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
VAC extract improved PMS symptoms in Japanese patients, with no substantial adverse events. This is the first study to report the effect of VAC extract in Japanese patients.
The inhibitory effect of β-alanyl-L-histidinato zinc (AHZ) on bone resorption in tissue culture was investigated. Calvaria were removed from weanling rats (3-week-old male) and cultured for periods up to 48 h in Dulbecco’s modified Eagle medium (high glucose, 4.5%) supplemented with antibiotics and bovine serum albumin. The experimental cultures contained 10–7 to 10–4 mol/l AHZ. The bone-resorbing factors, parathyroid hormone (1–34) (PTH; 10–7 mol/l), prostaglandin E2 (10–5 mol/l), interleukin-1α (IL1α; 50 U/ml), and lipopoly-sacharide (10 μg/ml), caused a significant decrease in bone calcium content. The decreases in bone calcium content induced by bone-resorbing factors were completely inhibited by the coexistence of AHZ (10–6 to 10–4 mol/l). Also, AHZ (10–5 mol/l) completely inhibited the PTH (10–7 mol/l) or IL1α (50 U/ml)-induced increase in medium glucose consumption and lactic acid production by bone tissue. Furthermore, AHZ (10–5 mol/l) fairly blocked both PTH (10–7 mol/l)-increased acid phosphatase and decreased alkaline phosphatase activities of bone tissue. The inhibitory effect of AHZ (10–5 mol/l) on PTH (10–7 mol/l)-stimulated bone resorption was clearly prevented by the presence of 10–4 mol/l dipicolinate, a chelator of zinc. However, zinc sulfate (10–7 to 10–4 mol/l) did not inhibit the PTH (10–7 mol/l)-stimulated bone resorption in tissue culture. These findings indicate that AHZ had a direct inhibitory effect on bone resorption in vitro, and the AHZ effect was found in the chemical form of zinc-chelated dipeptide.
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