Discrimination of post- and presynaptic GABA(B) receptor-mediated responses by tetrahydroaminoacridine in area CA3 of the rat hippocampus

1. The effects of the K⁺ channel blocker 9-amino-1,2,3,4- tetrahydroacridine (THA) on the actions of baclofen and γ-aminobutyric acid (GABA) at post- and presynaptic GABA(B) receptors were studied with whole- cell voltage-clamp recording in area CA3 of rat hippocampal slices. 2. The effect of THA on postsynaptic GABA(B) receptor-mediated responses was studied in neurons perfused internally with potassium gluconate and guanosine triphosphate (GTP). At a holding potential of -70 mV, the GABA(B) receptor agonist (±)-baclofen (30 μM) induced an outward current and increased membrane conductance. In the presence of the excitatory amino acid receptor antagonists 6,7-dinitroquinoxaline-2,3-dione (DNQX) and (±)-2-amino-5- phosphonovalerate (APV), stimulation in stratum pyramidale or proximal stratum radiatum evoked GABA(A) receptor-mediated, fast monosynaptic inhibitory postsynaptic currents (IPSCs) and GABA(B) receptor-mediated, late monosynaptic IPSCs. THA (0.3 mM) blocked the baclofen-induced current and conductance increase and GABA(B) receptor-mediated IPSCs. 3. The effect of THA on presynaptic GABA(B) receptor-mediated responses was studied in neurons perfused internally with Cs⁺ and lidocaine N-ethyl bromide (QX-314), which blocked postsynaptic GABA(B) receptor-mediated responses. Stimulation in the presence of DNQX and APV evoked GABA(A) receptor-mediated IPSCs; when pairs of stimuli were delivered 200 ms apart the second IPSC was depressed. Baclofen reversibly depressed IPSCs, and partially occluded paired-pulse depression of IPSCs. The GABA(B) receptor antagonist CGP 35348 (0.5-1.0 mM) reversed baclofen-induced depression of IPSCs and partially blocked paired- pulse depression. Baclofen-induced and paired-pulse depression of IPSCs were not by affected by THA (0.3 mM). 4. Baclofen reversibly decreased the amplitude and frequency of spontaneous monosynaptic IPSCs (sIPSCs). Depression of sIPSCs by baclofen was unchanged by THA. 5. These results indicate that THA blocks the actions of baclofen and GABA at post- but not presynaptic GABA(B) receptors. We conclude that post- and presynaptic GABA(B) receptors in area CA3 of the rat hippocampus couple to different effector mechanisms; postsynaptic GABA(B) receptors activate THA-sensitive K⁺ channels, and presynaptic GABA(B) receptors decrease neurotransmitter release through a THA-insensitive mechanism.