Elsevier

Neuroscience

Volume 77, Issue 2, 21 February 1997, Pages 299-318
Neuroscience

Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain

https://doi.org/10.1016/S0306-4522(96)00428-9Get rights and content

Abstract

The anatomical distribution and density of cannabinoid receptors in the human brain was studied in one fetal (33 weeks gestation), two neonatal (aged three to six months) and eight adult (aged 21–81 years) human cases using quantitative receptor autoradiography following in vitro labelling of sections with the synthetic cannabinoid agonist [3H]CP55,940.

Cannabinoid receptors were distributed in a heterogeneous fashion throughout the adult human brain and spinal cord. The allocortex contained very high concentrations of cannabinoid receptor binding sites in the dentate gyrus, Ammons's horn and subiculum of the hippocampal formation; high concentrations of receptors were also present in the entorhinal cortex and amygdaloid complex. Cannabinoid receptor binding sites were also present throughout all regions of the neocortex, where they showed a marked variation in density between the primary, secondary and associational cortical regions: the greatest densities of receptors were present in the associational cortical regions of the frontal, limbic and temporal lobes, with moderate densities in the secondary sensory and motor cortical regions, and with the lowest densities of receptors in the primary sensory and motor cortical regions. Relatively high concentrations of cannabinoid receptors were consistently seen in cortical regions of the left (dominant) hemisphere, known to be associated with verbal language functions. In all of the cortical regions, the pattern and density of receptor labelling followed the neocortical laminar organization, with the greatest density of receptors localized in two discrete bands—a clearly delineated narrow superficial band which coincided with lamina I and a deeper broader, conspicuous band of labelling which corresponded to laminae V and VI. Labelling in the intervening cortical laminae (II–IV) showed lower densities, with a well delineated narrow band of label in the middle of laminae IV in the associational cortical regions. The thalamus showed a distinctive heterogeneous distribution of cannabinoid receptors, with the highest concentration of receptors localized in the mediodorsal nucleus, anterior nuclear complex, and in the midline and intralaminar complex of nuclei, i.e. in thalamic nuclei which have connectional affiliations with the associational cortical areas. The basal ganglia showed a distinctive heterogeneous pattern of receptor binding, with the very highest concentrations in the globus pallidus internus, moderate concentrations in the globus pallidus externus and ventral pallidum, and moderately low levels of binding throughout the striatal complex. In the midbrain, very high levels of cannabinoid receptor binding were present in the substantia nigra pars reticulata, with low levels of labelling in all other midbrain areas. The highest densities of cannabinoid receptor binding in the hindbrain were localized in the molecular layer of the cerebellar cortex and the dorsal motor nucleus of the vagus, with moderate densities of receptors in the nucleus of the solitary tract. The spinal cord showed very low levels of receptor binding. Studies on the distribution of cannabinoid receptors in the fetal and neonatal human brain showed similar patterns of receptor distribution to that observed in the adult human brain, except that the density of receptor binding was generally markedly higher, especially in the basal ganglia, substantia nigra and cerebellar cortex. The pattern of cannabinoid receptor labelling in the striatum showed a striking patchy pattern of organization which was especially conspicuous in the fetal brain.

These results show that cannabinoid receptor binding sites in the human brain are localized mainly in: forebrain areas associated with higher cognitive functions; forebrain, midbrain and hindbrain areas associated with the control of movement; and in hindbrain areas associated with the control of motor and sensory functions of the autonomic nervous system. The possible role of these receptors is discussed with respect to the known behavioural and psychomotor effects of cannabinoids in humans.

Section snippets

Tissue collection

The human brain tissue used in these studies was obtained from the New Zealand Neurological Foundation Human Brain Bank in the Department of Anatomy, University of Auckland. This study was performed under ethical approval by the University of Auckland Human Subjects Ethics Committee.

All subjects had previously been in good health, with no known history of neurological disease or drug treatment, and all had died suddenly without the opportunity of receiving any form of medical treatment. The

Results

The principal aim of this study was to precisely define the anatomical localization and density of cannabinoid receptors in all major regions of the adult human brain and spinal cord. In addition, studies were also undertaken on the distribution and density of cannabinoid receptors in the fetal and neonatal brain in order to investigate the ontogenic development of cannabinoid receptors in the regions of the human brain which contain some of the highest concentrations of receptors in adults. In

Discussion

This study represents the first detailed investigation on the overall distribution of cannabinoid receptors throughout the human CNS. The study has clearly demonstrated a heterogeneous distribution of cannabinoid receptors throughout the adult human brain and spinal cord. The results show that cannabinoid receptor binding sites in the human brain are localized mainly in: forebrain areas associated with higher cognitive functions; forebrain, midbrain and hindbrain areas associated with the

Conclusion

The results of our detailed quantitative autoradiographic studies show that cannabinoid receptors are heterogeneously distributed in a similar pattern in the fetal, neonatal and adult human brains. The high concentrations of receptors in motor and cognitive regions of the brain correlate well with the known behavioural, psychomotor and psychological effects of cannabis. Further studies determining the distribution and action of putative endogenous ligands such as anandamide[11]for this receptor

Acknowledgements

This study was supported by grants from the Health Research Council of New Zealand, the New Zealand Neurological Foundation and the New Zealand Lottery Board. M.G. was supported by the J. B. Miller Postgraduate Scholarship from the New Zealand Neurological Foundation Inc.

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