GAMMA-HYDROXYBUTYRATE IS A GABA(B) RECEPTOR AGONIST THAT INCREASES A POTASSIUM CONDUCTANCE IN RAT VENTRAL TEGMENTAL DOPAMINE NEURONS

gamma-Hydroxybutyric acid (GHB) is an abused substance that occurs nat urally in the basal ganglia. Electrophysiological recordings of membra ne voltage and current were made to characterize the effects of GHB on dopamine neurons in the ventral tegmental area of the rat midbrain sl ice. Perfusate containing GHB caused a concentration-dependent membran e hyperpolarization (EC50 = 0.88 +/- 0.21 mM) and a reduction in input resistance (EC50 = 0.74 +/- 0.21 mM). The highest concentration of GH B studied (10 mM) hyperpolarized neurons by 20 +/- 3 mV and reduced in put resistance by 58% +/- 9%. Changes in membrane potential and input resistance were blocked by the gamma-aminobutyric acid antagonist CGP- 35348 (300 mu M), but neither bicuculline (30 mu M) nor strychnine (10 mu M) was an effective antagonist. Voltage-clamp recordings demonstra ted that GHB (1 mM) evoked 80 +/- 6 pA of outward current (at -60 mV) that reversed at -110 mV (in 2.5 mM K+). Increasing concentrations of extracellular K+ progressively shifted the reversal to more depolarize d potentials. In tetrodotoxin (0.3 mu M) and tetraethylammonium (10 mM ), depolarizing voltage steps (to -30 mV) evoked calcium-dependent cur rent spikes that were completely blocked by GHB (1 mM). These data sug gest that GHB is an agonist at gamma-aminobutyric acid receptors and w ould be expected to inhibit DA release by causing K+-dependent membran e hyperpolarization.