Abstract
Using drugs acting on nicotinic acetylcholine receptors (nAChRs), we examined temporal-parietal and frontal cortex, hippocampus, and cerebellum to identify sites of cognition enhancement in 4- and 27-month rabbits. First, we compared radioligand receptor binding for neuronal αβ heteromeric nAChRs ([3H]epibatidine) and α7 homomeric nAChRs ([3H]methyllycaconitine) in rabbits and rats. In cerebellum, nAChR levels of both species are low, about at the detection limit of the radioligand binding assays. Next, we compared nAChRs in 4- and 27-month vehicle-treated rabbits trained in delay eyeblink conditioning. Older rabbits conditioned more poorly and had lower αβ heteromeric nAChR binding in hippocampus than young rabbits. For cognition enhancement, galantamine (mild cholinesterase inhibitor and allosteric modulator of nAChRs) or MEM-3389 (α7nAChR agonist formerly identified as AR-R 17779) was injected before conditioning. Drugs improved learning in both age groups. In 27-month rabbits, drugs increased expression of frontal and temporal-parietal αβ heteromeric nAChRs and hippocampal αβ and α7nAChRs. In 4-month rabbits, drugs increased expression of α7 homomeric nAChRs in frontal and temporal-parietal cortex and hippocampus, but increased expression of αβ heteromeric nAChRs only occurred in temporal-parietal cortex. Increased expression of αβ nAChRs was more extensive in older drug-treated rabbits, whereas increased expression of α7nAChRs was more prevalent in younger drug-treated rabbits, suggesting different substrates for amelioration (27-month rabbits) vs facilitation (4-month rabbits) of learning. Results provide evidence for cortical as well as hippocampal nAChR modulation of delay eyeblink conditioning and demonstrate that more sensitive binding assays are required to assess nAChR effects in cerebellum.
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Acknowledgements
We thank Susan Seta, LaToya Roker, Renee Procopio, and Steve Purcell for their assistance with rabbit familiarization training and behavioral testing. We gratefully acknowledge Janssen Pharmaceutica, NV, and Ortho-McNeil Neurologics for supplying galantamine and Memory Pharmaceuticals for supplying MEM-3389, formerly identified as AR-R-17779. This research was supported by grants from the National Institute on Aging, 1 R01 AG021925 and 1 R01 AG023742 to DSW-P and from the National Institute on Drug Abuse, R01 DA17302 and P30 DA 13429 to L-YL-C.
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Li, JG., Lehr, M., Liu-Chen, LY. et al. Nicotinic Acetylcholine Receptors and Modulation of Learning in 4- and 27-Month-Old Rabbits. Neuropsychopharmacol 33, 2820–2830 (2008). https://doi.org/10.1038/npp.2008.1
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DOI: https://doi.org/10.1038/npp.2008.1
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