Pharmacological modulation of GABAA receptor-mediated postsynaptic potentials in the CA1 region of the rat hippocampus

1 It is unclear whether GABA(A) receptor-mediated hyperpolarizing and depolarizing synaptic potentials (IPSP(A)s and DPSP(A)s, respectively) are evoked by (a) the same populations of GABAergic interneurones and (b) exhibit similar regulation by allosteric modulators of GABA(A) receptor function. We have attempted to address these questions by investigating the effects of (a) known agonists for presynaptic receptors on GABAergic terminals, and (b) a range of GABA(A) receptor ligands, on each response. 2 The GABA uptake inhibitor NNC 05-711 (10 mu M) enhanced whereas bicuculline (10 mu M) inhibited both IPSP(A)s and DPSP(A)s. 3 (-)-Baclofen (5 mu M), [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAGO; 0.5 mu M), and carbachol (10 mu M) caused substantial depressions (up to 99%) of DPSP(A)s that were reversed by CGP 55845A (1 mu M), naloxone (10 mu M) and atropine (5 mu M), respectively. In contrast, 2-chloroadenosine (CADO; 10 mu M) only slightly depressed DPSP(A)s. Quantitatively, the effect of each agonist was similar to that reported for IPSP(A)s. 4 The neurosteroid ORG 21465 (1 - 10 mu M), the anaesthetic propofol (50 - 500 mu M), the barbiturate pentobarbitone (100-300 mu M) and zinc (50 mu M) all enhanced DPSP(A)s and IPSP(A)s. 5 The benzodiazepine (BZ) agonist flunitrazepam (10-50 mu M) and inverse agonist DMCM (1 mu M) caused a respective enhancement and inhibition of both IPSP(A)s and DPSP(A)s. The BZ omega(1) site agonist zolpidem (10-30 mu M) produced similar effects to flunitrazepam. 6 The anticonvulsant loreclezole (1-100 mu M) did not affect either response. 7 These data demonstrate that similar populations of inhibitory interneurones can generate both IPSP(A)s and DPSP(A)s by activating GABA(A) receptors that are subject to similar allosteric modulation.