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

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 and limbic 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, some of the highest levels of cannabinoid receptor binding sites in the human brain were present in the substantia nigra pars reticulata, with very 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 and substantia nigra. 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. (AB