Cannabinoids inhibit agonist-stimulated formation of inositol phosphates in rat hippocampal cultures.
The effect of cannabinoids on phosphoinositide metabolism stimulated by activation of muscarinic receptors, alpha 1-adrenoceptors or glutamate receptors was examined in rat hippocampal cultures. Carbachol stimulated phosphoinositide turnover by 5.5-fold over basal level, whereas glutamate and norepinephrine stimulated phosphoinositide turnover by 2-fold. Addition of cannabinoids, such as delta 8-tetrahydrocannabinol, delta 9-tetrahydrocannabinol or the psychoinactive cannabidiol inhibited formation of inositol phosphates evoked by carbachol, glutamate or norepinephrine by 55-90%. The cannabinoids alone only slightly inhibited the basal unstimulated formation of inositol phosphates. The inhibitory effect of the cannabinoids was dose-dependent and was achieved within the range of pharmacologically relevant concentrations. IC50 values for delta 8-tetrahydrocannabinol, delta 9-tetrahydrocannabinol and cannabidiol were 9.6 +/- 1.0, 9.7 +/- 0.3 and 7.9 +/- 0.4 microM, respectively. Pretreatment with pertussis toxin (100 ng/ml, 18 h) did not affect the carbachol-induced stimulation of phosphoinositide turnover or its inhibition by the cannabinoids. This suggests that the inhibition by the cannabinoids of the stimulated formation of inositol phosphates is not mediated through a pertussis toxin-sensitive GTP-binding protein nor through the known effect of the cannabinoids on adenylate cyclase inhibition.
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Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.
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D037361:Adenylate Cyclase Toxin; D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology*; D002217:Carbachol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002478:Cells, Cultured; D018691:Excitatory Amino Acid Antagonists; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D005971:Glutamates / Q000494:pharmacology; D018698:Glutamic Acid; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007295:Inositol Phosphates / Q000096:biosynthesis*; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D037342:Pertussis Toxin; D011247:Pregnancy; D051381:Rats; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D002186:Cannabinoids; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D007295:Inositol Phosphates; D010566:Virulence Factors, Bordetella; D018698:Glutamic Acid; D002217:Carbachol; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D009638:Norepinephrine