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Vol. 287, Issue 1, 261-265, October 1998

Gamma-Hydroxybutyrate is a GABAB Receptor Agonist that Increases a Potassium Conductance in Rat Ventral Tegmental Dopamine Neurons1

Theresa E. Madden and Steven W. Johnson

Departments of Physiology and Pharmacology (T.E.M., S.W.J.) and Neurology (S.W.J.), Oregon Health Sciences University, Portland, Oregon

gamma -Hydroxybutyric acid (GHB) is an abused substance that occurs naturally in the basal ganglia. Electrophysiological 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 gamma -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 gamma -aminobutyric acid receptors and would be expected to inhibit DA release by causing K+-dependent membrane hyperpolarization.

0022-3565/98/2871-0261$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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