title: Adenosine receptor antagonists induce persistent bursting in the rat hippocampal CA3 region via an NMDA receptor-dependent mechanism.
abstract: Adenosine receptor antagonists initiate repetitive bursting activity in the CA3 region of hippocampal slices. Although some studies have suggested that this effect is irreversible, this has been difficult to establish because many adenosine antagonists wash out of brain slices extremely slowly. Furthermore the cellular mechanism that underlies persistent bursting is unknown. To resolve these issues, we studied the effects of nonselective (8-p-sulfophenyltheophylline, 8SPT, 50-100 microM), A(l)-selective (8-cyclopentyl-1, 3-dipropylxanthine, 100 nM; xanthine carboxylic acid congener, 200 nM), and A(2A)-selective (chlorostyryl-caffeine; 200 nM) adenosine antagonists in the CA3 region of rat hippocampal slices using extracellular recording. Superfusion with all of the adenosine antagonists except chlorostyryl-caffeine induced bursting, and the burst frequency after 30 min drug superfusion did not differ for the different antagonists. Most slices showed a period of rapid initial bursting, followed either by stable bursting at a lower frequency or a pattern of oscillating burst frequency. In either case, the bursting continued after drug washout. Virtually identical patterns of long-term bursting activity were observed when 8SPT was washed out or applied continuously. Control experiments using exogenous adenosine to characterize the persistence of 8SPT in tissue demonstrated >95% washout at 60 min, a time when nearly all slices still showed regular bursting activity. When the N-methyl-D-aspartate (NMDA) antagonists DL-2-amino-5-phosphonovaleric acid (AP5; 50 microM) or dizocilpine (10 microM) were applied before and during 8SPT superfusion, bursting occurred in the presence of the NMDA antagonists but did not persist once the 8SPT was washed out. AP5 had no effect on persistent bursting when applied after the initiation of spiking. The selective calcium/calmodulin-dependent protein kinase inhibitor 1-[N, O-bis-(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN-62; 3 microM), which has been shown to block NMDA receptor-dependent synaptic plasticity in the CA1 region, also significantly decreased the long-term effect of 8SPT. Thus adenosine antagonists initiate persistent spiking in the CA3 region; this activity does not depend on continued occupation of adenosine receptors by antagonists, and can be blocked by treatments that prevent NMDA receptor-dependent plasticity.
authors.affiliation: Institut für Pharmakologie und Toxikologie, Universität Leipzig, D04107 Leipzig, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Thümmler
authors.forename: T V
authors.initials: TV
authors.lastname: Dunwiddie
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018674:Adrenergic Antagonists / Q000494:pharmacology*; D000818:Animals; D002110:Caffeine / Q000031:analogs & derivatives / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000737:chemistry* / Q000166:cytology / Q000502:physiology*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000737:chemistry / Q000502:physiology; D010507:Periodicity; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D015290:Second Messenger Systems / Q000187:drug effects; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology*
chemical_list: D018674:Adrenergic Antagonists; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D058915:Purinergic P1 Receptor Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D014970:Xanthines; C081320:8-(3-chlorostyryl)caffeine; D002110:Caffeine; D016202:N-Methylaspartate; C063302:KN 62; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; C031433:8-(4-sulfophenyl)theophylline; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C054469:8-(4-carboxymethyloxy)phenyl-1,3-dipropylxanthine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D013806:Theophylline