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Attenuation in rats of impairments of memory by scopolamine, a muscarinic receptor antagonist, by mecamylamine, a nicotinic receptor antagonist

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Abstract

Rationale

Scopolamine, a muscarinic antagonist, impairs learning and memory for many tasks, supporting an important role for the cholinergic system in these cognitive functions. The findings are most often interpreted to indicate that a decrease in postsynaptic muscarinic receptor activation mediates the memory impairments. However, scopolamine also results in increased release of acetylcholine in the brain as a result of blocking presynaptic muscarinic receptors.

Objectives

The present experiments assess whether scopolamine-induced increases in acetylcholine release may impair memory by overstimulating postsynaptic cholinergic nicotinic receptors, i.e., by reaching the high end of a nicotinic receptor activation inverted-U dose-response function.

Results

Rats tested in a spontaneous alternation task showed dose-dependent working memory deficits with systemic injections of mecamylamine and scopolamine. When an amnestic dose of scopolamine (0.15 mg/kg) was co-administered with a subamnestic dose of mecamylamine (0.25 mg/kg), this dose of mecamylamine significantly attenuated the scopolamine-induced memory impairments. We next assessed the levels of acetylcholine release in the hippocampus in the presence of scopolamine and mecamylamine. Mecamylamine injections resulted in decreased release of acetylcholine, while scopolamine administration caused a large increase in acetylcholine release.

Conclusions

These findings indicate that a nicotinic antagonist can attenuate impairments in memory produced by a muscarinic antagonist. The nicotinic antagonist may block excessive activation of nicotinic receptors postsynaptically or attenuate increases in acetylcholine release presynaptically. Either effect of a nicotinic antagonist—to decrease scopolamine-induced increases in acetylcholine output or to decrease postsynaptic acetylcholine receptor activation—may mediate the negative effects on memory of muscarinic antagonists.

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Acknowledgments

Special thanks to Jamie Richards, Disha Goswami, Emily Pajerski, Huzefa Chinwala, Laura Manning, Sydney Muchnik, Heather Lin, and Fiona Weingartner for their valuable participation on this project.

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Authors and Affiliations

  1. Department of Biology, Syracuse University, 114 Life Sciences Complex, Syracuse, NY, 13244, USA

    L. A. Newman & P. E. Gold

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  1. L. A. Newman
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  2. P. E. Gold
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Correspondence to P. E. Gold.

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Supported by NSF IOS 13-18490, the Alzheimer’s Association, and the Syracuse University Center for Aging and Policy Studies (NIA P30 AG034464). L.A.N. was a postdoctoral trainee on NICHD Training Grant HD00733.

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Newman, L.A., Gold, P.E. Attenuation in rats of impairments of memory by scopolamine, a muscarinic receptor antagonist, by mecamylamine, a nicotinic receptor antagonist. Psychopharmacology 233, 925–932 (2016). https://doi.org/10.1007/s00213-015-4174-9

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