Nicotinic acetylcholine receptors and modulation of learning in 4- and 27-month-old rabbits.

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 alphabeta heteromeric nAChRs ([3H]epibatidine) and alpha7 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 alphabeta heteromeric nAChR binding in hippocampus than young rabbits. For cognition enhancement, galantamine (mild cholinesterase inhibitor and allosteric modulator of nAChRs) or MEM-3389 (alpha7nAChR 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 alphabeta heteromeric nAChRs and hippocampal alphabeta and alpha7nAChRs. In 4-month rabbits, drugs increased expression of alpha7 homomeric nAChRs in frontal and temporal-parietal cortex and hippocampus, but increased expression of alphabeta heteromeric nAChRs only occurred in temporal-parietal cortex. Increased expression of alphabeta nAChRs was more extensive in older drug-treated rabbits, whereas increased expression of alpha7nAChRs 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.