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Delta-9-tetrahydrocannabinol (Δ 9 -THC) has profound effects on higher cognitive functions, and exposure to Δ 9 -THC has been associated with the appearance or exacerbation of the clinical features of schizophrenia. These actions appear to be mediated via the CB 1  receptor, the principal cannabinoid receptor expressed in the brain. However, the distribution of the CB 1  receptor in neocortical regions of the primate brain that mediate cognitive functions is not known. We therefore investigated the immunocytochemical localization of the CB 1  receptor in the brains of macaque monkeys and humans using antibodies that specifically recognize the N- or C-terminus of the CB 1  receptor. In monkeys, intense CB 1  immunoreactivity was observed primarily in axons and boutons. Across neocortical regions of the monkey brain, CB 1 -immunoreactive (IR) axons exhibited considerable heterogeneity in density and laminar distribution. Neocortical association regions, such as the prefrontal and cingulate cortices, demonstrated a higher density, and exhibited a unique laminar pattern of CB 1 -IR axons, compared with primary sensory and motor cortices. Similar regional and laminar distributions of CB 1 -IR axons were also present in the human neocortex. CB 1 -IR axons had more prominent varicosities in human tissue, but this difference appeared to represent a postmortem effect as similar morphological features increased in unperfused monkey tissue as a function of postmortem interval. In electron microscopy studies of perfused monkey prefrontal cortex, CB 1  immunoreactivity was predominantly found in axon terminals that exclusively formed symmetric synapses. The high density, distinctive laminar distribution, and localization to inhibitory terminals of CB 1  receptors in primate higher-order association regions suggests that the CB 1  receptor may play a critical role in the circuitry that subserves cognitive functions such as those that are disturbed in schizophrenia.

Immunocytochemical Distribution of the Cannabinoid CB 1 Receptor in the Primate Neocortex: A Regional and Laminar Analysis