Alterations in dopamine transmission occur during drug abuse and addiction. To understand these changes, it is necessary to first understand the basic physiology that underlies dopamine transmission.
The aim of this Pathway to Independence Award (K99/ROO) proposal is to investigate the mechanisms of dopamine transmission while providing the candidate (Dr Christopher Ford) with the necessary mentored training in electrophysiological and electrochemical techniques. The applicant's long-term career goal is to develop into an independent investigator studying the molecular and cellular basis of addiction. To meet this goal, this proposal is designed to (1) provide the candidate with the technical and theoretical training required to determine how dopamine mediates transmission in the ventral tegmental area (VTA), and (2) provide the candidate with the career-development training required to establish his own independent research career as an R01-funded assistant professor. The career development plan involves mentorship by a highly established drug abuse researcher (Dr John T Williams) in electrophysiological and electrochemical techniques. Combining these two tools to examine dopamine transmission has not been performed to date and as such has the potential to provide a unique opportunity for the candidate to initiate an independent career. The central aim of this proposal is to determine the relationship between extracellular dopamine and its physiological consequences. The objective during the mentored phase will be to determine the mechanisms regulating dopamine transmission. The hypothesis to be tested is that dopamine mediates transmission in the VTA in a tightly regulated, synaptic manner. The objective during the independent phase will be to define the concentration and duration of dopamine mediating transmission. The hypothesis being that transient, high concentrations of dopamine mediate transmission. A lack of knowledge of the basic mechanisms of dopamine transmission has hindered progress towards determining how transmission becomes dysregulated during the course of drug addiction. Thus this work has the potential to identity and direct new strategies to treat drug abuse and addiction.
Determining the mechanisms by which dopamine mediates transmission is a key first step to providing the framework necessary for understanding how this system is altered as a result of chronic drug use. A better understanding of the events linking dopamine release to its physiological actions will be significant as it has the potential to direct new strategies for the treatment of drug abuse and addiction.
|Ford, C P (2014) The role of D2-autoreceptors in regulating dopamine neuron activity and transmission. Neuroscience 282:13-22|
|Neve, K A; Ford, C P; Buck, D C et al. (2013) Normalizing dopamine D2 receptor-mediated responses in D2 null mutant mice by virus-mediated receptor restoration: comparing D2L and D2S. Neuroscience 248:479-87|
|Courtney, Nicholas A; Mamaligas, Aphroditi A; Ford, Christopher P (2012) Species differences in somatodendritic dopamine transmission determine D2-autoreceptor-mediated inhibition of ventral tegmental area neuron firing. J Neurosci 32:13520-8|
|Gantz, Stephanie C; Ford, Christopher P; Neve, Kim A et al. (2011) Loss of Mecp2 in substantia nigra dopamine neurons compromises the nigrostriatal pathway. J Neurosci 31:12629-37|
|Ford, Christopher P; Gantz, Stephanie C; Phillips, Paul E M et al. (2010) Control of extracellular dopamine at dendrite and axon terminals. J Neurosci 30:6975-83|
|Bender, Kevin J; Ford, Christopher P; Trussell, Laurence O (2010) Dopaminergic modulation of axon initial segment calcium channels regulates action potential initiation. Neuron 68:500-11|
|Ford, Christopher P; Phillips, Paul E M; Williams, John T (2009) The time course of dopamine transmission in the ventral tegmental area. J Neurosci 29:13344-52|