Diazepam tolerance and withdrawal assessed in an animal model of subjective drug effects

Tolerance to and withdrawal from drugs of dependence involves subjective symptoms and physical signs. Until recently, only physical signs associated with these phenomena could be assessed in animals. Recently, however, drug discrimination methodology has been used to bioassay for the occurrence of subjective events in animals; the work reviewed in this paper describes extensions of this general technique to test for subjective aspects of withdrawal from and tolerance to benzodiazepine drugs in rats. The durg dicrimination procedure reinforces differential responding where the controlling stimulus is the presence or absence of a drug‐produced internal stimulus. Although it is impossible to determine the quality (subjective nature) of such stimuli in animals, it is possible to operationally define relationships between classes of stimuli. With regard to the discriminative stimulus produced by pentylenetetrazol (PTZ), data to date show that anxiogenic drugs substitute for PTZ and anxiolytic drugs block the PTZ stimulus. Because in humans severe anxiety is a frequently seen component of withdrawal from dependence on benzodiazepine drugs, this laboratory initiated experiments to determine if animals trained to detect PTZ and then given chronic treatment with benzodiazepines would substitute a withdrawal state for the PTZ stimulus. Data reviewed in this paper show that following diazepam administration, treatment with the benzodiazepine antagonist Ro 15‐1788 (RO) produced a dose‐related PTZ‐like stimulus. When given to nondependent animals, RO neither substituted for nor blocked nor enhanced the PTZ stimulus. In additional studies, RO produced a PTZ‐like stimulus when administered once every 3 d in rats maintained chronically on diazepam. Further, rats given a 2‐d regimen of diazepam, 80 mglkgl8 hr, were subsequently tolerant to the PTZ‐blocking action of diazepam. These data demonstrate that the discrimination of PTZ is a useful procedure for assessing subjective aspects of tolerance to and withdrawal from benzodiazepines in animals.