Alterations in dynamics of NAcc medium spiny neuron due to cocaine

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Alterations in dynamics of NAcc medium spiny
neuron due to cocaine

• University of Missouri Columbia
• Wes Smith, John Gall, Satish Nair, Jyotsna Nair
• Medical University of South Carolina
• Peter Kalivas
• First Annual
• Biologically Accurate Modeling Meeting (BAMM)
• 2005

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Neuroplasticity in Addiction

• Neuroplasticity in cocaine addiction is a
  consequence of repeated exposure to the drug,
  genetic predilection and environmental cues.
• Dopamine is crucial for the reward potential of
  the drug in the acute stage of cocaine use.
• With repeated cocaine use, pyramidal cells
  projecting from prefrontal cortex to Nacc have a
  loss of membrane bistability and the lack of up
  state indicating reduced neuronal activity
  (Trantham et al. 2002).

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Neuroplasticity in Addiction(Kalivas, 2005)
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Objectives

• The objective of the reported research is to
  develop a biologically realistic modeling
  framework for the NAcc neuron with the focus here
  being on the altered dynamics in the PFC-NAcc
  glutamatergic pathway due to chronic cocaine
  abuse.
• The model includes the dynamics of the relevant
  ion channels, neurotransmitters, receptors, and
  intracellular processes involved with the cocaine
  pathway, including the switching dynamics between
  the Up/Down states in soma membrane potential
  with glutamate, and modulation of phosphoproteins
  via DA binding.

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Methods

• The compartmentalization of the neuronal cell is
  carried out such that it will contain a central
  spherical soma compartment and four dendritic
  trunks extending from the soma are modeled while
  higher order dendrites are simulated by 5
  compartments stemming from each of the trunks.
•   DA activation only considered two states
  relatively high PKA concentrations, and
  relatively low PKA concentrations.
• There are distal dendrites that have added
  surface area to account for the spines, although
  the density of the iGluRs was still calculated
  solely from the spine surface area per dendrite. 
  
• When Glu is released, all synapses per distal
  dendrite were perfused by 5,000 Glu molecules
  (one vesicle).

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Results

• The activation of the soma via the dendrites is
  shown in the presence of high synaptic DA and low
  synaptic DA. On the left side, the 50 Hz vesicle
  release to all synapses was enough to invoke
  firing in the presence of DA. On the right side,
  the 50 Hz vesicle only instigated an UP state due
  to the lack of synaptic DA. 5 Hz vesicle release
  maintained baseline activation. Prolonged up
  states are observed do to the rate of unbinding
  of the Glu receptors.

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Results
The ability for a 50 Hz pulse of vesicle release
to elicit a somatic action potential depends upon
the presence of synaptic DA and the amount of
neuroplasticity undergone.
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Conclusion

• A model of the Nucleus Accumbens medium spiny
  neuron is modeled to include dynamics of receptor
  binding for the glutamate input, as well as ionic
  channel interactions. In simulation, vesicles
  released from the presynapse, revealing strong
  correlation with observed data for the baseline
  dynamics. The diseased or chronic Nacc neuron
  exhibiting the neuroplastic characteristic of
  dendritic spine growth is modeled. The increased
  level of spine area is seen to cause increased
  instability in the neuron, leading to an increase
  in spontaneous firing, and decreased up state
  robustness.