Elsevier

Neuroscience

Volume 109, Issue 4, 22 February 2002, Pages 757-765
Neuroscience

Hippocampal α7 and α4β2 nicotinic receptors and working memory

https://doi.org/10.1016/S0306-4522(01)00538-3Get rights and content

Abstract

Nicotine and other nicotinic receptor agonists have been found in a variety of studies to improve memory, while nicotinic receptor blockade can impair memory. The critical neural mechanisms for nicotinic involvement with memory are still under investigation. Initial evidence supports the involvement of the ventral hippocampus. Lesions in this area block nicotine-induced memory improvement and mecamylamine-induced impairment. Local ventral hippocampal application of the nicotinic channel blocker mecamylamine impairs memory in the 8-arm radial maze. Both α4β2 and α7 nicotinic receptors seem to be involved. Ventral hippocampal infusions of high doses of the α4β2 nicotinic antagonist dihydro-β-erythrodine (DHβE) and the α7 nicotinic antagonist methyllycaconitine (MLA) impair memory performance on the 8-arm radial maze. However, high doses of these drugs may limit specificity and they cause preconvulsant effects, which in themselves may affect memory. The current study used the more challenging 16-arm radial maze to determine the effects of lower doses of these drugs on memory and to differentiate effects on working and reference memory.

Adult female Sprague–Dawley rats were trained on a working and reference memory task in the 16-arm radial maze and then were implanted with bilateral chronic guide cannulae directed to the ventral hippocampus. After recovery from surgery, the rats received acute intrahippocampal infusions of dose combinations of DHβE and MLA. In the first study, DHβE (0 and 6.75 μg/side) and MLA (0, 6.75, 13.5 and 27 μg/side) were administered in a counter-balanced order. In the second study, lower doses of DHβE (0, 1.6375, 3.275 and 6.75 μg/side) were administered alone or with MLA (0 and 6.75 μg/side) in a counter-balanced order. In the first study, DHβE caused a significant increase in both working and reference memory errors. MLA at a dose of 27 μg/side caused a significant increase in working memory errors, but this dose had no significant effect on reference memory errors. Interestingly, no additive effects were seen with combined administration of DHβE and MLA in this study, and at the doses used, no effects were seen on response latency. In the second study, lower doses of DHβE did not cause a significant deficit in working memory performance. Co-administration of MLA with these subthreshold doses did precipitate a memory impairment. The current results confirm the specificity of the memory deficits caused by these drugs.

These results support the involvement of α4β2 and α7 nicotinic receptors in the ventral hippocampus as being critical for memory function.

Section snippets

Subjects

Young adult female Sprague–Dawley rats (Taconic Farms, Germantown, NY, USA) weighing between 200 and 325 g were used in this study (study 1, n=11; study 2, n=8). The rats were housed in groups of three to four during initial training and singly after cannulation. The rat colony room had a reverse 12:12 light:dark cycle. All testing was conducted in the dark phase. The rats had ad libitum access to drinking water but were kept on a restricted feeding schedule to maintain body weights of

Study 1

Both DHβE and MLA caused a significant increase in working memory errors (Fig. 2). With MLA, a significant increase in working memory errors was seen with the high dose of 27 μg/side (F(1,30)=9.13, P<0.01). The low MLA dose (6.75 μg/side) did not cause a significant working memory impairment and the intermediate MLA (13.5 μg/side) did not cause a significant increase in working memory errors (F(1,30)=3.35, P<0.08). There was a significant linear dose–effect of MLA (P<0.05). The DHβE dose used

Discussion

These results show that significant working memory deficits can be produced by either α7 or α4β2 nicotinic receptor antagonist treatment in the ventral hippocampus. This replicates our earlier finding in the 8-arm radial maze (Felix and Levin, 1997). In that study, however, significant deficits caused by MLA and DHβE were not seen unless high doses were given. In the current study with the more challenging 16-arm maze, significant impairments were seen at lower doses of both MLA and DHβE. This

Acknowledgements

This research was supported by National Institute on Drug Abuse Grant number DA 11943.

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