Elsevier

Neuroscience

Volume 94, Issue 3, October 1999, Pages 685-696
Neuroscience

Autoradiographic comparison of [3H](−)nicotine, [3H]cytisine and [3H]epibatidine binding in relation to vesicular acetylcholine transport sites in the temporal cortex in Alzheimer's disease

https://doi.org/10.1016/S0306-4522(99)00295-XGet rights and content

Abstract

The laminar binding distribution of three nicotinic receptor agonists, [3H](−)nicotine, [3H]cytisine, and [3H]epibatidine, and their relation to the [3H]vesamicol binding, which is known to represent the vesicular acetylcholine transport sites, was performed employing in vitro autoradiography on the medial temporal cortex (Brodmann area 21). Autopsied brain tissue from nine Alzheimer patients and seven age-matched controls were used. The binding pattern of the three nicotinic ligands in the normal cortex was in general similar, showing binding maxima in the cortical layers I, III and V. The binding of [3H](−)nicotine, [3H]cytisine, and [3H]epibatidine was lower in the older controls and more uniform throughout the layers as compared with younger controls. There was a significant age-related decrease in the binding of the three nicotinic ligands within the controls (age range: 58 to 89 years; P[3H](−)nicotine=0.002, P[3H]epibatidine=0.010, P[3H]cytisine=0.037). In the older controls, the [3H]epibatidine binding was much decreased as compared with that of [3H](−)nicotine and [3H]cytisine. This may indicate a higher selectivity of [3H]epibatidine for a nicotinic receptor subtype that is particularly affected by aging. The laminar binding pattern of [3H]vesamicol showed one maximum in the outer cortical layers II/III. The [3H]vesamicol binding did not change with aging. The binding of all ligands was significantly decreased in all layers of the temporal cortex in Alzheimer's disease, but the [3H]vesamicol binding decreased only half as much as the nicotinic receptors. Also, choline acetyltransferase activity was percentually more reduced than [3H]vesamicol binding in Alzheimer's disease. The cortical laminar binding pattern of all 3H-ligands was largely absent in the Alzheimer's disease cases.

The less severe loss of vesicular acetylcholine transport sites as compared with the loss of the nicotinic receptors and choline acetyltransferase activity may suggest that vesamicol binding sites might be more preserved in presynaptic terminals still existing and thereby expressing compensatory capacity to maintain cholinergic activity.

Section snippets

Drugs

(−)-[N-methyl-3H]nicotine (62.7 and 84.0 Ci/mmol), [3H]cytisine (30.1 and 26.0 Ci/mmol), l-[piperidinyl-3,4-3H]AH5183 ([3H]vesamicol, 50.5 and 35.0 Ci/mmol), and [3H]epibatidine (52.0 and 56.0 Ci/mmol) were purchased from New England Nuclear (NEN Boston, MA, USA). (−)Nicotine hydrogen tartrate salt was obtained from Sigma Chemical Co., St Louis, MO, USA l-(−)vesamicol hydrochloride was purchased from Research Biochemicals International (Natick, MA, USA).

Brain tissues and preparation

Autopsied brain tissue specimens from seven

Results

The results of ApoE genotyping showed that five controls were ApoE ϵ3/3 carrier, one was ApoE ϵ2/3 carrier and one was ApoE ϵ3/4 carrier. Among the AD cases, three patients were ApoE ϵ3/3 carrier, four patients were ϵ3/4 carrier, one was ϵ2/4 carrier and one ϵ4/4 carrier (Table 1). The analysis of ChAT activity indicated a significant decrease in the medial temporal cortex of the AD group (60%; P<0.01; Table 2a).

The autoradiographical distribution of [3H](−)nicotine, [3H]epibatidine, [3

Discussion

The binding of three nicotinic agonists, i.e. [3H](−)nicotine, [3H]epibatidine, and [3H]cytisine, to nAChRs, and that of [3H]vesamicol to VAChT sites, was evaluated in the medial temporal cortex, obtained at autopsy from nine patients with AD and seven controls, by in vitro autoradiography.

The laminar binding distribution of the nAChR ligands in the medial temporal cortex of the controls was similar to that recently observed for post mortem control cases in the superior temporal sulcus,79 with

Conclusions

The laminar binding distribution of the nAChR ligands [3H](−)nicotine, [3H]epibatidine and [3H]cytisine in medial temporal cortex of controls was in general similar, with maxima in layers I, III and V, in the result using quantitative in vitro autoradiography. The binding of all nAChR ligands decreased at older age, especially that of [3H]epibatidine, which may indicate binding to a nAChR subtype that is particularly affected by aging. [3H]Vesamicol showed one binding maximum in the layers

Acknowledgments

The authors sincerely thank Dr Irina Alafuzoff and Dr Ritva Ravid for, respectively, providing the human brain samples from the Huddinge Brain Bank and from the Netherlands Brain Bank in Amsterdam. Kajsa Blomgren is acknowledged for ApoE genotyping, Dr Alf Johansson and Dr Göran Sperber for the help in analysing the autoradiograms, and Drs Larry Frye and Daniel Laryea for linguistical help. This work was financially supported by the Loo and Hans Osterman's foundation, KI foundations and the

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