Tolerance to and physical dependence on morphine were produced in rats by the implantation of morphine pellets. When both reached peak levels, the rats were sacrificed and malic dehydrogenase, lactic dehydrogenase and glucose-6-phosphate dehydrogenase were measured by sensitive microchemical methods in eight hypothalamic nuclei and in the cortex, cerebellum and liver. In the medial portion of the ventromedial nucleus of the hypothalamus, glucose-6-phosphate dehydrogenase was 20 per cent lower in the morphine-dependent animals than in the controls. This was the only significant change (P < 0·01) detected for any of the three dehydrogenases in any of the regions or organs examined. The data indicate that chronic morphine administration does not produce a generalized change in the activity of major metabolic pathways in either the brain or liver. The regionally selective effect on glucos-6-phosphate dehydrogenase activity may reflect an involvement of the ventromedial hypothalamus in at least some aspects of the development of tolerance and physical dependence on narcotics.