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Enhancement of Anandamide Formation in the Limbic Forebrain and Reduction of Endocannabinoid Contents in the Striatum of Δ 9 ‐Tetrahydrocannabinol‐Tolerant Rats
Author(s) -
Di Marzo V.,
Berrendero F.,
Bisogno T.,
González S.,
Cavaliere P.,
Romero J.,
Cebeira M.,
Ramos J. A.,
FernándezRuiz J. J.
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.0741627.x
Subject(s) - cannabinoid , cannabinoid receptor , forebrain , striatum , chemistry , medicine , endocrinology , endocannabinoid system , hippocampus , anandamide , 2 arachidonoylglycerol , limbic system , receptor , biology , agonist , central nervous system , biochemistry , dopamine
Recent studies have shown that the pharmacologicaltolerance observed after prolonged exposure to synthetic or plant‐derivedcannabinoids in adult rats is accompanied by down‐regulation/desensitizationof brain cannabinoid receptors. However, no evidence exists on possiblechanges in the contents of the endogenous ligands of cannabinoid receptors inthe brain of cannabinoid‐tolerant rats. The present study was designed toelucidate this possibility by measuring, by means of isotope dilution gaschromatography/mass spectrometry, the contents of both anandamide(arachidonoylethanolamide; AEA) and its biosynthetic precursor, N ‐arachidonoylphosphatidylethanolamine (NArPE), and2‐arachidonoylglycerol (2‐AG) in several brain regions of adult male ratstreated daily with Δ 9 ‐tetrahydrocannabinol(Δ 9 ‐THC) for a period of 8 days. The areas analyzed includedcerebellum, striatum, limbic forebrain, hippocampus, cerebral cortex, andbrainstem. The same regions were also analyzed for cannabinoid receptorbinding and WIN‐55,212‐2‐stimulatedguanylyl‐5′‐ O ‐(γ‐[ 35 S]thio)‐triphosphate([ 35 S]GTPγS) binding to test the development of the wellknown down‐regulation/desensitization phenomenon. Results were as follows: Asexpected, cannabinoid receptor binding and WIN‐55,212‐2‐stimulated[ 35 S]GTPγS binding decreased in most of the brain areas ofΔ 9 ‐THC‐tolerant rats. The only region exhibiting no changesin both parameters was the limbic forebrain. This same region exhibited amarked (almost fourfold) increase in the content of AEA after 8 days ofΔ 9 ‐THC treatment. By contrast, the striatum exhibited adecrease in AEA contents, whereas no changes were found in the brainstem,hippocampus, cerebellum, or cerebral cortex. The increase in AEA contentsobserved in the limbic forebrain was accompanied by a tendency of NArPE levelsto decrease, whereas in the striatum, no significant change in NArPE contentswas found. The contents of 2‐AG were unchanged in brain regions fromΔ 9 ‐THC‐tolerant rats, except for the striatum where they dropped significantly. In summary, the present results show that prolonged activation of cannabinoid receptors leads to decreased endocannabinoid contents and signaling in the striatum and to increased AEA formation in the limbic forebrain. The pathophysiological implications of these findings are discussed in view of the proposed roles of endocannabinoids in the control of motor behavior and emotional states.