It is well established that the inositol lipids mediate signal transduction in several cellular populations. Many neurotransmitters, hormones and growth factors act at plasma membrane receptors to induce the hydrolysis of phosphatidylinositols and hence the generation of various inositol phosphates (IP). The best known member of this family is 1,4,5-IP3, which is associated with the release of Ca2+ from intracellular pools. It has also been proposed that two others inositides, 1,3,4,5-IP4 and IP6, may be involved in Ca2+ homeostasis. In order to study the possible relevance of these various inositides in neuronal tissues, we have localized the respective receptors in rat and human brain under both acidic and basic pH conditions. In the hippocampal formation, [3H]1,3,4,5-IP4 binding sites are concentrated in the hilus and the molecular layer while a clearly different pattern of distribution is seen for [3H]1,4,5-IP3, its highest concentration of labelling being concentrated in the oriens and radiatum laminae. This contrasting profile of distribution is also observed in other brain areas such as the caudate-putamen, the septo-hippocampal area, and the molecular and granular layers of the cerebellum. Moreover, while highest amounts of specific [3H]1,4,5-IP3 binding are obtained at pH 8.5, the opposite is found for [3H]1,3,4,5-IP4, with high binding levels seen under acidic conditions. [3H]IP6 binding sites are broadly distributed with specific labelling concentrated in areas enriched with neuronal perikarya such as the granular cell layer of the dentate gyrus, the pyramidal cell layers of the hippocampus and the granular cell layer of the cerebellum.(ABSTRACT TRUNCATED AT 250 WORDS)