title: Suppression of presynaptic responses to adenosine by activation of NMDA receptors.
abstract: The interactions between adenosine and NMDA receptors has been investigated using the paired-pulse paradigm in hippocampal slices. This technique allows the study of drug effects specifically at presynaptic terminals. The inhibitory effect of adenosine on population spikes, and the decrease of paired-pulse inhibition assessed using either population spikes or population excitatory postsynaptic potentials, were suppressed by performing the experiments in magnesium-free medium, or by superfusion of the slices with N-methyl-D-aspartate (NMDA) at a concentration (4 microM) which did not itself affect potential size. The suppressant effect of NMDA was prevented by 2-amino-5-phosphonopentanoic acid. All these interactions were still seen in the presence of bicuculline methobromide, 30 microM. Neither alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) nor kainate produced a suppression of adenosine responses. The presence of NMDA did not modify the effects of baclofen on population potentials or paired-pulse inhibition. Activating NMDA receptors by the induction of long-term potentiation or by superfusion with glycine also reduced significantly the effects of adenosine on population spikes and paired-pulse interactions. Increasing population potential size by a mechanism which did not involve the activation of NMDA receptors (increasing stimulus strength) did not change sensitivity to adenosine. When adenosine receptor-selective agonists were tested, it was found that NMDA did not modify the inhibitory effect of the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine, but did enhance the excitatory effect of the adenosine A(2A) receptor agonist 2-[p-(2-carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680). The combined response to NMDA and CGS21680 was prevented by the adenosine A(2A) receptor selective antagonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385). It is concluded that NMDA receptor activation can suppress neuronal sensitivity to adenosine by acting at presynaptic sites, and that this interaction results from an increase in the excitatory action of adenosine A(2A) receptors, rather than a depression of A(1) receptor function.
authors.affiliation: Institute of Biomedical and Life Sciences, West Medical Building, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: M R
authors.initials: MR
authors.lastname: Nikbakht
authors.forename: T W
authors.initials: TW
authors.lastname: Stone
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D005998:Glycine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D010627:Phenethylamines / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000502:physiology; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013997:Time Factors; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D018690:Excitatory Amino Acid Agonists; D018755:GABA Agonists; D010627:Phenethylamines; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D016194:Receptors, N-Methyl-D-Aspartate; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C048599:N(6)-cyclopentyladenosine; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D001418:Baclofen; D000241:Adenosine; D007608:Kainic Acid; D005998:Glycine