Autoradiographic comparison of cholinergic and other transmitter receptors in the normal human hippocampus

Abstract

The vulnerability of the human hippocampal complex to disease, trauma, and aging indicates the necessity to target this area therapeutically. The distribution and density of transmitter receptors provide a rational basis for this approach, and in this study the topography of 11 different pharmacological sites is compared with the cholinergic innervation, which is partcularly vulnerable in dementia. The regional distribution of cholinergic innervation to the normal adult human hippocampus and adjacent cortex, marked by acetylcholinesterase (AChE) fiber and terminal reactivity, is notable for its concentration in CA2/3 of Ammon's horn and the dentate fascia. Neither nicotinic (high‐affinity nicotine binding) nor muscarinic (“M₁” or “M₂”) cholinergic receptor binding paralleled this distribution. In Ammon's horn, 5‐HT₂ and kainate receptor binding more closely resembled the pattern of AChE, being concentrated in CA2–4 compared with CA1. By contrast, muscarinic M₁ and M₂, 5‐HT_1A, benzodiazepine (including zolpidem‐insensitive binding), NMDA (MK801), and AMPA/QUIS receptors were higher in CA1 and/or subiculum. Kainate binding, like AChE, was high in CA4. 5‐HT₂ and nicotinic binding partially mimicked the pattern of AChE around the granule layer. In the subicular complex and parahippocampal gyrus, where cholinergic activity is relatively lower, muscarinic, 5‐HT_1A, and benzodiazepine binding were relatively high and the nicotinic receptor was remarkable for its highest density compared to other areas examined. In stratum lacunosum‐moleculare of CA1, which was relatively low in AChE activity, there was a dense band of nicotinic, M₂, and benzodiazepine receptor binding. These observations, while reflecting the anatomical complexity of chemical signaling in the hippocampal region, indicate a unique distribution for the nicotinic receptor and suggest that the cholinergic input may specifically interact with 5‐HT and excitatory amino acid systems via 5‐HT₂ and kainate receptor subtypes in governing signaling to the dentate and CA3 regions.