DESCRIPTION (provided by applicant): Abuse of methamphetamine is a serious public health concern worldwide but no effective medications exist for treating this disorder. One reason that stimulant use disorders may be so difficult to treat is that they activate numerous neurotransmitter systems. The goal of the present proposal is to examine the blood-brain barrier (BBB), rather than a specific neurotransmitter system, as a possible target for medications development. Exciting new pilot data collected in mice showed that minocycline, a broad-spectrum antibiotic and inhibitor of glial cell activation, decreased the ability of methamphetamine to disrupt the BBB. In addition, a new technique developed in Denmark in patients with multiple sclerosis showed that it is possible to measure subtle changes in BBB permeability. This technique, called dynamic contrast-enhanced magnetic resonance imaging (DCE- MRI), has not yet been applied to studies of substance abuse. The present proposal is designed to determine whether methamphetamine-induced disruptions in the BBB can be detected in methamphetamine abusers. If the results are positive, future studies will be proposed to examine the ability of glial inhibitors to alter methamphetamine-induced changes in BBB permeability. Participants will reside on a research unit during a 9- day inpatient study. They will receive in randomized order either active or placebo methamphetamine on separate days during 2-day blocks. On the first day of each 2-day block, participants will receive placebo or active methamphetamine. DCE-MRI scans, as well as subjective responses to drug, will be assessed both before and repeatedly after drug administration. On the second day of each 2-day block, participants will be given the opportunity to self-administer the drug that they had received the previous day. Specific Aim 1 is to investigate drug-induced changes in BBB permeability using DCE-MRI. We hypothesize that methamphetamine will increase BBB permeability relative to placebo. Specific Aim 2 is to examine the potential correlation between BBB permeability in individual participants and measures of abuse liability (subjective responses and drug self-administration behavior). We hypothesize that BBB permeability will be directly correlated with increased magnitude of positive subjective responses, as well as MA self- administration. The proposed study tests a highly novel hypothesis, which has the potential to substantially impact current thinking about treatment approaches to substance dependence, by targeting the BBB rather than a specific neurotransmitter system. However, there is very limited precedent for this study and the proposed DCE-MRI procedure has not been used previously in addiction.

PUBLIC HEALTH RELEVANCE: Recent pilot work conducted in mice has shown that methamphetamine-induced increases in blood-brain barrier (BBB) permeability are reduced by minocycline, a broad-spectrum antibiotic and glial inhibitor, suggesting that the BBB may represent a new target for medications development. The present study is designed to examine the ability of methamphetamine to alter blood-brain barrier permeability in humans using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). If the results are positive, future proposals will examine the ability of different medications to alter drug-induced changes in BBB permeability.