Tolerance to the luteinizing hormone and prolactin suppressive effects of delta-9-tetrahydrocannabinol develops during chronic prepubertal treatment of female rats.

To determine if prepubertal female rats develop tolerance to the hormone suppressive action of delta-9-tetrahydrocannabinol (THC), we tested the ability of THC (10 mg/kg i.p.) to block luteinizing hormone (LH) and prolactin (PRL) surges acutely at first proestrus in animals that were treated repetitively with THC before puberty. Rats were pretreated with 10 mg THC/kg b.wt. twice daily beginning at 27 days of age and the blocking efficacy of THC treatment at first proestrus was compared to that in animals that were previously untreated or were pretreated only with drug vehicle. Vaginae were opened at 30 days of age to permit identification of first proestrus by vaginal smears, and serial blood samples for LH and PRL radioimmunoassays were collected before and after treatment at proestrus. In previously untreated or vehicle-pretreated animals, THC treatment at 1300 hr on the day of first proestrus inhibited the afternoon surges of LH and PRL, whereas hormone surges occurred in control animals injected with only vehicle at 1300 hr proestrus (P less than .05). In contrast, animals pretreated with THC exhibited marked LH and PRL surges whether treated at 1300 hr proestrus with THC or vehicle. Among animals receiving only vehicle at proestrus, there was no difference in serum LH concentrations or in timing of the LH surge between the group pretreated with THC and the group pretreated with vehicle. These results are consistent with the hypothesis that ovulation eventually occurs in the pubertal rat treated chronically with THC because tolerance develops to its gonadotropin suppressive effects.