Effects of systemic and intraventricular administration of cannabinoids on schedule-controlled responding in the squirrel monkey.

The effects of a number of cannabinoids in squirrel monkeys trained to respond on a chain fixed-interval fixed-ratio schedule of food presentation were determined after intraperitoneal (i.p.) and intraventricular (i.v.t.) administration. The order of potency was (+/-)-9-nor-9 beta-OH hexahydrocannabinol, 11-OH-delta 9-tetrahydrocannabinol, delta 9-tetrahydrocannabinol (delta 9-THC), cannabinol and cannabidiol. (+/-)-9-Nor-9 alpha-OH-hexahydrocannabinol was inactive at doses up to 3 mg/kg i.p. and 0.1 mg/kg i.v.t. Although the order of potency was the same by both routes of administration, the i.v.t./i.p. potency ratio differed markedly. This demonstrates the importance of route of administration in assessing structure-activity relationships of cannabinoids and suggests that differences in penetration to the central nervous system may be an important determinant of behavioral activity. Although 11-OH-delta 9-THC was more potent than the parent compound delta 9-THC by both routes, the potency difference was less after i.v.t. administration. It was also demonstrated that metabolic conversion of [3H]delta 9-THC does not take place in squirrel monkey brain when administered i.v.t. which could account for the direct i.v.t. effects of delta 9-THC. These observations suggest that metabolic conversion of delta 9-THC in the liver is not necessary for its behavioral effects.