Enhancement of Anandamide Formation in the Limbic Forebrain and Reduction of Endocannabinoid Contents in the Striatum of Δ9‐Tetrahydrocannabinol‐Tolerant Rats

• Published in: Journal of neurochemistry Vol. 74; no. 4; pp. 1627 - 1635
• Main Authors: Di Marzo, V., Berrendero, F., Bisogno, T., González, S., Cavaliere, P., Romero, J., Cebeira, M., Ramos, J. A., Fernández‐Ruiz, J. J.
• Format: Journal Article
• Language: English
• Published: Oxford UK Blackwell Science Ltd 01-04-2000; Blackwell
• Subjects: 2‐Arachidonoylglycerol; Anandamide; Biological and medical sciences; Cannabinoid receptor binding; Drug addictions; Endocannabinoids; Medical sciences; Tolerance; Toxicology; Δ9‐Tetrahydrocannabinol; Vertebrata; Mammalia; Rat; Animal; Rodentia; Central nervous system; Tolerance; Basal ganglion; Corpus striatum; Limbic system; Cannabinoid; Brain (vertebrata)
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2000.0741627.x

: 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 Δ9‐tetrahydrocannabinol
(Δ9‐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‐(γ‐[35S]thio)‐triphosphate
([35S]GTPγS) 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
[35S]GTPγS binding decreased in most of the brain areas of
Δ9‐THC‐tolerant rats. The only region exhibiting no changes
in both parameters was the limbic forebrain. This same region exhibited a
marked (almost fourfold) increase in the content of AEA after 8 days of
Δ9‐THC treatment. By contrast, the striatum exhibited a
decrease in AEA contents, whereas no changes were found in the brainstem,
hippocampus, cerebellum, or cerebral cortex. The increase in AEA contents
observed in the limbic forebrain was accompanied by a tendency of NArPE levels
to decrease, whereas in the striatum, no significant change in NArPE contents
was found. The contents of 2‐AG were unchanged in brain regions from
Δ9‐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.