Benzodiazepines: Drug Discrimination and Physiological Dependence

2015

The benzodiazepines are among the most widely used of all prescribed drugs. Concern about abuse of these drugs has prompted the development of preclinical methods for assessing various pharmacological effects of diazepam-like drugs which are relevant to their abuse and dependence liability. This abstract describes results from a series of ongoing experiments to assess discriminative stimulus effects and physiological dependence-producing properties of benzodiazepines.

Drug discrimination: In drug discrimination procedures, animals are trained to respond differentially depending on the nature of drug pretreatment. The procedure can provide information analogous to a human testing situation in which subjects categorize drugs with respect to their subjective effects.

In ongoing drug discrimination experiments, four baboons were trained to discriminate lorazepam (1.0 mg/kg) and two baboons were trained to discriminate pentobarbital (5.6 mg/kg) in a two-lever drug versus no-drug discrimination procedure. Food delivery depended on 20 consecutive responses on one lever in sessions preceded by an intramuscular injection of the training drug (60-min pretreatment time), and on 20 consecutive responses on the other lever following no drug. All baboons completed 100% of the response runs on the appropriate level in training sessions. Test sessions were conducted in which a drug dose different from the training dose was administered (either orally or intramuscularly), and 20 consecutive responses on either lever produced food. Pentobarbital-trained baboons consistently generalized to lorazepam, diazepam, alprazolam, and pentobarbital. Although lorazepam-trained animals consistently generalized to lorazepam, diazepam, alprazolam, bromazepam, and triazolam, only one of four baboons generalized to pentobarbital (tested through a wide range of doses, and at 30- and 60-min pretreatment intervals). These results demonstrate an interesting asymmetry in cross- generalization with benzodiazepines and barbiturates. In related experiments, oral doses of Ro 15-1788 (a benzodiazepine antagonist), naltrexone (an opioid antagonist), and caffeine were administered alone or immediately before an injection of lorarepam or pentobarbital. Ro 15-1788 (0.1-1.0 mg/kg) had no effect on the pentobarbital stimulus and produced a surmountable antagonism of the lorazepam stimulus. Naltrexone (1.0-10.0 mg/kg) had no effect on the pentobarbital or lorazepam stimulus. Caffeine (0.1-10.0 mg/kg) produced variable effects within and across animals. When administered alone, neither Ro 15-1788, naltrexone, nor caffeine generalized to the pentobarbital or lorazepam stimulus. The differential effects of Ro 15-1788 on the stimulus effects of lorazepam and pentobarbital along with the asymmetry in cross-drug generalization between lorazepam- and pentobarbital-trained baboons suggest that the stimulus effects of these two compounds depend upon different mechanisms of action.

Physiological dependence: Physiological dependence is an important aspect of the behavioral toxicity of benzodiazepines and may be related to the abuse liability of these drugs. In ongoing experiments to explore the development of physiological dependence on benzodiazepines in baboons, reliable observational procedures were developed for assessing benzodiazepine withdrawal by scoring a series of 15 withdrawal signs and body postures. In one study baboons implanted with intragastric catheters were given diazepam (20 mg/kg/day) continuously for 45 days. Termination of diazepam administration (spontaneous withdrawal) resulted in a mild to intermediate withdrawal syndrome over the next 15 days characterized by suppressed food intake, tremor and abnormal body posturing. Parametric studies have been undertaken to characterize precipitated withdrawal by administering intramuscular injections of the benzodiazepine antagonist, Ro 15-1788, 5.0 mg/kg, after periods of chronic benzodiazepine administration. Intensity and consistency of withdrawal signs are an increasing function of diazepam dose (0.125-20.0 mg/kg/day) and duration of diazepam administration (1 hr, 1, 3, 7, 35 days). Results to date indicate that reliable precipitated withdrawal occurs with diazepam doses as low as 0.25 mg/kg/day administered for 7 days. Precipitated withdrawal after higher diazepam doses administered for longer durations is characterized by emesis, retching, tremor, and convulsion. Compared to spontaneous withdrawal, precipitated withdrawal is more intense, has a more rapid onset, and is of briefer duration.

 

Selections from the book: “Problems of Drug Dependence, 1983. Proceedings of the 45th Annual Scientific Meeting, the Committee on Problems of Drug Dependence, Inc.” Louis S. Harris, Ph.D., ed. A collection of papers which together record a year’s advances in drug abuse research; also includes reports on tests of new compounds for efficacy and dependence liability. National Institute on Drug Abuse Research Monograph 49, March 1984.