Abstract-Physicaland psychic dependence on opioids and CNS depressants in rodents were examined using the drug-admixed food (DAF) method.A comparison of several methods for developing physical dependence on opioids was made. The DAF method has the advantage of rapidly inducing a high degree of physical dependence without causing morbidity or mortality. When morphine-dependent rats were pretreated with several opioids, naloxone-precipitated weight loss was suppressed in a dose-dependent manner.A procedure for the development of severe physical dependence on CNS depressants was also established. Drug con centrations were rapidly increased until animals showed moderate to severe CNS depression, and then this condition was maintained for at least 10 days. With this procedure, animals became severely dependent on CNS depressants. Another technique, intermittent infusion, was developed that has been used to quantify short acting CNS depressant dependence potential.The sedative effects of pentobarbital were used as an index in the determination of the injection intervals.These results suggest that the DAF method and the new approaches are useful tools for assessing the physical dependence potential of new drugs. Moreover, oral self-administration and weight pulling procedures were utilized along with the DAF method. Pro cedures for the oral self-administration of opioids and CNS depressants were estab lished. Opioid-dependent rats pulled the weight to obtain the DAF even though they had free access to normal food. This weight-pulling procedure may be useful for assessing the degree of reinforcing effects for drugs in rats.
I. Physical dependence 1. OpioidOn the basis of many years of study with the opioids, well defined methods have been developed for the assessment of physical de pendence.Physical dependence on opioids can quickly be induced in rodents by a variety of techniques, including implantation of mor phine pellets (1-3), infusion of opioids (4-6), treatment with slow release emulsion (SRE) of opioids (7,8) and implantation of a re servoir of morphine solution (9). The drug admixed food (DAF) method developed by Yanaura et al. (10,11) is an easy way to produce physical dependence on opioids in rodents without the stress of surgery or injection. It is well-known that the degree and severity of physical dependence are influenced by dose, frequency (dosing inter val) and duration of drug administration and that the frequency is the most important factor (12). From these points of view, we examined physical dependence on opioids using the DAF method. a) Effects of dose: Rats were chronically administered 5 doses of morphine (0.0625, 0.125, 0.25, 0.5 and 1.0 mg/g of food) for 7 days by the DAF method. physical dependence on morphine was car ried out using withdrawal signs precipitated by naloxone (3.0 mg/kg, s.c.) challenge. The average daily morphine intake for 7 days was 5. 29, 10.58, 21.49, 38.19 and 76.94 mg/kg/ day in animals treated with morphine at doses of 0.0625, 0.125, 0.25, 0.5 and 1.0 mg/g of food, resp...