The introduction of new short-acting benzodiazepines and partial agonists has led to an increased interest in the reinforcing effects of the benzodiazepines. However, rigorous study of factors influencing the reinforcing effects of benzodiazepines has been limited due to the lack of success in establishing these drugs as orally delivered reinforcers for laboratory animals. We have developed procedures to establish orally delivered benzodiazepines as reinforcers for rhesus monkeys. Benzodiazepine naive monkeys reject these drug solutions and prefer water. Thus, a training or acquisition procedure is necessary. With midazolam a fading procedure was used whereby increasing amounts of drug were added to an ethanol solution (that was already serving as a reinforcer). In the second phase ethanol solution was gradually decreased to zero, leaving only the midazolam. Upon completion of this procedure midozalam functioned as a reinforcer. The procedure used with diazepam was simple, diazepam was substituted for midazolam. Recently we have successfully substituted triazolam and alprazolam for midazolam. At this point we have four benzodiazepines serving as reinforcers (midazolam, diazepam, triazolam & alprazolam).
The aim of this grant is to expand the study of the development and maintenance of orally delivered benzodiazepines as reinforcers for rhesus monkeys. An important feature is that benzodiazepines with different pharmacokinetic and pharmacodynamics profiles will be examined to see if there are differences in reinforcing effects. The importance of prior drug history in determining acquisition of reinforcing effects will be examined as well as the procedure of establishing reinforcing effects by substituting one benzodiazepine for another. The fundamental variable of dose will be carefully examined across a broad range of values and across benzodiazepined. The effects of the benzodiazepine receptor antagonist, flumazenil, will be examined in terms of changes in benzodiazepine reinforced responding. Procedures that permit a choice between different liquids are a rigorous and often rapid method for determining relative reinforcing effects. In the present application such procedures will be used to study choices between different concentrations of the same drug. Also, a progressive ratio procedure will be used to measure reinforcing effects of different doses. The results of the two procedures will be compared. Results obtained from these studies will be integrated with the results we have obtained in studies of drugs from other pharmacological classes. The results of this research will add substantially to our knowledge of factors controlling the acquisition and maintenance of benzodiazepine reinforced behavior.
