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NIDA Proteomics Center
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Investigators
> Ralph DiLeone
Phosphoprotein Profile of
Hypothalamic-limbic Circuits Integral to Motivated Behavior and Addiction
Ralph DiLeone, Department of Psychiatry,
Yale University
Addiction burdens our public health system and
provides a dramatic example neural plasticity leading to maladaptive behavior.
The long-term objectives of this proposed research are to understand the changes
in proteins that occur in a key brain area that underlies motivated behavior and
addiction. It is critical that we understand how reward and motivation circuits
of the brain are integrated to develop a more complete view of drug addiction.
Drugs of abuse have profound effects on the mesolimbic dopamine circuit,
including the nucleus accumbens, while the hypothalamus has been better studies
for control over food intake. The neuropeptide melanin-concentrating hormone (MCH)
and its receptor serve as a molecular link between these two well-studied brain
regions. The MCH peptide is produced in the lateral hypothalamus, a region that
has been historically associated with reinforcing behavior, while the receptor
is expressed in the nucleus accumbens. MCH in the nucleus accumbens inhibits
neuronal firing and influences food intake and reward-related behavior. This
proposal seeks to define the molecular mechanisms underlying these powerful
behavioral effects. Specifically, proteomic analysis will allow for
unprecedented sensitivity in detecting key molecular changes in the nucleus
accumbens in response to MCH receptor signaling. The results from the proposed
experiments will shed light on mechanisms of MCH action in the nucleus accumbens
while also serving to provide a model for how neuropeptides regulate complex
animal behaviors such as drug addiction.
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