50911) (30 μM). Most potent were l-Leu, l-Ile and l-Phe, as were the dipeptides l-Phe-Phe and l-Phe-Leu, and less potent were l-Met, l-Val, l-Cys, l-Cystine, l-Tyr, l-Thr, l-Arg and l-Ser. Inactive were l-Trp, l-His, l-Lys and l-Pro. These potentiators gave leftward shifts of the baclofen concentration-response curves with a Hill slope of 2, and a marked increase in the maximal hyperpolarizing responses. Selected l-amino acids and dipeptides are a class of naturally occurring GABA_B potentiators, which may be allosteric modulators.