title: Disinhibition of hippocampal CA3 neurons induced by suppression of an adenosine A1 receptor-mediated inhibitory tonus: pre- and postsynaptic components.
abstract: Intracellular recordings were performed on hippocampal CA3 neurons in vitro to investigate the inhibitory tonus generated by endogenously produced adenosine in this brain region. Bath application of the highly selective adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine at concentrations up to 100 nM induced both spontaneous and stimulus-evoked epileptiform burst discharges. Once induced, the 1,3-dipropyl-8-cyclopentylxanthine-evoked epileptiform activity was apparently irreversible even after prolonged superfusion with drug-free solution. The blockade of glutamatergic excitatory synaptic transmission by preincubation of the slices with the amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (10 microM), but not with the N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosphonovaleric acid (50 microM), prevented the induction of epileptiform activity by 1,3-dipropyl-8-cyclopentylxanthine. The generation of the burst discharges was independent of the membrane potential, and the amplitude of the slow component of the paroxysmal depolarization shift increased with hyperpolarization, indicating that the 1,3-dipropyl-8-cyclopentylxanthine-induced bursts were synaptically mediated events. Recordings from tetrodotoxin-treated CA3 neurons revealed a strong postsynaptic component of endogenous adenosinergic inhibition. Both 1,3-dipropyl-8-cyclopentylxanthine and the adenosine-degrading enzyme adenosine deaminase produced an apparently irreversible depolarization of the membrane potential by about 20 mV. Sometimes, this depolarization attained the threshold for the generation of putative calcium spikes, but no potential changes resembling paroxysmal depolarization shift-like events were observed. At the concentrations used in electrophysiological experiments (30-100 nM), 1,3-dipropyl-8-cyclopentylxanthine displayed only a negligible inhibitory action on total cyclic nucleotide phosphodiesterase activity measured by means of a radiochemical assay in a homogenate of the rat cerebral cortex. Furthermore, even high concentrations of the selective phosphodiesterase inhibitor rolipram (10 microM), which displays no affinity to adenosine receptors, did not mimic the electrophysiological actions of 1,3-dipropyl-8-cyclopentylxanthine, thus excluding the possibility that the effects of the A1 receptor antagonist on neuronal discharge behavior can be ascribed to an inhibition of phosphodiesterases. The present data demonstrate that endogenously released adenosine exerts a vigorous control on the excitability of hippocampal CA3 neurons on both the pre- and postsynaptic sites. The long-lasting disinhibition following a transient suppression of adenosinergic inhibition strongly suggests that, besides its well-known short-term effects on neuronal activity, adenosine might also contribute to the long-term control of hippocampal excitability.
authors.affiliation: Department of Physiology, University of Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Alzheimer
authors.forename: B
authors.initials: B
authors.lastname: Sutor
authors.forename: G
authors.initials: G
authors.lastname: ten Bruggencate
mesh_terms: D000818:Animals; D004827:Epilepsy / Q000139:chemically induced; D006168:Guinea Pigs; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D009433:Neural Inhibition; D009474:Neurons / Q000201:enzymology / Q000502:physiology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D014970:Xanthines / Q000494:pharmacology
chemical_list: D018047:Receptors, Purinergic P1; D014970:Xanthines; C051360:1,3-dipropyl-8-cyclopentylxanthine; D010727:Phosphoric Diester Hydrolases