Discrimination of post- and presynaptic GABAB 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 gamma-aminobutyric acid (GABA) at post- and presynaptic GABAB receptors were studied with whole-cell voltage-clamp recording in area CA3 of rat hippocampal slices. 2. The effect of THA on postsynaptic GABAB receptor-mediated responses was studied in neurons perfused internally with potassium gluconate and guanosine triphosphate (GTP). At a holding potential of -70 mV, the GABAB receptor agonist (+/-)-baclofen (30 microM) 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 GABAA receptor-mediated, fast monosynaptic inhibitory postsynaptic currents (IPSCs) and GABAB receptor-mediated, late monosynaptic IPSCs. THA (0.3 mM) blocked the baclofen-induced current and conductance increase and GABAB receptor-mediated IPSCs. 3. The effect of THA on presynaptic GABAB receptor-mediated responses was studied in neurons perfused internally with Cs+ and lidocaine N-ethyl bromide (QX-314), which blocked post-synaptic GABAB receptor-mediated responses. Stimulation in the presence of DNQX and APV evoked GABAA 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 GABAB 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 GABAB receptors. We conclude that post- and presynaptic GABAB receptors in area CA3 of the rat hippocampus couple to different effector mechanisms; postsynaptic GABAB receptors activate THA-sensitive K+ channels, and presynaptic GABAB receptors decrease neurotransmitter release through a THA-insensitive mechanism.
Lambert
N A
NA
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina.
Wilson
W A
WA
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects; D058787:GABA-A Receptor Antagonists; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D013619:Tacrine / Q000494:pharmacology*
D058787:GABA-A Receptor Antagonists; D009943:Organophosphorus Compounds; D015221:Potassium Channels; D011810:Quinoxalines; D011963:Receptors, GABA-A; D013619:Tacrine; C056723:FG 9041; D015763:2-Amino-5-phosphonovalerate; C066430:CGP 35348; D001418:Baclofen