The overall objective of this research is to study the addictive potency and neuronal substrates of action of long acting narcotic blocking agents developed as substitutes for methadone. Included for study are methadone itself, morphine and morphine agonists, endogenous opiate peptides, and a variety of long-acting agents such as acetylmethadol, as well as its metabolites, including noracetylmethdol, methadol, and normethadol. The studies of addictive potential include behavioral assays of opiate physical dependence capacity and addiction liability, a self-administration paradigm of opioid behavioral dependence, and neurobehavioral studies involving the effects on physical dependence of direct stimulation of brain systems containing endogenous opiate peptides. The studies of brain receptor mechanisms upon which acetylmethadol and other long acting narcotic substitutes may act to achieve narcotic blockade include studies of the effects of narcotic and narcotic blocking agents on neurotransmitter-stimulated receptor and cyclic nucleotide systems, studies of opiate binding to membrane receptors in the presence and absence of blocking agents such as acetylmethadol, and studies of alterations in receptor and second-messenger systems during chronic administration of narcotic and blocking agents and during withdrawal. Additional studies of the effects of specific brain lesions on the binding of opiates and opiate blocking agents to brain tissue are being pursued.