Dec 11, 2002
By Will Boggs, MD
A new class of inhibitors of fatty acid amide hydrolase (FAAH) shows benzodiazepine-like effects in rat models, according to a report in the December 2nd advance online publication of Nature Medicine.
FAAH catalyzes the hydrolysis of anandamide, a naturally occurring substance that meets all key criteria of an endogenous cannabinoid, the authors explain, and mutant mice lacking FAAH show signs of enhanced anandamide activity at cannabinoid receptors. The therapeutic potential of FAAH inhibitors, however, has not been explored.
Dr. Danielle Piomelli from University of California, Irvine, California and colleagues tested a class of potent, selective, and systemically active inhibitors of FAAH in rats.
Two of these compounds blocked FAAH-catalyzed hydrolysis of anandamide in primary cultures of intact cortical rat neurons without inhibiting its carrier-mediated uptake, the authors report, resulting in an accumulation of anandamide in the neurons.
When administered intraperitoneally to rats, the compounds produced a profound, rapid (< 15 minutes), and prolonged (> 6 hours) dose-dependent inhibition of brain FAAH activity and significant elevations in brain levels of anandamide.
In two validated models of anxiety, the FAAH inhibitors evoked anxiolytic-like responses in rats at doses corresponding to those required to inhibit FAAH activity in vivo, the researchers note. Apart from a modest decrease in ambulation at higher doses, these compounds elicited no other changes in motor behavior in treated rats.
"The behavioral profile of these agents--characterized by anxiolysis and mild analgesia--reveals a key role for anandamide in the regulation of emotional states and indicates a new mechanistic approach to anti-anxiety therapy," the authors conclude.
"Direct-acting cannabinoids (like THC and Marinol) are very different pharmacologically from drugs that block endocannabinoid inactivation (like our FAAH inhibitors)," Dr. Piomelli told Reuters Health. "That's because blocking inactivation is a way to take advantage of endocannabinoids' natural functions, and does not cause generalized activation of cannabinoid receptors (responsible for the high)."
"There is life beyond Valium and Prozac," Dr. Piomelli concluded. "The territory of neuropsychiatric pharmacology is still largely uncharted, and the effectiveness of our agents offers a taste of what remains to be discovered."
Nat Med 2002. http://www.nature.com/naturemedicine
© 2002 Reuters Ltd