TOLERANCE TO THE EFFECT OF Δ1‐TETRAHYDROCANNABINOL ON CORTICOSTERONE LEVELS IN MOUSE PLASMA PRODUCED BY REPEATED ADMINISTRATION OF CANNABIS EXTRACT OR Δ1‐TETRAHYDROCANNABINOL

Abstract

1 Three injections of cannabis extract (500 mg/kg s.c. given over 3 or 5 days) diminished thymus gland weight but not the weights of spleen or liver in weanling female and adult male mice kept at room temperature. 2 Both cannabis extract (500 mg/kg s.c.) and Δ¹-tetrahydrocannabinol (Δ¹-THC; 10 and 20 mg/kg i.p.) elevated corticosterone levels in mouse plasma. 3 A pretreatment that consisted of three daily subcutaneous injections of 500 mg/kg of cannabis extract and that was shown to produce tolerance to the ‘cataleptic’ effect of Δ¹-THC (2 mg/kg i.v.) in mice, also produced tolerance to the effect of Δ¹-THC (10 mg/kg i.p.) on corticosterone levels in mouse plasma. However, this pretreatment did not reduce the rise in plasma corticosterone concentration produced by immobilization. 4 Tolerance to the effect of Δ¹-THC (10 mg/kg i.p.) on corticosterone levels in mouse plasma was also produced by the pretreatment of mice with a single injection of Δ¹-THC (10 mg/kg s.c). Three daily injections of Δ¹-THC (10 or 30 mg/kg s.c.) also produced tolerance. 5 In a thermoneutral environment (30–32° C) in which cannabis extract does not produce hypothermia, the drug no longer reduced thymus gland weight. However the effect of cannabis extract and of Δ¹-THC on corticosterone plasma levels was the same at room temperature as at 30–32° C. Tolerance to the latter effect of Δ¹-THC was also produced equally readily under the two conditions. 6 It is concluded that pretreatment with cannabis extract or Δ¹-THC can produce tolerance to the effect of Δ¹-THC on corticosterone levels in mouse plasma and does so without impairing the effect of immobilization stress on corticosterone release. In addition, both the rise in corticosterone plasma levels produced by cannabis or Δ¹-THC and the development of tolerance to this effect can still take place in the absence of hypothermia.