The overall aim of this proposal is to continue to attempt to understand more of the factors that lead to and result from abuse of stimulants, depressants, and hallucinogens. 1.The first aim of this project is a continuation of research that was initiated to determine the effects of cocaine self-administration on blood ACTH and cortisol levels in rhesus monkeys. Self-administered cocaine leads to dose-related increases in these stress hormones, and these increases occurred as well when cocaine was delivered non-contingently. Do these increases occur as well when sedative-hypnotic agents are used to maintain responding. In other words, how general is this finding? 2. The stress hypothesis of drug self-administration suggests that stress, as indicated by increased blood levels of cortisol and ACTH produces increases in the reinforcing effects of drugs. The effects in monkeys of several pre-session stressors on the reinforcing effects of cocaine and other drugs will be measured by changes in progressive ratio performance. The ability of these stressor to increase ACTH and cortisol levels prior to a session, and the effects of the self-administered drugs on these elevated levels will be determined as well. 3. In the rat model of sedative self-administration, the reinforcing effects of a neurosteroid, and other sedative hypnotics will be established, and the ability of picrotoxin, flumazenil, and betaCCE to modify the reinforcing effects of these drugs will be measured. 4.The stress hypothesis of sedative self-administration will be measured in the rat in much the same way it has been done by other investigators using cocaine and opioids. 5. (-) MDMA, which is thought to act primarily by releasing serotonin, has a similar potency and efficacy as a reinforcer in the monkey as (+) MDMA, which is thought to act primarily by increasing levels of dopamine. Therefore, serotonin-releasing drugs may function as reinforcers, whereas serotonin agonists (e.g., LSD) do not. To test this notion, the ability of the isomers of other substituted phenyliospropylamines to maintain responding will be tested, and the effects of several serotonin antagonists and several dopamine antagonists on the reinforcing effects of these drugs will be measured as well. 6. We continue to evaluate the abuse liability of stimulants, hallucinogens, and sedatives as part of the research effort of the College on Problems of Drug Dependence. These drugs can be those that the WHO or the FDA is considering for scheduling decisions, drugs made by industrial or academic medicinal chemists, or industrial drugs that are being considered for clinical testing.