BACLOFEN INHIBITION OF THE HYPERPOLARIZATION-ACTIVATED CATION CURRENT, I-H, IN RAT SUBSTANTIA-NIGRA ZONA COMPACTA NEURONS MAY BE SECONDARY TO POTASSIUM CURRENT ACTIVATION

1. The properties of the hyperpolarization-activated cation current (I -h), and its modulation by gamma-aminobuturic acid-B (GABA(B)) recepto r activation and protein kinase A, were investigated using whole cell voltage clamp of substantia nigra zona compacta principal neurons in r at midbrain slices in vitro. 2. At 30 degrees C, I-h activated between -75 and -155 mV, with a V-1/2 of -115 mV. At 35 degrees C, the activa tion curve shifted positive by 10 mV. I-h had an estimated reversal po tential of -27 mV. Ion substitution experiments showed that the curren t was carried by Na+ and K+. 3. Application of the GABA(B) receptor ag onist baclofen (30 mu M) induced an outward potassium current (G(IRK)) , increased neuronal membrane conductance and inhibited I-h. The inhib ition of I-h was voltage independent. Baclofen induced an 11-mV positi ve shift in the reversal potential of I-h. 4. Extracellular barium (30 0 mu M) markedly reduced the baclofen-evoked outward current and assoc iated increase in membrane conductance due to G(IRK) activation. There was also very little inhibition of I-h by baclofen in the presence of barium. When cesium was the major intracellular cation, both the incr ease in membrane conductance due to G(IRK) activation and the inhibiti on of I-h evoked by baclofen were reduced by a similar extent. 5. Neit her forskolin (10 mu M) nor the protein kinase A inhibitor, H89 (10 mu M), had any effect on I-h or its inhibition by baclofen. 6. These dat a suggest that the inhibition of I-h by baclofen is secondary to the a ctivation of G(IRK), i.e., due directly to alteration of membrane cond uctance, rather than a distinct effect, and is not mediated by inhibit ion of adenylyl cyclase.