Enhancement of Anandamide Formation in the Limbic Forebrain and Reductionof Endocannabinoid Contents in the Striatum ofΔ[sup 9]-Tetrahydrocannabinol-Tolerant Rats.

Abstract: Recent studies have shown that the pharmacological tolerance observed after prolonged exposure to synthetic or plant-derived cannabinoids in adult rats is accompanied by down-regulation/desensitization of brain cannabinoid receptors. However, no evidence exists on possible changes in the contents of the endogenous ligands of cannabinoid receptors in the brain of cannabinoid-tolerant rats. The present study was designed to elucidate this possibility by measuring, by means of isotope dilution gas chromatography/mass spectrometry, the contents of both anandamide (arachidonoylethanolamide; AEA) and its biosynthetic precursor, N-arachidonoylphosphatidylethanolamine (NArPE), and 2-arachidonoylglycerol (2-AG) in several brain regions of adult male rats treated daily with change[sup 9]-tetrahydrocannabinol (change[sup 9]-THC) for a period of 8 days. The areas analyzed included cerebellum, striatum, limbic forebrain, hippocampus, cerebral cortex, and brainstem. The same regions were also analyzed for cannabinoid receptor binding and WIN-55,212-2-stimulated guanylyl-5'-O-(gamma-[[sup 35]S]thio)-triphosphate ([[sup 35]S]GTP gamma S) binding to test the development of the well known down-regulation/desensitization phenomenon. Results were as follows: As expected, cannabinoid receptor binding and WIN-55,212-2-stimulated [[sup 35]S]GTP gamma S binding decreased in most of the brain areas of change[sup 9]-THC-tolerant rats. The only region... [ABSTRACT FROM AUTHOR]