Changes in rat brain energetic metabolism after exposure to anandamide or Delta(9)-tetrahydrocannabinol

The objective of this study was to investigate whether single and repeated administration of the cannabinoids anandamide or Delta(9)-tetrahydrocannabinol affected brain energetic metabolism. Single administration of either anandamide (20 mg/kg) or Delta(9)-tetrahydrocannabinol (10 mg/kg) in rats induced a behaviour typical with cannabinoids. An increase in both brain mitochondria oxidative phosphorylation and cerebral lipoperoxidation was shown ex vivo. The cannabinoid CB(1) receptor-specific antagonist, N-piperidino-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR141716A; 3 mg/kg), reversed the anandamide-induced metabolic effects. Prolonged exposure to anandamide (20 mg/kg, 16 days) induced behavioural tolerance and the disappearance of the increased mitochondria oxygen uptake and lipoperoxidation. Repeated Delta(9)-tetrahydrocannabinol injection (10 mg/kg, twice daily, 4.5 days) reduced brain metabolism and uncoupled respiration from oxidative phosphorylation. The present findings showed that both anandamide and Delta(9)-tetrahydrocannabinol enhanced the energetic brain metabolism, probably via the cannabinoid CB(1) receptor; the anandamide-tolerant brain of rats showed tolerance to the drug for metabolic effects, while the brain of Delta(9)-tetrahydrocannabinol-tolerant rats showed metabolic signs of neuronal damage, i.e. low energy production.