EFFECTS OF SR 141716A AFTER ACUTE OR CHRONIC CANNABINOID ADMINISTRATION IN DOGS

The effects of dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR 141716A), a specific cannabinoid receptor antagonist, were assesse d in the dog static ataxia test after either acute treatment with two cannabinoid receptor agonists, Delta(9)-tetrahydrocannabinol and arach idonylethanolamide (anandamide), or chronic treatment with Delta(9)-te trahydrocannabinol. As previously reported, acute intravenous (i.v.) i njected Delta(9)-tetrahydrocannabinol produced dose-dependent cannabin oid effects, including marked static ataxia, prancing, loss of muscle tone, and incoordination. The behavioral profile of anandamide was dis tinctly different in that it produced a loss of muscle tone and consid erable sedation with little static ataxia, prancing, or incoordination . Despite these qualitative differences between the two agonists, SR 1 41716A blocked the acute behavioral effects of both drugs indicating a cannabinoid receptor mechanism of action. Interestingly, SR 141716A w as able to precipitate a withdrawal syndrome in Delta(9)-tetrahydrocan nabinol-tolerant dogs, but failed to produce any observable effects in dogs receiving chronic vehicle injections. Acute toxicity caused by a nandamide, which was not blocked by SR 141716A, precluded conducting d ependence studies with this drug. The Delta(9)-tetrahydrocannabinol pr ecipitated withdrawal syndrome included diarrhea, vomiting, excessive salivation, decreases in social behavior, and increases in restless be havior and trembling. This is the first demonstration of a precipitate d withdrawal syndrome in a non-rodent species. (C) 1998 Elsevier Scien ce B.V. All rights reserved.