DESCRIPTION: Applicant's Abstract Although methamphetamine (MA) is significantly abused in the U.S., information on the effects of the drug on the brain is largely limited to animal studies. The extent to which the results of animal studies generalize to the human is not known. Broad objective. Our broad objective is to identify those changes in brain of human chronic users of MA which may be responsible for the behavioural and possible neurotoxicological consequences of long-term drug exposure. Specific aims. During the previous funding period, we demonstrated neurochemical changes in autopsied brain of human MA users suggesting that MA may produce alterations in a dopamine receptor-linked pathway and might cause oxidative stress. Our major specific aims are to establish whether dopamine receptor-modulated adenylyl cyclase activity is altered and whether levels of indices of oxidative stress and damage are increased in brain of human MA users. Design. Neurochemical indices will be measured in autopsied brain of chronic MA users, a matched control group, and in brain of users of cocaine and users of heroin as disease control groups. Health relevance: We expect that our investigation, utilizing, to our knowledge, the only collection of autopsied human brain specimens from long-term MA users, will provide unique and important information relevant to the behavioural effects of chronic MA exposure in the human. It is also important to know whether MA causes oxidative stress and damage in human brain. Ultimately, these data may contribute to the development of new approaches to the problem of drug addiction.