# MECHANISMS OF NIMODIPINE LEARNING ENHANCEMENT IN AGING

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 1993 · $198,505

## Abstract

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.

## Key facts

- **NIH application ID:** 3120551
- **Project number:** 5R01AG008796-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **SAM.gov UEI:** KG76WYENL5K1
- **Principal Investigator:** JOHN F DISTERHOFT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $198,505
- **Award type:** 5
- **Project period:** 1990-03-01 → 1995-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3120551

## Citation

> US National Institutes of Health, RePORTER application 3120551, MECHANISMS OF NIMODIPINE LEARNING ENHANCEMENT IN AGING (5R01AG008796-04). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3120551. Licensed CC0.

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