delta 9-Tetrahydrocannabinol (delta 9-THC) was injected into the preoptic area of the anterior hypothalamus or into the third or fourth cerebral ventricle of the conscious mouse through a chronically implanted cannula and the effects on body temperature and oxygen consumption rate were measured. At an ambient temperature of 22 degrees C, injections of delta 9-THC into the fourth ventricle (5 and 10 microgram) produced dose-dependent falls in rectal temperature. Hypothermia was also observed after injections of the drug into the hypothalamus (5 and 10 microgram) or into the third ventricle (10 microgram). The hypothermia produced by delta 9-THC was associated with a fall in oxygen consumption rate. Falls in rectal temperature and in oxygen consumption rate were significantly greater after injection of delta 9-THC than after injection of the drug vehicle, Tween 80. The falls in rectal temperature and oxygen consumption rate produced by injection of delta 9-THC into the fourth ventricle were abolished by elevation of the ambient temperature from 22 to 32 degrees C. A pretreatment that consisted of subcutaneous injections of delta 9-THC (20 mg/kg) given once daily for three days produced tolerance to the hypothermic effect of the drug when injected on day 4 either into the fourth ventricle (10 microgram) or into a lateral tail vein (2.0 mg/kg). The results suggest that delta 9-THC acts centrally to alter thermoregulation in mice not only when it is injected directly into the hypothalamus or cerebral ventricles but also when it is given intravenously. After intraventricular or intravenous administration the drug may act at extrahypothalamic as well as at hypothalamic sites. The data also support the hypothesis that in mice, tolerance to the hypothermic effect of A9-THC is pharmacodynamic and does not depend on changes in metabolism or distribution of the drug.