Muscarinic cholinergic receptor subtypes in the human brain. II. Quantitative autoradiographic studies

doi:10.1016/0006-8993(86)90449-X

Brain Research

Volume 362, Issue 2, 8 January 1986, Pages 239-253

https://doi.org/10.1016/0006-8993(86)90449-X Get rights and content

Abstract

The distribution and characteristics of M₁ and M₂ muscarinic cholinergic receptors as defined by their affinity for the antagonist pizenzepine were studied in the human brain using in vitro quantitative autoradiographic techniques. The binding of N-[³H]methylscopolamine ([³H]NMS) to cortical and striatal microtome tissue sections was saturable and presented aK_d of 0.25 nM. The sensitivity of [³H]NMS-binding sites to 100 μM carbachol and 300 nM pirenzepine was analyzed in 30 brain areas. In selected brain regions, complete competition curves using carbachol, pirenzepine and atropine were analyzed. Finally, the regional distribution of M₁ sites was studied using [³H]pirenzepine ([³H]PZ) as ligand. The binding of [³H]NMS to striatum, hippocampus and amygdala was very sensitive to pirenzepine but not to carbachol. The opposite situation was found in thalamus, hypothalamus, substantia innominata, pons and medulla, while intermediate sensitivity to both displacers was observed in different layers of the cortex and in the claustrum. Competition experiments showed that [³H]NMS binding was displaced with the same affinity by atropine in all the regions studied, while the IC₅₀ of carbachol varied from 5 μM in the nucleus facialis to 830 μM in the caudate. Pirenzepine IC₅₀ values for [³H]NMS sites varied from 66 nM to 1 μM. Results using [³H]PZ further confirm this pattern of distribution, with high densities of binding observed in the striatum, hippocampus and amygdala and very low in thalamic and brainstem areas. These results show that the putative M₁ and M₂ muscarinic receptor subtypes present a differential anatomical distribution in the human brain. This differential distribution is comparable to that observed in the rat brain. Some basal ganglia and limbic areas are enriched in M₁ sites, while thalamus, brainstem, medulla and also the hypothalamus and substantia innominata contain predominantly receptors of the M₂ type. The cerebral cortex is an example of a region containing a mixed population of M₁ and M₂ sites. These results provide an anatomical description of the distribution of subtypes of the muscarinic receptor in the human brain, which can be related to the known pharmacological effects of muscarinic agents in brain function.

Reference (44)

BaisdenR.H. et al.
Cholinergic and non-cholinergic septo-hippocampal projections: a double-label horseradish peroxidase-acetylcholinesterase study in the rabbit
Brain Research
(1984)
BiglV. et al.
Cholinergic projections from the basal forebrain to frontal, parietal, temporal, occipital and cingulate cortices: a combined fluorescent tracer and acetylcholinesterase analysis
Brain Res. Bull.
(1982)
CaulfieldM.P. et al.
Cortical muscarinic receptor subtypes and Alzheimer's disease
Lancet
(1982)
Corte´sR. et al.
Quantitative light microscopic autoradiographic localization of cholinergic muscarinic receptors in human brain: brainstem
Neuroscience
(1984)
Corte´sR. et al.
Muscarinic cholinergic receptor subtypes in the rat brain. I. Quantitative autoradiographic studies
Brain Research
(1986)
FibigerH.C.
The organization and some projections of cholinergic neurons of the mammalian forebrain
Brain Res. Rev.
(1982)
GoocheeC. et al.
Application of computer-assisted image processing to autoradiographic methods for studying brain functions
TINS
(1983)
GoyalR.K. et al.
Neurohormonal, hormonal and drug receptors for the lower esophageal splincter
Prog. Gastroenterol.
(1978)
LowryO.H. et al.
Protein measurement with the folin phenol reagent
J. Biol. Chem.
(1951)
MesulamM.M. et al.
Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1–Ch6)
Neuroscience
(1983)

Cited by (129)

Cortical layers: Cyto-, myelo-, receptor- and synaptic architecture in human cortical areas
2019, NeuroImage
Citation Excerpt :
However, the typical six-layered pattern of cytoarchitecture cannot be found in most receptor types; consequently, the borders between receptor-dense and receptor-sparse layers do not consistently coincide with the borders of layers detectable in cyto- or myeloarchitectonic studies. Rather, receptor densities seem to show a type- and region-specific layering pattern (Amunts et al., 2010; Caspers et al., 2013, 2015; Cortés et al., 1986, 1987; Eickhoff et al., 2007, 2008; Hoyer et al., 1986a,b; Jansen et al., 1989; Morosan et al., 2005; Palomero-Gallagher et al., 2008, 2009, 2013, 2015, Pazos et al., 1987a,b; Scheperjans et al., 2005a,b; Vogt et al., 2013; Zilles et al., 2002a, 2004, 2015a; Zilles and Amunts, 2009; Zilles and Palomero-Gallagher, 2001, 2017). Since most receptors are found on dendrites and not on the cell bodies of pyramidal cells and interneurons (Kooijmans et al., 2014), and the dendrites of pyramidal cells cross many cytoarchitectonically defined layers, the layering pattern of receptors is not bound to a single layer of cell bodies (cytoarchitecture) or myelinated nerve fibers (myeloarchitecture).
Cortical layers have classically been identified by their distinctive and prevailing cell types and sizes, as well as the packing densities of cell bodies or myelinated fibers. The densities of multiple receptors for classical neurotransmitters also vary across the depth of the cortical ribbon, and thus determine the neurochemical properties of cyto- and myeloarchitectonic layers. However, a systematic comparison of the correlations between these histologically definable layers and the laminar distribution of transmitter receptors is currently lacking. We here analyze the densities of 17 different receptors of various transmitter systems in the layers of eight cytoarchitectonically identified, functionally (motor, sensory, multimodal) and hierarchically (primary and secondary sensory, association) distinct areas of the human cerebral cortex. Maxima of receptor densities are found in different layers when comparing different cortical regions, i.e. laminar receptor densities demonstrate differences in receptorarchitecture between isocortical areas, notably between motor and primary sensory cortices, specifically the primary visual and somatosensory cortices, as well as between allocortical and isocortical areas. Moreover, considerable differences are found between cytoarchitectonical and receptor architectonical laminar patterns. Whereas the borders of cyto- and myeloarchitectonic layers are well comparable, the laminar profiles of receptor densities rarely coincide with the histologically defined borders of layers. Instead, highest densities of most receptors are found where the synaptic density is maximal, i.e. in the supragranular layers, particularly in layers II–III. The entorhinal cortex as an example of the allocortex shows a peculiar laminar organization, which largely deviates from that of all the other cortical areas analyzed here.
Contribution of cholinergic interneurons to striatal pathophysiology in Parkinson's disease
2019, Neurochemistry International
Citation Excerpt :
As mentioned above, as striatal DA levels fall in PD, the cholinergic tone rises (Barbeau, 1962; Duvoisin, 1967; Hornykiewicz and Kish, 1987). This elevation is clinically important, as antagonizing mAChRs – which appears to be the highest concentration of cholinergic receptors found in the striatum (Cortes and Palacios, 1986; Cortes et al., 1986) – might effectively reverses many motor (and non-motor) symptoms of PD (Bonsi et al., 2011; Ferreira et al., 2013; Langmead et al., 2008; Pisani et al., 2007; Rascol et al., 2011; Rezak, 2007; Y. Smith et al., 2012). Charcot was the first, in 1879, to note the beneficial effects of belladonna alkaloids (agents with potent anticholinergic properties) containing atropine on the parkinsonian motor signs.
Parkinson's disease (PD) is a neurodegenerative disorder caused by the loss of nigral dopaminergic neurons innervating the striatum, the main input structure of the basal ganglia. This creates an imbalance between dopaminergic inputs and cholinergic interneurons (ChIs) within the striatum. The efficacy of anticholinergic drugs, one of the earliest therapy for PD before the discovery of L-3,4-dihydroxyphenylalanine (L-DOPA) suggests an increased cholinergic tone in this disease. The dopamine (DA)-acetylcholine (ACh) balance hypothesis is now revisited with the use of novel cutting-edge techniques (optogenetics, pharmacogenetics, new electrophysiological recordings). This review will provide the background of the specific contribution of ChIs to striatal microcircuit organization in physiological and pathological conditions. The second goal of this review is to delve into the respective contributions of nicotinic and muscarinic receptor cholinergic subunits to the control of striatal afferent and efferent neuronal systems. Special attention will be given to the role played by muscarinic acetylcholine receptors (mAChRs) in the regulation of striatal network which may have important implications in the development of novel therapeutic strategies for motor and cognitive impairment in PD.
Cyto- and receptor architectonic mapping of the human brain
2018, Handbook of Clinical Neurology
Citation Excerpt :
GABAA: matrix < striosomes (Faull and Villiger, 1988; Waldvogel et al., 1999). The caudate, putamen, and accumbens contain by far the highest M1, M2, M3, and M4 receptor densities detected in the human forebrain, whereas the globus pallidus presents one of the lowest densities (Fig. 24.5G; Lin et al., 1986; Cortés et al., 1986, 1987; Araujo et al., 1988; Lowenstein et al., 1990; Rodriguez-Puertas et al., 1997; Piggott et al., 2002, 2003; Zilles et al., 2002a, b; Matsumoto et al., 2005; Palomero-Gallagher et al., 2006, 2009a; Amunts et al., 2010). Nicotinic α4β2 receptor concentrations in the striatum are comparable to those of the hippocampus and cingulate cortex (Lange et al., 1993; Pimlott et al., 2004), higher than in the primary motor and insular cortices (Zilles et al., 2002b; Pimlott et al., 2004; Palomero-Gallagher et al., 2006, 2009a), and lower than in the entorhinal cortex (Pimlott et al., 2004).
Mapping of the human brain is more than the generation of an atlas-based parcellation of brain regions using histologic or histochemical criteria. It is the attempt to provide a topographically informed model of the structural and functional organization of the brain. To achieve this goal a multimodal atlas of the detailed microscopic and neurochemical structure of the brain must be registered to a stereotaxic reference space or brain, which also serves as reference for topographic assignment of functional data, e.g., functional magnet resonance imaging, electroencephalography, or magnetoencephalography, as well as metabolic imaging, e.g., positron emission tomography. Although classic maps remain pioneering steps, they do not match recent concepts of the functional organization in many regions, and suffer from methodic drawbacks.
This chapter provides a summary of the recent status of human brain mapping, which is based on multimodal approaches integrating results of quantitative cyto- and receptor architectonic studies with focus on the cerebral cortex in a widely used reference brain. Descriptions of the methods for observer-independent and statistically testable cytoarchitectonic parcellations, quantitative multireceptor mapping, and registration to the reference brain, including the concept of probability maps and a toolbox for using the maps in functional neuroimaging studies, are provided.
Transmitter Receptor Distribution in the Human Brain
2015, Brain Mapping: An Encyclopedic Reference
Transmitter receptors are key molecules of signal processing in the brain. They occur at different densities between different cortical regions and layers, as well as subcortical nuclei. The differences enable mapping of these structures based on the density of a single or multiple receptors in each structure. We summarize data of selected receptor types of classical transmitter systems in the human cerebral cortex, cerebellum, hippocampus, amygdala, basal ganglia, and thalamus. A short review of developmental and age-related changes is also provided. Finally, we show the relevance of multireceptor analyses (receptor fingerprints) for the characterization of functional systems at the molecular level.
Human Brain Imaging of Acetylcholine Receptors
2014, Imaging of the Human Brain in Health and Disease
The neurotransmitter acetylcholine (ACh) is widely distributed within the central nervous system (CNS) and is involved in a number of important processes, including roles in sensory and motor processing, sleep, nociception, mood, stress response, attention, arousal, memory, motivation, and reward. The actions of ACh are mediated through the muscarinic ACh receptor (mAChR) and nicotinic ACh receptor (nAChR). Postmortem studies indicated marked changes in the mAChR and nAChR in the brain associated with several neurological disorders. Selective radioligands have been developed for mapping these receptors using single photon emission computed tomography (SPECT) and positron emission tomography (PET). A number of clinical studies have identified the changes in ACh receptors (AChRs) in aging, neurodegenerative diseases, and many other types of neurological disorder. In addition, a number of clinical studies elucidated the mechanisms of action of pharmaceuticals and tobacco addiction. This chapter presents a summary of the research regarding the clinical brain imaging of AChRs by SPECT and PET, and discusses the potential usefulness of these techniques in the pathofunctional analysis of CNS diseases.
Periaqueductal Gray
2012, The Human Nervous System, Third Edition

View all citing articles on Scopus

View full text

Muscarinic cholinergic receptor subtypes in the human brain. II. Quantitative autoradiographic studies

Abstract

Brain Research

Brain Res. Bull.

Lancet

Neuroscience

Brain Research

Brain Res. Rev.

TINS

Prog. Gastroenterol.

J. Biol. Chem.

Neuroscience

Brain Research

Brain Research

Life Sci.

Neurosci. Lett.

Brain Research

Brain Research

J. Neurosci. Meth.

Brain Research

Life Sci.

Life Sci.

Life Sci.

Eur. J. Pharmacol.