Abstract-Cannabinoids have been shown to disrupt memory processes in mammals including humans. Although the CB1 neuronal cannabinoid receptor was identified several years ago, neuronal network mechanisms mediating cannabinoid effects are still controversial in animals, and even more obscure in humans. In the present study, the localization of CB1 receptors was investigated at the cellular and subcellular levels in the human hippocampus, using control post mortem and epileptic lobectomy tissue. The latter tissue was also used for [ 3 H]GABA release experiments, testing the predictions of the anatomical data. Detectable expression of CB1 was confined to interneurons, most of which were found to be cholecystokinin-containing basket cells. CB1-positive cell bodies showed immunostaining in their perinuclear cytoplasm, but not in their somadendritic plasmamembrane. CB1-immunoreactive axon terminals densely covered the entire hippocampus, forming symmetrical synapses characteristic of GABAergic boutons. Human temporal lobectomy samples were used in the release experiments, as they were similar to the controls regarding cellular and subcellular distribution of CB1 receptors. We found that the CB1 receptor agonist, WIN 55,212-2, strongly reduced [ 3 H]GABA release, and this effect was fully prevented by the specific CB1 receptor antagonist SR 141716A.This unique expression pattern and the presynaptic modulation of GABA release suggests a conserved role for CB1 receptors in controlling inhibitory networks of the hippocampus that are responsible for the generation and maintenance of fast and slow oscillatory patterns. Therefore, a likely mechanism by which cannabinoids may impair memory and associational processes is an alteration of the fine-tuning of synchronized, rhythmic population events. ᭧ 2000 IBRO. Published by Elsevier Science Ltd. All rights reserved.Key words: CB1 receptor, cholecystokinin, presynaptic, synchronization, memory, release.Most behavioral effects of the active compound of marijuana and hashish are mediated by the CB1 cannabinoid receptor (CB1). 23 Although the impacts of cannabinoid-consumption on human and animal behaviour are well known, 1,3,7,43 the underlying physiological processes and the precise sites of cannabinoid actions in neural networks remain to be identified. The hippocampal formation is one of the brain areas with the highest level of CB1 receptor expression. 18,26,29 In accordance, at the behavioral level, cannabinoids typically interfere with hippocampal functions, i.e. they disrupt memory consolidation and associations both in humans and animals. 3,17 Although several recent experiments attempted to determine the mechanisms of cannabinoid action and the precise cellular and subcellular localization of the CB1 receptor in the rodent and primate hippocampus, the data they provide are inconsistent. 4,20,27,31,34,35,38,44,45 In the rodent hippocampus, a specific class of GABAergic interneurons was shown to express CB1 receptors. 20,27,45 Detailed electron microscopic investigation rev...