Partial Agonist and Antagonist Effects of Δ9‐tetrahydrocannabinol (Δ9THC) in rats

Studies have suggested that Δ 9 THC, in vitro and in vivo, acts as partial agonist at cannabinoid (CB) receptors. For example, in vitro Δ 9 THC produces lesser maximum effects than WIN55,212 and, when co‐administered, will attenuate the effects of WIN55,212 (Shen and Thayer, 1999). In vivo studies have demonstrated lesser effects of Δ 9 THC in comparison to other CB agonists but, to date, have not examined potential antagonist effects of Δ 9 THC. The present studies evaluated whether Δ 9 THC is able to antagonize the effects of AM4054, a full CB1 agonist, in vivo. The hypothermic effects of Δ 9 THC, AM4054, and SR141716A were determined in male SD rats; rectal temperatures were recorded for 6hrs after drug injection. AM4054, 0.03–1.0 mg/kg, produced dose‐related decreases in temperature; a dose of 1.0 mg/kg decreased temperature by 5°C. SR141716A, 0.3–1 mg/kg, did not affect body temperature but was able to attenuate the hypothermic effects of 0.03–0.3 mg/kg AM4054. Doses of 1.0–10.0 mg/kg Δ 9 THC also decreased temperature but had lesser effects than AM4054; 10.0 mg/kg Δ 9 THC decreased temperature by 2.4°C. The doses of Δ 9 THC that decreased temperature also dose‐dependently attenuated the hypothermic effects of 0.3–1.0 mg/kg AM4054. These data indicate that Δ 9 THC can have both agonist and antagonist effects in whole animals, consistent with its characterization as a partial agonist at CB receptors. (Supported by PHS: DA19205)