Gamma-hydroxybutyrate is a GABA(b) receptor agonist that increases a potassium conductance in rat ventral tegmental dopamine neurons

γ-Hydroxybutyric acid (GHB) is an abused substance that occurs naturally in the basal ganglia. Electro physiological recordings of membrane voltage and current were made to characterize the effects of GHB on dopamine neurons in the ventral tegmental area of the rat midbrain slice. Perfusate containing GHB caused a concentration-dependent membrane hyperpolarization (EC₅₀ = 0.88 ± 0.21 mM) and a reduction in input resistance (EC₅₀ = 0.74 ± 0.21 mM). The highest concentration of GHB studied (10 mM) hyperpolarized neurons by 20 ± 3 mV and reduced input resistance by 58% ± 9%. Changes in membrane potential and input resistance were blocked by the γ-aminobutyric acid antagonist CGP-35348 (300 μM), but neither bicuculline (30 μM) nor strychnine (10 μM) was an effective antagonist. Voltage-clamp recordings demonstrated 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 depolarized potentials. In tetrodotoxin (0.3 μM) and tetraethylammonium (10 mM), depolarizing voltage steps (to -30 mV) evoked calcium-dependent current spikes that were completely blocked by GHB (1 mM). These data suggest that GHB is an agonist at γ-aminobutyric acid receptors and would be expected to inhibit DA release by causing K⁺-dependent membrane hyperpolarization.