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Department of Pharmacological and Physiological Sciences, University of Chicago, IL 60637.

1. The effects of activation of GABAB receptors on Ca2+ currents (ICa) were investigated by application of whole-cell patch-clamp techniques to pyramidal neurones and non-pyramidal interneurones from the rat hippocampus grown in cell culture. 2. (+/-)-Baclofen (10 microM) reduced ICa evoked in pyramidal neurones at 0 mV from a holding potential of -80 mV by 33 +/- 3%. Inhibition could be observed at the peak of ICa with significant inhibition still present after 200 ms at 0 mV. When Ba2+ was used as the charge carrier (IBa) baclofen inhibited 28 +/- 3% of the current at -20 mV from a holding potential of -80 mV. The GABAB receptor antagonist 2-OH-saclofen (50-200 microM) blocked the actions of baclofen. 3. The selective Ca2+ channel blocker, omega-conotoxin fraction GVIA (omega-CgTX), was used to characterize the Ca2+ currents inhibited by baclofen. omega-CgTX (5 microM) blocked 24 +/- 3% of IBa. Following block of the omega-CgTX-sensitive current, baclofen inhibited significantly less current than under control conditions. 4. Addition of the dihydropyridine Ca2+ channel antagonist nimodipine (1 microM) inhibited 18 +/- 5% of ICa at 0 mV from a holding potential of -80 mV and 44 +/- 9% from a holding potential of -40 mV. In addition, nimodipine partially occluded subsequent responses to application of baclofen. 5. In the presence of both 5 microM-omega-CgTX and 200 nM-nimodipine, responses to baclofen were almost completely blocked at depolarized holding potentials where the dihydropyridines are most effective. 6. Inclusion of 500 microM-guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S) in the patch pipette enhanced the response to a subsaturating concentration of baclofen and rendered the response irreversible. Subsequent addition of the adenosine receptor agonist 2-Cl-adenosine (2-CA) (1 microM; which also reduces ICa under control conditions) was without effect, suggesting that these two receptor-effector pathways converge. 7. The actions of baclofen on ICa were blocked by pre-treatment of the cultures with pertussis toxin (250 ng/ml). 8. Baclofen also inhibited ICa in non-pyramidal neurones from the hippocampus, but was slightly less effective. 9. Baclofen reduced both excitatory- and inhibitory postsynaptic currents (EPSCs and IPSCs) recorded as a consequence of extracellular stimulation of presynaptic neurones. This action was blocked by 2-OH-saclofen (200 microM) and also by pretreatment of the cultures with pertussis toxin.(ABSTRACT TRUNCATED AT 400 WORDS)

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