Levels, Metabolism, and Pharmacological Activity of Anandamide in CB1 Cannabinoid Receptor Knockout Mice

Journal of Neurochemistry - Tập 75 Số 6 - Trang 2434-2444 - 2000
Vincenzo Di Marzo1, C. S. Breivogel, Tao Qing, D.Troy Bridgen, Raj K. Razdan, Anne Zimmer, Andreas Zimmer, Billy R. Martin
1Istituto per la Chimica di Molecole di Interesse Biologico, Consiglio Nazionale delle Ricerche, Arco Felice, Italy.

Tóm tắt

Abstract: Anandamide [arachidonylethanolamide (AEA)] appears to be an endogenous agonist of brain cannabinoid receptors (CB1), yet some of the neurobehavioral effects of this compound in mice are unaffected by a selective CB1 antagonist. We studied the levels, pharmacological actions, and degradation of AEA in transgenic mice lacking the CB1 gene. We quantified AEA and the other endocannabinoid, 2‐arachidonoyl glycerol, in six brain regions and the spinal cord by isotope‐dilution liquid chromatography‐mass spectrometry. The distribution of endocannabinoids and their inactivating enzyme, fatty acid amide hydrolase, were found to overlap with CB1 distribution only in part. In CB1 knockout homozygotes (CB1‐/‐), the hippocampus and, to a lesser extent, the striatum exhibited lower AEA levels as compared with wild‐type (CB1+/+) controls. These data suggest a ligand/receptor relationship between AEA and CB1 in these two brain regions, where tonic activation of the receptor may tightly regulate the biosynthesis of its endogenous ligand. 2‐Arachidonoyl glycerol levels and fatty acid amide hydrolase activity were unchanged in CB1‐/‐ with respect to CB1+/+ mice in all regions. AEA and Δ9‐tetrahydrocannabinol (THC) were tested in CB1‐/‐ mice for their capability of inducing analgesia and catalepsy and decreasing spontaneous activity. The effects of AEA, unlike THC, were not decreased in CB1‐/‐ mice. AEA, but not THC, stimulated GTPγS binding in brain membranes from CB1‐/‐ mice, and this stimulation was insensitive to CB1 and CB2 antagonists. We suggest that non‐CB1, non‐CB2 G protein‐coupled receptors might mediate in mice some of the neuro‐behavioral actions of AEA.

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Journal of Neurochemistry

Tập 75 Số 6

2434-2444

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