Comparison of the action of baclofen with gamma‐aminobutyric acid on rat hippocampal pyramidal cells in vitro.

Abstract

Intracellular recordings from CA1 pyramidal cells in the hippocampal slice preparation were used to compare the action of baclofen, a GABA analog, with GABA. Ionophoretic application of GABA or baclofen into stratum (s.) pyramidale evoked hyperpolarizations associated with reductions in the input resistance of the cell. Baclofen responses were easier to elicit in the dendrites than in the cell body layer. Blockade of synaptic transmission, with tetrodotoxin or Cd, did not reduce baclofen responses, indicating a direct post-synaptic action. (+)-Bicuculline (10 .mu.M) and bicuculline methiodide (100 .mu.M) had little effect on baclofen responses but strongly antagonized somatic GABA responses of equal amplitude. The bicuculline resistance of the baclofen response was not absolute, as higher concentrations of these compounds did reduce it. Pentobarbitone (100 .mu.M) enhanced somatic GABA responses without affecting baclofen responses. (-)-Baclofen was .apprx. 200 times more potent than (+)-baclofen. The reversal potentials for the somatic GABA and baclofen responses were -70 mV and -85 mV respectively. When the membrane was depolarized, the baclofen response was reduced. This apparent voltage sensitivity was not seen with somatic GABA responses. Altering the Cl- gradient across the cell membrane altered the reversal potential of the somatic GABA response but not that of the baclofen response. A 10-fold shift in the extracellular K concentration would cause a 48 mV shift in the reversal potential of the baclofen response. Ba2+ reduced the baclofen response, but not the GABA response. Orthodromic stimulation produced a fast inhibitory post-synaptic potential (IPSP) and a slow IPSP. The properties of the fast and slow IPSP were remarkably similar to those of the somatic GABA and baclofen responses, respectively. Application of GABA to the pyramidal cell dendrites evoked, in addition to a depolarization, 2 types of hyperpolarization. One type of hyperpolarization was bicuculline sensitive, had a reversal potential of about -65 mV and appeared to be Cl- dependent. The other hyperpolarization was more easily observed in bicuculline methiodide (100 .mu.M). This response was similar to that evoked by baclofen since it had a high reversal potential (.apprx. -90 mV), was relatively insensitive to changes in the Cl- gradient across the cell membrane and was reduced by Ba. The bicuculline-sensitive hyperpolarization could be evoked by the dendritic or somatic ionophoresis of muscimol and THIP (4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-(2H)-one). Baclofen, acting on dendritic GABAB-like receptors, opens voltage-sensitive K channels. The fast and slow IPSP in these cells may be mediated by GABAA and GABAB receptors, respectively.