Activation of postsynaptic nAChRs increases noise

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Synaptic Mechanisms Underlying Nicotine-Induced
Excitation of Brain Reward Areas
Daniel McGehee, PhD University of
Chicago Department of Anesthesia Critical
Care Committee on Neurobiology Committee on Cell
Physiology
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Nicotiana tobacum
(North, Central, and South America) Active
Component Nicotine Leaves 0.5-9 nicotine dry
weight 40-60 mg lethal in humans 430,000
deaths/ year in U.S. are from smoking related
causes 150 billion in medical costs and lost
productivity per year 75 of adult smokers
want to quit Only a few percent succeed.
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Predicted stoichiometry of neuronal nAChRs
Subunits a7
a4b2 predominate in
CNS Antagonists MLA, aBGT b2 -
DHbE All - MEC Agonists Cholin
e b2 - epibatidine PCa/PNa 20
1.5
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The Dopamine Reward System
Horizontal slice preparation
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Where are the nAChRs that enhance DA release?
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Dopamine cells in the VTA express Ih
-60 mV
-120 mV
50 pA
250 ms
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Nicotine enhances excitatory inputs to VTA DA
neurons
1 mM nicotine
DNQX
EPSC amplitude ()
control
25 pA
nicotine
10 ms
Time (s)
MLA
Control
1 mM nicotine
1 mM nicotine
EPSCs / 5 sec
1 mM nicotine
Time (s)
Time (s)
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Presynaptic a7 nAChRs enhance glutamate release
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Pairing of pre- and postsynaptic activity induces
LTP in VTA
Pairing protocol
1 second
post
EPSC amplitude ()
pre
Time (min)
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Pairing nicotine with post-synaptic activation
induces LTP
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Presynaptic a7 nAChRs contribute to LTP induction
in VTA
12
Nicotine increases spontaneousGABA transmission
in the VTA
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GABA transmission is modified by non-a7 nAChRs
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Nicotine enhances and then depresses GABAergic
synaptic transmission
15
Low nicotine concentrations desensitize nAChRs
on GABA neurons
1 mM nicotine
250 nM nicotine
Effect of 1 mM nicotine ()
IPSCs per 5 sec


Time (s)
nicotine (nM)
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Timecourse of nicotine effects in the brain
reward areas during smoking
LTP
Adapted from Henningfield et al 1993
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PPTg
X
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(No Transcript)
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Bupropion

• An atypical antidepressant recently approved as a
  smoking cessation aid.
• Mechanism of action is unknown.
• Weak DAT inhibitor.
• Broad-spectrum antagonist of nAChRs.

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Bupropion Blocks nAChRs on VTA DA Neurons
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Bupropion Blocks nAChR Modulation of Excitatory
Input to VTA DA Neurons
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Bupropion Blocks nAChR Modulation of Inhibitory
Input to VTA DA Neurons
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Bupropion Also Reduces the Basal Frequency of
Spontaneous IPSCs
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Buproprion effects are not due to DAT inhibition
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Bupropion limits nAChR activity within brain
reward pathways
X
X
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Age-Dependent Differences in Susceptibility Drug
Abuse
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Adults Show Lower Sensitivity to Nicotine Than
Young Rats
EPSC Response to 1mM Nicotine
IPSC Response to 1mM Nicotine
400
600
500
300
400

Frequency ( Control)
Frequency ( Control)
200
300

200
100
100
0
0
Pup
Adult
Adult
Pup
120
70
60
100
50
80
40
Response Prevalence
Response Prevalence
60
30
40
20
20
10
0
0
Adult
Pup
Adult
Pup
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The McGehee Lab
Huib Mansvelder Jonathan Genzen J. Russel
Keath Edward Lin Lindy Nakamura Amiinah
Kung Wendy Chan Dan Locks Hong Cheng Katrina
Oppen Greg Sobolski Wil Van Cleve
Dan McGehee Zara Fettig Mike Iacoviello Ben Chang
Ben Cho Michelle Madonia Sonya Dave Funding
from NIDA, NINDS and The Brain Research
Foundation