Our laboratory has demonstrated that the dihydropyridine calcium antagonist nimodipine markedly facilitates associative learning in aging rabbits. Further, we have demonstrated in young adult rabbits that among the neural changes induced by classical conditioning is a reduction in the afterhyperpolarization (AHP) that follows a burst of action potentials by hippocampal CA1 neurons. This AHP is generated through the activation of a Ca2+-dependent K+ conductance. Nimodipine antagonism of neuronal calcium conductance may cause a reduction of the AHP in hippocampal neurons of the aging rabbits, thereby including a biophysical change similar to one found in the young adult hippocampus following learning. This pharmacologically- induced reduction of the AHP may in turn facilitate learning. We outline a series of behavioral neurophysiological and biophysical experiments to test this hypothesis. We will also address basic questions regarding how aging might alter the AHP, Ca2+ and K+ currents in CA1 pyramidal neurons. Hippocampus, a brain region affected by aging, will be studied; trace eyeblink conditioning, a hippocampally-dependent associative learning task, will be used. Behavioral pharmacological experiments will define the nimodipine dose/response curve, the retention period of the nimodipine induced learning facilitation, effects on tone conditioned stimulus (CS) sensitivity and control for nonspecific performance enhancement. The possible contribution of enhanced cerebral blood flow, in addition to modulation of neuronal function, will be evaluated by measuring nimodipine enhancement of blood flow and by determining the effects of flunarizine, a non-dihydropyridine Ca2+ channel blocker, on learning in aging rabbits. Single hippocampal neurons will be studied in vivo as an index of nimodipine's action on elements of the conditioned reflex arc during learning. Biophysical experiments will be performed on CA1 pyramidal neurons in brain slices and acutely dissociated neurons to determine the effect of aging on the AHP, Ca2+ and faster K+ currents; on responsitivity to neurotransmitters including acetylcholine, norepinephrine and serotonin; and on size of the AHP reduction after associative learning. Our experimental program is designed to investigate cellular mechanisms by which learning is impaired by aging and by which pharmacological intervention with nimodipine might facilitate learning in aging rabbits. In general, our research is addressed to the alterations in calcium metabolism which are known to occur in the aging brain. The particular compound which we propose to investigate, nimodipine, has been approved by the FDA for clinical use in humans in the US and is already being used in Europe. Therefore, it is likely that these experiments will make a rather direct contribution to the clinical amelioration of learning deficits in the aging human in the near future.
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