This application describes a five-year program of research to study the psychopharmacology of stimulants and opioids. The research will utilize a number of different methodologies including behavioral. pharmacological, neurochemical, and electrophysiological techniques to further characterize the effects of these substances and to elucidate their underlying mechanisms of action. Based on detailed observations, we have identified general behavioral features or dimensions (i.e., perseveration and environmental engagement) which distinguish the response profiles associated with different types of stimulants and which appear to transcend species differences. We have developed operationally defined measures of these behavioral dimensions that subsume a variety of specific responses and studies are designed to further refine these measures and to test our hypotheses regarding underlying monoaminergic systems and mechanisms. The apparently pervasive characteristics of the stimulant response we propo se to study in rats may be relevant to the broad ranges of stimulant effects in humans and to the widespread use of these agents in the treatment of hyperkinetic children. The acute and chronic behaviorally activating effects of opioids will be characterized in rats and the role of opioid receptor mediated mechanisms and monoamine systems underlying the various response components will be investigated using a variety of pharmacological, neurochemical, and discrete intracerebral injection techniques. Similar behavioral and mechanistic studies are also planned to compare and contrast the activating effects of putative sigma receptor agonists (e.g., SKF-10,047) and PCP with those produced by morphine-like agents (mu-receptor agonists) and opioid peptides. In addition, a series of experiments will be directed at further examining the role of endogenous opioid systems in the opiate-like response activation associated with mild stress. Our research concerning opioid-induced alterations of stimulus-directed behavior will also be continued. Opioid-induced behavioral activation may be relevant to narcotic euphoria and drug-seeking behavior and, in addition, may serve as an appropriate animal behavior model for various forms of psychopathology in which endogenous opioids have been inplicated.
