The effects of (--)trans-delta 9-tetrahydrocannabinol (THC) on tonic PRL secretion were investigated in long term ovariectomized or hypophysectomized/pituitary-autografted female rats and in flask incubations of anterior pituitary tissue. Intravenous injection of 0.25-8.0 mg THC/kg BW into ovariectomized rats markedly suppressed serum PRL 60 min later relative to control PRL levels. In a second experiment, ovariectomized rats bearing intraatrial cannulae were injected with 0.5 mg THC/kg BW, iv, and serial blood samples were drawn. PRL was significantly suppressed at 10 min, with persistence of the suppression for the duration of the 70-min sampling period in this time-course study. In contrast, the administration of 1.0 mg THC/kg BW, iv, to hypophysectomized/pituitary-autografted female rats failed to influence PRL secretion throughout a 120-min posttreatment sampling period. The apparent inability of THC to directly suppress PRL release from pituitary tissue was further studied by in vitro flask incubations of anterior pituitary tissue. Although a 1-h exposure of rat anterior pituitary tissue to bromocryptine (CB-154; 2.2 X 10(-4) M) suppressed subsequent PRL release, similar exposure to 10(-6) or 10(-4) M THC had no influence. The failure of THC to alter tonic PRL secretion in hypophysectomized/pituitary-autografted rts or PRL release from pituitary tissue in vitro strongly suggests that the central nervous system rather than the pituitary is the site of THC action in the acute suppression of tonic PRL secretion.