Nimodipine enhances spontaneous activity of hippocampal pyramidal neurons in aging rabbits at a dose that facilitates associative learning

Abstract

The functional activity of hippocampal neurons is strongly correlated with behavioral performance in a vertebrate model learning system, rabbit eyeblink conditioning. Using this system, we have previously shown that (a) complete removal of the hippocampus blocks acquisition of the conditioned response; (b) a calcium-dependent postsynaptic afterhyperpolarization is reduced in pyramidal cells recorded intracellularly in hippocampal slices taken from conditioned rabbits; and (c) nimodipine, a 1,4-dihydropyridine calcium-channel antagonist, facilitates acquisition of the conditioned response in aging rabbits. Although calcium-channel antagonists directly block neuronal calcium currents in vitro, they also alter cerebral blood flow in vivo. Thus, the effects of nimodipine on hippocampal neuronal activity in awake animals were examined, with controls for cerebrovascular changes. A total of 457 pyramidal cells and 160 theta cells were studied. During infusion of nimodipine, pyramidal cell firing activity was enhanced and theta interneuron activity was suppressed at all doses tested in aging animals. This effect was rapidly reversed when infusion of the drug ceased. The greatest enhancement of neuronal firing was seen at the most behaviorally effective dose of nimodipine. The enhancement of pyramidal cell firing was age-dependent with greater increases in firing activity seen in aging than in young animals, but with a similar dose-dependent pattern of effects in the two age groups. Two other calcium-channel antagonists, nifedipine and flunarizine, did not significantly alter spontaneous firing rates of hippocampal neurons. A calcium-channel agonist, BAY-K-8644, produced less easily interpretable results. BAY-K-8644 enhanced interneuron activity at one dose, but enhanced pyramidal cell activity at a dose one log unit higher. The calcium-channel agonist's enhancement of pyramidal cell actvity at highest dose was sustained up to 1 h after drug infusion. Nimodipine's enhancement of the activity of hippocampal pyamidal cells is consistent with the hypothesis that these neurons, which play a necessary role in some forms of learning, may mediate the calcium-channel antagonist's behavioral effects.