This is a response to the notice of Special Research Scientist Development Awards (SDA) for 1995 by NIDA. The notice has prompted the candidate to take this opportunity to acquire expertise in the newly emerging technology of functional magnetic resonance imaging (fMRI) and to apply that expertise towards a career in the human neurobiology of addiction. The known relationship between acute opiate withdrawal and noradrenergic neuronal activation has been exploited in this proposal to design interpretable fMRI experiments that address critical questions about drug addiction in humans. The most powerful use of fMRI requires hypotheses specifying explicitly 1) which brain structures will have a change in fMRI signal intensity, 2) whether the fMRI signal intensity will increase or decrease and 3) the temporal sequence of the changes. It is evident that information about deep brain structures is critical for understanding the neurobiology of drug addiction: however, the current state of fMRI data acquisition and analysis is still in the development stages for subcortical structures. To circumvent this temporary limitation, these experiments will first attempt to produce interpretable brain maps of the effects of pharmacological manipulations of the firing rate in noradrenergic neurons which project to cortex and are known to produce predictable changes in cortical neuronal activity. Once cortical fMRI signal changes can be clearly correlated with pontine fMRI signal changes, then we will use fMRI to study precipitated opiate withdrawal which is known in experimental animals and inferred in humans to markedly increase the firing rate of noradrenergic neurons. Cortical fMRI signal changes can be reliably measured, and will be used as a window to see the effects of the pharmacological manipulations on deeper brain structures. Concerted effort will be made to directly demonstrate fMRI signal intensity change in the region of dorsal pons containing the majority of noradrenergic neurons. The SDA funding mechanism will allow the candidate, already a well trained and experienced neuroscientist, the opportunity to bring that knowledge to bear in the design and interpretation of neurobiologically relevant imaging experiments, while giving her the opportunity to become proficient in fMRI techniques and to gain additional clinical training in the assessment and treatment of substance abuse. The Nuclear Magnetic Resonance Center and the Addiction Services at Massachusetts General Hospital are superb training sites for accomplishment of these goals.
