Spontaneous and precipitated withdrawal with a synthetic cannabinoid, WIN 55212-2

Physical dependence on the synthetic cannabinoid-receptor agonist R(+). . [ 2,3-dihydro-5-methyl-3-[(morpholinyl) methyl]pyrrolo[1,2,3-de]-1,4-benzoxaz inyl]-(1-naphthalenyl) methanone mesylate (WIN 55212-2) was demonstrated in rats by the use of a chronic continuous infusion. Spontaneous withdrawal, of moderate intensity, was shown for the first time with this class of drug s of abuse. Behavioral withdrawal signs were also elicited after challenge with (N-(piperidin-1 -y1)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4meth yl-1 H-pyrazole-3-carboxamide HCl (SR141716A), a specific CB1 cannabinoid-r eceptor antagonist. In both instances, the high-dose regimen (4, 8, 16 and 16 mg/kg/day, i.p. on days 1-4, respectively) was sufficient to evoke a typ ical withdrawal syndrome quantified by the signs wet-dog shakes and facial rubs. These results are discussed relative to those obtained with Delta (9) -tetrahydrocannabinol and anandamide. With bg-tetrahydrocannabinol, precipi tated but not spontaneous or abrupt withdrawal was observed, and this was a scribed to pharmacokinetic properties. Anandamide, which showed little, if any, physical dependence potential, behaved atypically. Possible implicatio ns regarding pharmacotherapeutic and human abuse issues are discussed. (C) 2001 Published by Elsevier Science B.V.