ANANDAMIDE, AN ENDOGENOUS CANNABINOID, HAS A VERY-LOW PHYSICAL-DEPENDENCE POTENTIAL

Using hlorophenyl)-4-methyl-1H-pyrazole-3-carboxaminoide . HCl (SR 141 716A), a cannabinoid antagonist, several investigators (de-Fonseca et al., 1997; Aceto et al., 1995, 1996; Tsou et al., 1995) demonstrated p hysical dependence on THC [Delta(9)-tetrahydrocannabinol]. This demons tration prompted us to determine whether anandamide, an endogenous can nabinoid agonist, would also produce physical dependence. A low-dose r egimen (10, 20, 40 and 40) or a high-dose regimen (25, 50, 100 and 100 ) expressed as mg/kg/24 hr was infused i.p. on a continuous basis, fro m days 1 through 4, respectively. During the infusion, especially at t he high-dose regimen, the rats became immobile and developed eyelid pt osis. Abrupt discontinuation of anandamide did not elicit rebound beha vioral activity. Neither arachidonic acid, a precursor and metabolite of anandamide (50, 100, 200 and 200 mg/kg/24 hr on days 1 through 4, r espectively), nor 2-Me-F-AN [2-methylarachidonyl-(2'-fluoroethyl)-amid e], a metabolically stable analog of anandamide (5, 10, 20 and 20 mg/k g/24 hr for 4 days, respectively), had remarkable effects. Notably, gr oups pretreated with anandamide or 2-Rne-F-AN and challenged with SR 1 41716A did not show significantly elevated behavioral scores when comp ared with SR 141716A controls. On the other hand, nearly all groups re ceiving SR 141716A showed significant activation of these behaviors co mpared with vehicle controls, which suggests that this cannabinoid ant agonist itself was activating behavior. We concluded that anandamide h as little if any capacity for physical dependence. The finding that SR 141716A activated behavior supports the hypothesis that the cannabimi metic system exerts a depressant effect in the CNS.