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BEHAVIORAL PHARMACOLOGY

⁹-Tetrahydrocannbinol Accounts for the Antinociceptive, Hypothermic, and Cataleptic Effects of Marijuana in Mice

Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (S.A.V., D.T.B., Q.T., B.R.M., A.H.L.); and Research Triangle Institute, Research Triangle Park, North Carolina (B.F.T.)

Although it is widely accepted that ⁹-tetrahydrocannabinol (⁹-THC) is the primary psychoactive constituent of marijuana, questions persist as to whether other components contribute to marijuana's pharmacological activity. The present experiments assessed the cannabinoid activity of marijuana smoke exposure in mice and tested the hypothesis that ⁹-THC mediates these effects through a CB₁ receptor mechanism of action. First, the effects of ⁹-THC on analgesia, hypothermia, and catalepsy were compared with those of a marijuana extract with equated ⁹-THC content after either i.v. administration or inhalation exposure. Second, mice were exposed to smoke of an ethanol-extracted placebo plant material or low-grade marijuana (with minimal ⁹-THC but similar levels of other cannabinoids) that were impregnated with varying quantities of ⁹-THC. To assess doses, ⁹-THC levels in the blood and brains of drug-exposed mice were determined following both i.v. and inhalation routes of administration. Both marijuana and ⁹-THC produced comparable levels of antinociception, hypothermia, and catalepsy regardless of the route of administration, and these effects were blocked by pretreatment with the CB₁ antagonist SR141716 [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl]. Importantly, the blood and brain levels of ⁹-THC were similar in mice exhibiting similar pharmacological effects, regardless of the presence of non-⁹-THC marijuana constituents. The present experiments provide evidence that the acute cannabinoid effects of marijuana smoke exposure on analgesia, hypothermia, and catalepsy in mice result from ⁹-THC content acting at CB₁ receptors and that the non-⁹-THC constituents of marijuana (at concentrations relevant to those typically consumed) influence these effects only minimally, if at all.

Address correspondence to: Dr. Aron H. Lichtman, Department of Pharmacology and Toxicology, Virginia Commonwealth University, Box 980613, Richmond, VA 23298-0613. E-mail: alichtma{at}hsc.vcu.edu

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