Young and older good learners have higher levels of brain nicotinic receptor binding

Abstract

Neuronal alphabeta heteromeric and alpha7 homomeric nicotinic acetylcholine receptors (nAChRs) were compared in 4- and 27-month rabbits selected for learning proficiency. Sixty 4- and 60 27-month rabbits received the alpha7 nAChR agonist (MEM-3389), galantamine, or vehicle during training in trace eyeblink classical conditioning. Brain tissue from the best and worst young and older learners was analyzed with radioligand binding. Vehicle-treated 4- and 27-month good learners had higher alphabeta heteromeric nAChR binding in hippocampus and temporal-parietal cortex than poor learners, and this result was replicated in both age groups of rabbits treated with galantamine. Results indicate that anatomically more numerous nAChRs or functional activation of a greater number of nAChRs may characterize animals demonstrating optimal learning. During normal aging the expression of high-affinity binding sites declines. Age-related changes in the expression of hippocampal alphabeta heteromeric nAChRs may account for some of the documented age-related impairment in learning. However, individual differences in alphabeta heteromeric nAChRs also exist early in life, as better learning in 4-month rabbits was associated with significantly higher binding.

Fig. 1

(A) Percentage of CRs in 10 90-trial training sessions of combined 600 and 750 ms trace eyeblink classical conditioning in 120 4- and 27-month rabbits treated with 3.0 mg/kg galantamine, 1.0 mg/kg MEM-3389, or vehicle. The effects of age, drug, and training session were statistically significant. (B) Data from A above averaged over the 10 training sessions to show the significant age and drug effects.

Fig. 2

Trials to a learning criterion of 8 CRs in 9 consecutive trials (in a session with a minimum of 40% CRs) in 120 rabbits tested in the 600 or 750 ms trace eyeblink classical conditioning paradigm treated with 3.0 mg/kg galantamine, 1.0 mg/kg MEM-3389, or vehicle. Rabbits in the 27-month age group took significantly more trials to attain learning criterion than 4-month rabbits, and galantamine and MEM-3389 significantly reduced trials to criterion over vehicle in 4-month but not in 27-month rabbits.

Fig. 3

Mean total percentage of CRs in rabbits selected as the best (“good learner”) and worst (“poor learner”) performers in 600 or 750 ms trace eyeblink classical conditioning. A total of 18 4-month old and 18 27-month good learner rabbits were compared to 18 each of 4- and 27-month poor learner rabbits treated with vehicle, 3.0 mg/kg galantamine, or 1.0 mg/kg MEM-3389. There were highly significant differences between good and poor learners as well as significant age and drug effects. Single asterisks over each good learner group indicate statistically significant differences between good and poor learners. The bar with an asterisk over galantamine and MEM-3389 groups of young rabbits indicates statistically significant differences between vehicle- and drug-treated good learners. Asterisks over the bar over all young rabbits indicate significant differences between 4- and 27-month rabbits. *p < 0.05; ***p < 0.001.

Fig. 4

(A) In vehicle-treated rabbits, there was significantly higher expression of αβ heteromeric nicotinic acetylcholine receptors (nAChRs) in hippocampus in 4- and 27-month good learners. (B) Four- and 27-month good learner rabbits also had significantly higher expression of αβ heteromeric nAChRs in temporal–parietal cortex. Expression of α7 homomeric nAChRs was not different between vehicle-treated good and poor learners in (C) hippocampus or (D) temporal–parietal cortex. *p < 0.05; **p < 0.01; ***p < 0.001.

Fig. 5

(A) In rabbits treated with galantamine or MEM-3389, there was significantly higher expression of αβ heteromeric nicotinic acetylcholine receptors (nAChRs) in hippocampus in 4- and 27-month good learners. (B) In temporal–parietal cortex, 27-month good learner rabbits treated with galantamine or MEM-3389 had significantly higher expression of αβ heteromeric nAChRs. *p < 0.05; **p < 0.01; ***p < 0.001.

Fig. 6

(A) In 27-month good learner rabbits treated with MEM-3389, there was significantly higher expression of α7 homomeric nicotinic acetylcholine receptors (nAChRs) in hippocampus. (B) There were no significant differences in temporal–parietal cortex between good and poor learners in α7 homomeric nAChRs in 4- or 27-month rabbits. *p < 0.05.

Fig. 7

Comparison of levels of αβ heteromeric nicotinic acetylcholine receptors (nAChRs) in hippocampus (A) and temporal–parietal cortex (B) and of α7 homomeric nAChRs in hippocampus (C) and temporal–parietal cortex (D) in 4- and 27-month vehicle- and drug-treated good and poor learner rabbits. In 4-month good learner rabbits, there were significantly higher levels of αβ heteromeric nAChR expression in galantamine-treated than in vehicle-treated rabbits, and in 27-month good learner rabbits, there were significantly higher levels of αβ heteromeric nAChR expression in vehicle-treated rabbits (A). In 27-month good learner rabbits, there were significantly higher levels of α7 homomeric nAChR expression in MEM-3389-treated than in vehicle-treated rabbits (C). *p < 0.05; **p < 0.01.