Research ReportDorsal hippocampal α7 and α4β2 nicotinic receptors and memory
Introduction
Neuronal nicotinic receptors have been found to be important in cognitive function in rodents as well as primates including rhesus monkeys and humans (see review, Levin and Simon, 1998). Studies using acute and chronic treatments of nicotine and nicotinic agonists have been shown to improve the working memory of rats. Whereas antagonists, such as mecamylamine, have been shown to have the reverse effect. Nicotine administration was shown to selectively improve working, but not reference memory in rats trained on a 16-arm radial maze (Levin et al., 1996, Levin et al., 1997). Both α7 and α4β2 nicotinic receptors have been shown to be involved. The anatomic localization of nicotinic receptor subtype involvement in memory function is still being determined.
Local infusion of specific receptor antagonists can be used to distinguish the role of specific nicotinic receptors in that region for memory function. Methyllycaconitine (MLA) is an extract from the seeds of Delphinium brownii. It has been found to act competitively at nicotinic acetylcholine receptors (Aiyar et al., 1979, Alkondon et al., 1992). MLA binding sites in rat brains was found to be the same as that of the α-bungarotoxin, which binds and blocks α7 nicotinic receptors (Davies et al., 1999, Wonnacott et al., 1993). However, there is evidence of cross-reactivity of MLA at α6-containing nicotinic receptors particularly in the brainstem dopaminergic nuclei (Klink et al., 2001). Dihydro-β-erythroidine (DHβE) is a plant alkaloid isolated from the seeds of Erythrina americana. DHβE is a tertiary amine that can penetrate the blood–brain barrier (Decker et al., 1995). It has been found to competitively bind to heteromeric neuronal ACh receptors containing α3, α4, and β2 subunits (Dwoskin and Crooks, 2001, Williams and Robinson, 1984). It therefore acts as a good antagonist with specificity for α4β2 nicotinic receptors, as well as α3β2 receptors in hippocampal neurons (Alkondon and Albuquerque, 1993). MLA and DHβE are therefore appropriate antagonists to use to investigate the effects of blocking α7 and α4β2 neuronal nicotinic receptors subtype combinations within the brain.
The hippocampus seems to be a particularly relevant site for nicotinic effects on memory. Both α7 and α4β2 nicotinic receptors are found in the hippocampus (Séguéla et al., 1993, Wada et al., 1989) and are believed to play a role in the release of acetylcholine (Changeux et al., 1998, Wonnacott, 1997). These receptors in ventral hippocampus were found in our early study to be important for working memory function. Increases in working memory errors were seen in rats run on an 8-arm radial maze when the two nicotinic antagonists MLA and DHβE were infused in the ventral hippocampus (Felix and Levin, 1997). Relatively high doses of these antagonists were used in this study which in addition to impairing working memory also caused increased latencies and caused preconvulsant responses such as piloerection, tremor, head bobbing, and teeth chattering, which may have had an effect on the data and may have interfered with the assessment of working memory (Felix and Levin, 1997). This issue was addressed in a subsequent study using the more challenging 16-arm maze that allows lower doses of the antagonist to be tested. MLA and DHβE still produced a deficit in working memory without any preconvulsant effects occurring and the latencies remaining constant. The 16-arm maze also provided a test for the possible effects that DHβE and MLA may have on reference memory. Only DHβE was found to have an effect on the reference memory in the ventral hippocampus (Levin et al., 2002).
When DHβE and MLA were co-administered into the ventral hippocampus, they had no additive effects, supporting the specificity of the two drugs for their receptor types (Levin et al., 2002). There were also no additive effects observed when DHβE and MLA were co-administered in the amygdala, but DHβE did attenuate the effect of MLA on working memory, which had not been previously seen. This suggests that the α4β2 and α7 receptors may interact, in some opposing fashion involving working memory (Addy et al., 2003).
Neuronal nicotinic receptors have been isolated in many different regions of the brain. The involvement in memory function of particular receptor subtypes found in differing regions of the brain is still being characterized. The hippocampal and amygdalar regions of the brain have already been found to be important in cognitive functions in both lesion and local drug infusion studies (Addy et al., 2003, Jarrard, 1995, Levin et al., 2002, Ohno et al., 1992). Studies using the specific antagonists MLA and DHβE have shown that the receptor subtypes α4β2 and α7 are particularly important in working memory function in the ventral hippocampus and basolateral amygdala (Addy et al., 2003, Levin et al., 2002). Studies have also shown that the cortical areas are also of importance for cognitive functions (Rahman et al., 1999). However, the significance for memory of α4β2 and α7 receptors in the dorsal hippocampus has not yet been determined.
The rationale of the study is to provide an analysis of α4β2 and α7 nicotinic receptors in the dorsal hippocampus regarding their involvement in memory in comparison to the previous work we have done in the ventral hippocampus and the basolateral amygdala. The competitive antagonists MLA and DHβE were used to determine the effects of specific blockade effects of the α7 and α4β2 receptors within the dorsal hippocampus. The 16-arm radial maze was used to distinguish between the involvement of the receptors in working or reference memory function.
Section snippets
Histology
The cannula placements were verified using histological techniques. For each area of the study, only rats that had drug infusion flow into the target areas on both sides of the dorsal hippocampus were included in the data analysis. Ten rats had correctly directed bilateral cannulae in the dorsal hippocampus and were included in the data analysis. Fig. 1 shows a coronal diagram of cannula placements in the dorsal hippocampus, located at the anterior–posterior (AP) coordinate of −1.2. The infused
Discussion
The functional effects of local DHβE and MLA infusions into the dorsal hippocampus indicate that α4β2 and α7 receptors in this region are important in working memory function. Although each nicotinic antagonist itself was found to impair working memory function, they were found to attenuate each other's effects.
This is similar in some ways to findings found in previous work in the ventral hippocampus and the basolateral amygdala using the same antagonists infused into rats trained on the 16-arm
Subjects
Young adult (3 to 6 month old) female Sprague–Dawley rats (Taconic Farms, Germantown, NY, USA) were used (N = 12). Females were used to facilitate comparison with previous studies using of radial-arm maze choice accuracy after locally infused nicotinic antagonists in the ventral hippocampus, amygdala, nucleus accumbens, frontal cortex, thalamus, ventral tegmental area, and substantia nigra which used female rats (Addy et al., 2003, Arthur and Levin, 2002, Bancroft and Levin, 2000, Bettany and
Acknowledgments
We thank Jerry Harrison and Paul Blackwelder for their assistance in animal testing and care. This research was supported by a grant from the National Institute of Mental Health grant MH64494.
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