Methamphetamine (METH) dependence has drastic consequences in terms of psychological and physicalhealth, and places great economic and legal burdens on communities. METH abuse and dependence, longa serious problem in the West, is now spreading in near-epidemic proportions to the eastern United Statesand has experienced dramatic growth in South Carolina in the past five years. Cue-elicited drug craving isbelieved to be a critical component in drug seeking, and relapse in the natural environment. Investigatorshave suggested that a critical characteristic of addiction is increased cue saliency and enhanced cue-drugmemory circuits which overwhelm inhibitory control normally exerted by the prefrontal cortex for natural cuesand reinforcers. Medication development for METH treatment is progressing, but much remains to belearned about the fundamental neurobiology of METH addiction. Cue exposure coupled with functionalneuroimaging techniques (PET, SPECT, fMRI) has been extremely useful in elucidating brain circuitry fornicotine, cocaine, and alcohol-dependent individuals. It has been suggested that identifying pharmacologicagents that alter human cue-induced craving and drug-seeking as measured with functional brain imagingcould well be an effective screening tool for potential pharmacotherapeutic agents and a productive path fordrug development.No circuitry map exists for METH cue activation in either preclinical models or human clinical imaging.Preclinical studies in rodents indicate that METH-treated animals may have impaired extinction learning.Our group has used the technique of fMRI to evaluate regional brain circuitry changes with alcohol and,more recently, cocaine cue stimulation. Working in close concert with Project #1, the primary aims of thisproposal are to develop procedures to assess brain circuitry through fMRI under conditions of cue-generatedcraving and cue extinction in non-treatment-seeking METH-dependent subjects. Using BOLD fMRI, multiplefMRIs will be assessed over time to measure changes in circuit activation with exposure to METH cues andneutral cues. We propose to recruit 60 non-treatment-seeking METH-dependent males and females of allethnic and racial groups between ages 18 and 50 to participate in this study. This study will consist of 3phases: 1) outpatient screening; 2) inpatient cue-exposure with repeated fMRIs overtime during METH andneutral cue exposure; and 3) Two weeks of outpatient follow-up. This project will work closely with Project#4 in the development of METH-specific environmental cues and with Project #1 in identifying specificcircuits underlying METH cue-reactivity and extinction. The bidirectional exchange of information betweenhuman and animal studies in identifying the critical circuitry involved in these important functions willaccelerate the pace of discovery.
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