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NIDA Proteomics Center
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Investigators
> Marina Picciotto
Proteomic Analysis of Nicotinic
Effects on the Mesolimbic Dopamine System
Marina Picciotto, Psychiatry, Pharmacology and Neurobiology,
Yale University
Nicotinic acetylcholine receptors (nAChRs) are expressed in most neurons in the
central and peripheral nervous system. Activation of nAChRs by nicotine can
result in stimulation of many different neurotransmitter systems and result in
many behavioral outcomes. Nicotine activates the mesolimbic dopaminergic (DA)
system, as has been seen with many other drugs of abuse. Indeed, actions of
nicotine on many brain areas may ultimately converge on the mesolimbic DA
system, and/or other systems, to result in the neurochemical changes that lead
to nicotine addiction. The development of nicotine addiction is likely due to
repeated intake of the drug that leads to changes in the brain at many levels
including changes in signal transduction and gene expression. We have shown that
chronic nicotine results in changes in MAP kinase and CREB signaling in
projection regions of the DA neurons and can activate the calcium-dependent
phosphatase calcineurin leading to altered glutamate signaling in VTA and
cortical neurons. We propose two Proteomics Aims: 1) to use iTraq to identify
targets of CREB that are regulated in the DA system following nicotine place
preference in wild type and genetically manipulated mice. These changes will be
correlated with behavioral effects of nicotine to identify the signal
transduction pathways and brain areas most critical for behavioral effects of
nicotine. In addition, these analyses will be carried out on knockout mice
lacking high affinity nAChRs that do not show relevant behavioral responses to
nicotine. This control will help identify signal transduction changes that are
not relevant to some of the behavioral effects of nicotine in models of
reinforcement.; 2) to use LTQ-Orbitrap to identify changes in phosphorylation
state of targets of calcineurin or CaMKI that might be involved in
calcium-mediated signaling downstream of nAChRs. We have identified a role for
calcium signaling in the VTA in locomotor sensitization to repeated nicotine
injection. We would now like to identify substrates for calcium-dependent
phosphatases and kinases that mediate those cellular and behavioral effects. |
