AGE-DEPENDENCE OF EFFECTS OF ADENOSINE-A1-RECEPTOR ANTAGONISM IN RAT HIPPOCAMPAL SLICES

1. Population excitatory postsynaptic potentials (EPSPs) and population spikes evoked in area CA 1 of hippocampal slices from aged Fischer 344 rats were significantly smaller in amplitude than responses obtained in slices from young Fischer 344 rats. 2. The A1 adenosine receptor antagonist 8-cyclopentyltheophylline (8-CPT) produced a concentration-dependent increase in synaptic potentials in slices from both young and aged rats. Low concentrations (1 nM) of 8-CPT were effective in producing increases in both population spike amplitudes and population EPSP slopes in young and aged rat slices. Response increases were maximized by 100 nM 8-CPT in slices from rats of both age groups. 3. Adenosine antagonism produced greater average increases in synaptic responses in hippocampal slices from aged rats at all concentrations tested (1.0 nM-1.0-mu-M). A qualitative age-related difference in the response to 8-CPT was also observed; 8-CPT produced a late component, consisting of multiple population spikes, in evoked responses in slices obtained from aged but not young rats. 4. Adenosine antagonism significantly increased the maximum evocable response (both spike amplitude and EPSP slope) in slices from aged rats, relative to increases observed in slices from young rats. This suggested that smaller synaptic potentials seen in slices from aged rats were in part due to greater levels of "tonic" adenosinergic inhibition. 5. Slices from young and aged rats were incubated in the adenosine reuptake inhibitor soluflazine (R64719; 1.0, 10, and 100-mu-M) and the inhibition of population EPSPs was observed for 60 min. No difference was observed in the rate of inhibition or the maximal level of inhibition produced by soluflazine, in slices from rats of either age group. 6. Application of (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclo-hepten-5, 10-imine hydrogen maleate (MK-801) and 2-amino-5-phosphonopentanoic acid (2-AP5), antagonists of N-methyl-D-aspartate (NMDA) excitatory amino acid (EAA) receptors, reduced the late multiple population spike component in slices from aged rats incubated in 8-CPF. A smaller direct effect of the NMDA antagonists was observed in slices from aged rats in the absence of 8-CPT treatment at maximal response levels. No effect of NMDA receptor antagonism was observed in slices from young rats under either condition. 7. Hippocampal tissue, from young and old rats utilized in the electrophysiological experiments, was assayed for Al adenosine binding site density with a saturating concentration of radiolabeled agonist and antagonist. Guanine nucleotide modulation of agonist binding was also measured. No age-related changes were observed in any of these measures. 8. We conclude that in a majority of hippocampal slices from aged rats tonic adenosinergic inhibition was apparently significantly enhanced and contributed to an age-related decline in synaptic efficacy. Slices from aged rats expressed an NMDA receptor-mediated synaptic response component that was greatly exacerbated by adenosine antagonism; this component was absent in slices from young rats. 9. This apparent age-related difference in adenosinergic inhibition could reflect an untested measure of adenosine function such as receptor-effector coupling. It did not appear to result from increased density of receptors or an enhanced rate of release. Adenosine is an important modulator of neuronal function in the hippocampus, and enhanced tonic inhibition in slices from aged rats, regardless of the mechanism, could contribute to other apparent age-related neuronal phenomena.