L-Arginine potentiates GABA-mediated synaptic transmission by a nitric oxide-independent mechanism in rat dopamine neurons

Abstract

Effects of l-Arginine in the nervous system are often attributed to nitric oxide. Using whole-cell patch pipettes to record membrane currents in voltage-clamp from dopamine neurons in the rat midbrain slice, the present studies found that l-Arginine potentiates GABA-dependent membrane currents via a nitric oxide-independent mechanism. l-Arginine (0.3–10 mM) increased the peak amplitude, half-width duration and time constant of decay of GABA B receptor-mediated inhibitory postsynaptic currents in a concentration-dependent manner. In the presence of CGP 35 348 (300 μM), a GABA B receptor antagonist, l-arginine also prolonged the duration of inhibitory postsynaptic currents mediated by GABA A receptors, but their amplitudes were reduced. l-Arginine (10 mM) also evoked 17±3 pA of outward current (at −60 mV) which was significantly increased in the presence of exogenous GABA (100 μM). Pressure-ejection of GABA from micropipettes produced outward currents mediated by GABA B receptors (recorded in bicuculline) or GABA A receptors (recorded in CGP 35 348); both types of receptor-mediated currents were increased by l-arginine (10 mM). In contrast, outward currents evoked by baclofen, a GABA B receptor agonist, were not potentiated by l-arginine. The GABA transport inhibitors NO 711 (1 μM) and nipecotic acid (1 mM) significantly increased the half-width duration and time-constant of decay of GABA B-mediated inhibitory postsynaptic currents, thus mimicking effects of l-arginine. However, nitric oxide donors failed to mimic effects of l-arginine on GABA B inhibitory postsynaptic currents, and inhibitors of nitric oxide synthesis failed to selectively block the action of l-arginine. These findings suggest that l-arginine potentiates GABA synaptic transmission by a nitric oxide-independent mechanism. Similarities between effects of l-arginine, NO 711 and nipecotic acid suggest that l-arginine inhibits a GABA transporter.