ESTABLISHING BENZODIAZEPINES AS ORAL REINFORCERS - MIDAZOLAM AND DIAZEPAM SELF-ADMINISTRATION IN RHESUS-MONKEYS

Oral benzodiazepine self-administration was examined in four adult mal e rhesus monkeys with histories of ethanol- and pentobarbital-reinforc ed behavior. Drug solutions and vehicle were concurrently available fo r 3-hr each day under fixed-ratio (FR) reinforcement schedules. Initia lly, the monkeys rejected a midazolam solution (0.1 mg/ml) after direc t substitution of the drug for an 8% ethanol solution. However, midazo lam self-administration was subsequently established by using a fading procedure in which increasing amounts of drug (0.0125-0.2 mg/ml) were gradually added to an 8% ethanol solution, followed by gradual reduct ion of the ethanol concentration to zero. Midazolam was an effective r einforcer for three of four monkeys tested, i.e., responding that was maintained by the drug solution exceeded that maintained by the drug v ehicle. The fourth monkey also self-administered midazolam but drug-ma intained responding was not consistently greater than vehide-maintaine d responding. The responding maintained by the drug was an inverted-U- shaped or bitonic function of midazolam concentration. The midazolam i ntake (in milligrams per kilogram) increased as a function of increase s in the drug concentration. At the higher concentrations, marked seda tive intoxication was observed. There was an inverse relationship betw een FR size (varied from FR 8 to FR 32) and the amount of drug self-ad ministered. The three monkeys in which midazolam functioned as a reinf orcer were then tested with diazepam (0.2 mg/ml), which maintained dru g self-administration behavior on direct substitution for 0.2-mg/ml mi dazolam. Diazepam-maintained responding usually exceeded water respond ing as the diazepam concentration was increased to 0.8 mg/ml. These da ta demonstrate robust reinforcing effects of both ''short-'' and ''lon g-acting'' benzodiazepines delivered by the oral route.