L-ARGININE POTENTIATES GABA-MEDIATED SYNAPTIC TRANSMISSION BY A NITRIC OXIDE-INDEPENDENT MECHANISM IN RAT DOPAMINE NEURONS

Effects of L-arginine in the nervous system are often attributed to ni tric oxide. Using whole-cell patch pipettes to record membrane current s in voltage-clamp from dopamine neurons in the rat midbrain slice, th e present studies found that L-arginine potentiates GABA-dependent mem brane currents via a nitric oxide-independent mechanism. L-Arginine (0 .3-10 mM) increased the peak amplitude, half-width duration and time c onstant of decay of GABA(B) receptor-mediated inhibitory postsynaptic currents in a concentration-dependent manner. In the presence of CGP 3 5348 (300 mu M), a GABA(B) receptor antagonist, L-arginine also prolon ged the duration of inhibitory postsynaptic currents mediated by GABA( A) receptors, but their amplitudes were reduced. L-Arginine (10 mM) al so evoked 17 +/- 3 pA of outward current (at - 60 mV) which was signif icantly increased in the presence of exogenous GABA (100 mu M). Pressu re-ejection of GABA from micropipettes produced outward currents media ted by GABA(B) receptors (recorded in bicuculline) or GABA(A) receptor s (recorded in CGP 35348); both types of receptor-mediated currents we re increased by L-arginine (10 mM). In contrast, outward currents evok ed by baclofen, a GABA(B) receptor agonist, were not potentiated by L- arginine. The GABA transport inhibitors NO 711 (1 mu M) and nipecotic acid (1 mM) significantly increased the half-width duration and time-c onstant of decay of GABA(B)-mediated inhibitory postsynaptic currents, thus mimicking effects of L-arginine. However, nitric oxide donors fa iled to mimic effects of L-arginine on GABA(B) inhibitory postsynaptic currents, and inhibitors of nitric oxide synthesis failed to selectiv ely block the action of L-arginine. These findings suggest that L-argi nine potentiates GABA synaptic transmission by a nitric oxide-independ ent mechanism. Similarities between effects of L-arginine, NO 711 and nipecotic acid suggest that L-arginine inhibits a GABA transporter. (C ) 1997 IBRO. Published by Elsevier Science Ltd.