Abstract-To produce physical dependence on morphine, phenobarbital and diazepam in rats, these drugs were mixed with the powder form of rat food in concentrations of 0.5 mg/g, 1 mg/g and 2 mg/g of food. One group of rats (the lower dose group) was continuously exposed for I week to two morphine-admixed foods with morphine to food ratios of 0.5 mg/g and 1 mg/g in a cage. The other group (the higher dose group) could choose between two morphine-admixed foods with morphine to food ratios of 1 mg/g and 2 mg/g. After I week, morphine-admixed foods were replaced with morphine free food for 2 days. Both groups of rats showed greatly reduced body weight and food intake after the first 24-48 hr withdrawal.The body weight decrease was greater for rats in the higher dose group. Control groups of morphine dependent rats were kept on the morphine added food diets and showed the same body weight increase as well as normal control rats during the course of these experiments.Physical dependence on phenobarbital and diazepam was produced using the same dosage schedules as with morphine.Both the lower and higher dose groups showed significant decrease in body weight due to withdrawal after 1 week of drug-food exposure. Levallorphan (0.5, 1, 3 and 5 mg/kg, s.c.) administered to morphine dependent rats had dose-de pendent effects on the intensity of abstinence symptoms (e.g., diarrhea, piloerection and wet shakes phenomena), maximal decrease in body weight and duration of de c reased body weight. Cross-physical dependence between phenobarbital and dia zepam was demonstrated by this method.Animals can be made drug dependent quickly and economically for utilization in studies on drug dependence and screening tests of drug dependence.The growth curve of body weight and total daily food intake should not be allowed to become depressed during the drug administration period for detection of drug dependence liability using decrease in body weight as indicator of abstinence symptoms. Hosoya (1) first reported physical dependence liability of morphine in rats using body weight decrease by withdrawal as indicator of ab stinence symptoms. In that case, morphine was injected subcutaneously twice daily for 5 weeks using a gradually increasing dosage schedule. The acquisition of morphine type drug dependence by means of other than the daily injection method in mice (2) and rats (3-6) has been reported. Nichols et al. (7,8), Davis and Nichols (9) and Kumar et al.(10) reported morphine dependence development and preference formation in rats with morphine dissolved in water, either forcibly or ad libiturn supplied. Goode (3) developed a method of subcutaneous reservoir of morphine type drugs. Rapid induction of physical dependence on morphine by both direct morphine administration and by drug substitution for morphine in morphine dependent rats (cross-physical dependence test) as well as by administration of an opiate antagonist to morphine dependent rats was confirmed by this

Abstract-Sex differences in physical dependence on sodium pentobarbital in the rat were studied by the drug-admixed food (DAF) method. With male rats, the concentration of pentobarbital in the food was gradually increased from 2 to 30 mg/g over a period of 50 days. The final level of drug intake was approximately 1.7 g/kg/day.At pentobarbital concentrations of 20 and 22 mg/g of food, sedation and mild muscle relaxation were observed.At the highest drug concentration, 30 mg/g of food, marked muscle relaxation was noted.With female rats, the con centration of pentobarbital in the food was gradually increased from 1 to 16 mg/g over a period of 47 days. The final level of intake was approximately 1 .0 mg/kg/ day. At drug concentrations of 12 and 14 mg/g, sedation and mild muscle relaxation appeared.At 16 mg/g, female rats showed marked muscle relaxation similar to that of the male rats. To produce severe loss of muscle tone, the male rats required twice as much pentobarbital as the female rats. After substitution of normal food for the pentobarbital-admixed food, various signs of pentobarbital withdrawal occurred in both sexes. These signs included vocalization, irritability, muscle rigidity, tremors and convulsions.Onset of withdrawal was more rapid in the females, and the maximum weight loss was greater, 8.0% compared to 3.8% in the males.Physical dependence on pentobarbital was easily developed in both sexes by the DAF method.There was a marked sex difference in withdrawal which we attribute to sex differences in drug metabolizing enzyme activity.

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