Dopamine is an immensely important neurotransmitter in the central nervous system. It contributes to motor control, reward-based learning, the regulation of mood and anxiety, and several other brain functions. Pathology of the central dopamine systems is clearly implicated in Parkinson's disease, dystonia, schizophrenia, attention deficit hyperactivity disorder, and substance abuse. Consequently, drugs that target dopamine systems have wide-ranging therapeutic applications and illicit uses. So, understanding brain dopamine activity per se and the mechanisms of action of dopamine-targeting drugs is immensely significant. Recently, the PI's laboratory has amassed a substantial body of evidence of a previously unknown dopamine phenomenon. Our findings, derived from voltammetric recordings in the rat brain, show that two key dopamine terminal fields, the dorsal striatum (key to motor function) and the core of the nucleus accumbens (a region of the ventral striatum key to substance abuse), are organized as a patchwork of spatially discrete kinetic domains. We have named these the fast and slow domains because the rates of dopamine release and uptake are significantly faster in the former compared to the latter domains. The actions of the drugs we have examined to date are likewise significantly domain-dependent. Thus far, we have investigated the kinetic and pharmacological properties of the domains. Our next objective is to explore their anatomy: we wish to know the size and distribution of the domains, their consistency between individual animals, and their relationship to established anatomical and neurochemical biomarkers of striatal structure. We propose to achieve this objective by combining high spatial resolution voltammetric recording with detailed immunohistochemical analysis of the recording sites by means of fluorescence microscopy.

Public Health Relevance

Because dopamine is implicated in numerous neurological and psychiatric disorders, it is has been a major target of therapeutic drug development. Drugs that act on DA are used to treat Parkinson's disease, schizophrenia, depression, ADHD and more. Moreover, drugs that act on DA are frequently abused and may be addictive. Thus, it is of great relevance to public health to understand how the brain dopamine systems function, how they are organized, how their dysfunction contributes to disease, and how they are altered by therapeutic drugs and drugs with potential for abuse and addiction.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-ETTN-G (03))
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Sieber, Beth-Anne
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University of Pittsburgh
Schools of Arts and Sciences
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Walters, Seth H; Taylor, I Mitch; Shu, Zhan et al. (2014) A novel restricted diffusion model of evoked dopamine. ACS Chem Neurosci 5:776-83
Shu, Zhan; Taylor, I Mitch; Walters, Seth H et al. (2014) Region- and domain-dependent action of nomifensine. Eur J Neurosci 40:2320-8