-aminobutyric acid A receptor (GABAAR)-mediated postsynaptic currents (IPSCs) were recorded from dopaminergic neurons of the ventral tegmental area of young rats in acute brain slices and from mechanically dissociated neurons. Low concentrations (0.1-0.3 µM) of muscimol, a selective GABAAR agonist, increased the amplitude, and reduced the paired pulse ratio of evoked IPSCs. Moreover, muscimol increased the frequency but not the amplitude of spontaneous IPSCs (sIPSCs). These data point to a presynaptic locus of muscimol action. Interestingly, 1 µM muscimol caused an inhibition of sIPSCs, which was reversed to potentiation by a GABAB receptor antagonist CGP52432. Isoguvacine, a different class of selective GABAAR agonist, mimicked the effects of muscimol on sIPSCs: increased them at low ( 0.5 µM), and decreased them at a higher concentration (1 µM). Hence, the activation of presynaptic GABAARs facilitates GABA release, which is limited by presynaptic GABABRs. Furthermore, muscimol facilitation of sIPSCs was eliminated in a medium containing tetrodotoxin or cadmium. Significantly, sIPSC frequency was greatly increased by gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol; THIP), an agonist with preferential effects on extrasynaptic GABAARs containing 4subunits, or by guvacine, a GABA transport blocker, which increases ambient GABA levels. In addition, sIPSC frequency was attenuated by furosemide, a selective antagonist of 6 subunits. Thus, the presynaptic GABAARs may situate at extrasynaptic sites and may contain 4/6 subunits. Given the marked sensitivity of extrasynaptic GABAARs to ambient GABA, alcohols and anesthetics, these receptors may present a critical site for regulating synaptic function in the developing brain in both physiological and pathological situations.