Frontal cortical α7 and α4β2 nicotinic acetylcholine receptors in working and reference memory
Introduction
The role of the nicotinic acetylcholine receptor (nAchR) in memory has been well established in both humans and animals. For example, systemic administration of high doses of mecamylamine, a nicotinic receptor antagonist, causes significant memory performance deficits in the radial arm maze (RAM) in rats (Levin and Simon, 1998). Conversely, low doses of mecamylamine were found to improve memory acquisition in other studies (Terry et al., 1999). Activation of nAchRs using agonists has been shown to improve memory performance in rats (Levin et al., 1995), rabbits (Woodruff-Pak, 2003) and monkeys (Spinelli et al., 2006). In humans, transdermally-administered nicotine resulted in improvements in a variety of recall tasks by non-subtype specific stimulation of nAchRs (Howe and Price, 2001). In another study, the α7 nAchR subtype was specifically shown to be involved in human memory function (Kitagawa et al., 2003).
Previous studies have shown that the hippocampus (Nott and Levin, 2006) and amygdala (Addy et al., 2003) are involved in nAchR mediated memory function. In both studies, antagonism of the α7 and α4β2 nAchR subtypes resulted in working memory impairments in the RAM. In addition to these regions, the study of nAchR related memory in other brain areas, such as the frontal cortex, is of importance. This is because the frontal cortex is well known to be involved in higher memory functions such as spatial working memory (Pasternak and Greenlee, 2005).
A study on nAchRs and muscarinic receptors in the rat prefrontal cortex concluded that they were linked with working memory but not reference memory (Granon et al., 1995). Besides this study, the role of nAchRs in the frontal cortex in memory in either humans or animals has received relatively little attention. This is surprising given our knowledge that losses of α4 subunit containing nAchR from the frontal cortex have been shown to be correlated to declining memory performance in Alzheimer's disease patients (Kendziorra et al., 2006). In fact, stimulation of the cholinergic system using nAchR agonists has been used to combat Alzheimer's disease related memory impairments caused by losses of frontal cortical nAchR (Claassen and Jansen, 2006). These findings, coupled with the knowledge that there is a relatively high concentration of nAchR in the frontal cortex (Hernandez and Terry, 2005), seem to point to an important role of frontal cortical nAchR in memory function. Therefore, we sought to elucidate the specific role of the α7 and α4β2 nAchR subtypes in the frontal cortex with regards to both working and reference memory in the present study.
Section snippets
Animals and cannula guide implantation
Male Sprague–Dawley rats (n = 56) aged between 6 and 7 weeks were housed in pairs and allowed to acclimatize to their new surroundings for 1 week. They were placed on a restricted diet at 75% free feeding levels water ad libitum. All protocols were approved by the Institutional Animal Care and Use Committee (IACUC) of the National University of Singapore. Rats were anesthetized by an i.p. injection of a ketamine (70 mg/kg) and xylazine (8 mg/kg) mixture. The intended site of infusion was at
Cannula placement and brain histology
The cannula placement was verified to be consistent and in close proximity to the intended injection site in the frontal cortex. Therefore, no data were excluded from statistical analysis. Histological examination also revealed minimal tissue damage in the areas surrounding the cannula track (Fig. 1). A summary of cannula positions in all rats is shown in Fig. 2 (Paxinos and Watson, 1998).
The agonist phase
On Day 0, all seven groups of mice performed at the same level in working memory (F6, 49 = 0.06298, p = 0.99) (
Discussion
The drugs used in the present study are nAchR subtype selective. PNU has been shown to be a potent agonist of the α7 nAchR (Ki = 27 nM) with negligible interactions with other nAchR subtypes (IC50 ≥ 60 μM). In addition, in vitro tests on 32 other receptors, ion channels and enzymes produced less than 30% inhibition of activity, except at the 5-HT3 receptor. This is because the 5-HT3 receptor is a structural analogue of the α7 nAchR (Bodnar et al., 2004). Nevertheless, PNU has a 67-fold binding
Acknowledgment
This work was supported in part by a grant from the Ministry of Education Singapore via the University Research Council of the National University of Singapore R-154-000-228-112 to F.-S. S.
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