Long-term and regional specific changes in [3H]flunitrazepam binding in kindled rat hippocampus

Expression of GABAA receptor subunit mRNAs in hippocampal pyramidal and granular neurons in the kindling model of epileptogenesis: an in situ hybridization study

“…In line with these observations, in fully kindled animals a decreased sensitivity of pyramidal neurons for GABA [20] and a reduced GABAAR mediated CI-uptake by synaptoneurosomes prepared from CA1/3 region was reported [66]. Binding studies in the same region revealed decreased GABAAR ligand binding although these changes were rather small [51,62,[67][68][69]. In view of these observations, the increased expression of GABAAR subunits is unexpected.…”

“…changes in GABAAR binding [29,51,62,67,69], in synaptic GABAergic inhibition [7,21,24,70,75,[77][78][79], in sensitivity for iontophoretically applied GABA [19] and in GABAAR mediated C1-uptake in synaptoneurosomes [66]. In this respect, it is of particular interest to compare the opposite changes in CA1-3 area, where a reduced GABAergic inhibition is manifested, with the changes in fascia dentata region where inhibition is strengthened [21,26,66,67,69,79]. Based on immunoprecipitation studies, it has been postulated that the muscimol and benzodiazepine binding GABAARS in the hippocampus are preferential assembled from associations of c~(1,2,4),/3(1-3) and 3'(2) subunits [8][9][10]61].…”

“…Since these subunits are dominant under normal conditions it can be concluded that there is no conspicuous change induced by kindling of the overall subunit composition of GABAARs. Moreover, the relative increases of the different a type subunits are comparable, suggesting no striking alteration in the pharmacological profile of benzodiazepine modulation in the fascia dentata [13,39,[57][58][59]63,72] [51,62,[67][68][69], the increased GABAR mediated CI-uptake by synaptoneurosomes prepared from fascia dentata [66] and the gradual strengthening of local recurrent inhibition in the course of kindling [7,21,26,53,70,79]. At long-term the changes in inhibition, receptor binding and in GABA-mediated flux had virtually subsided and the expression of GABAAR subunits also returned to control levels.…”

“…In CA1 area of the hippocampus, experimental evidence has been found in support of this hypothesis; a reduction of inhibitory synaptic transmission takes place in the course of kindling as shown by a reduced pairedpulse inhibition of local evoked field potentials [22,24,26,77,78], a diminished sensitivity of the pyramidal neurons for iontophoretically applied GABA [20] and a reduced binding of the GABA A receptor agonist [3H]muscimol [69] and of benzodiazepines [29,67]. In sharp contrast to the decreased inhibition in CA1, in the fascia dentata paired pulse inhibition is enhanced [7,21,26,70,79], together with an increase in the amplitude of miniature inhibitory postsynaptic currents [53], and a robust increase in both [3H]muscimol and [3H]flunitrazepam binding in this area [51,62,67,69]. The results of these studies imply local differences in the response of the GABAergic inhibition to kindling stimulations, specifically an impaired inhibition in CA1-3 area, leading to an increased propensity for seizures, along with a strengthened inhibition in fascia dentata, possibly limiting seizure activity.…”

Role of brain allopregnanolone in the plasticity of γ-aminobutyric acid type A receptor in rat brain during pregnancy and after delivery

“…The kinetic characteristics of the various binding sites located on the GABA A receptor, as well as the density and function of these receptors in different areas of the rat brain, are affected by acute stressful stimuli (handling, foot shock, swimming), postnatal development, aging, kindling, and long-term administration of anxiolytic, hypnotic, or anticonvulsant drugs (1)(2)(3)(4)(5)(6). Although recent studies have suggested that some of these changes may be mediated at the level of expression of receptor subunit genes (7)(8)(9)(10), the chemical or molecular events that underlie such rapid, shortterm, or persistent changes in the density and affinity of binding sites associated with GABA A receptors, as well as in the function of the receptor complex, remain to be characterized.…”