Cocaine and ExtinctionInduced

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Cocaine- and Extinction-Induced Neuroplasticity
in AMPA Receptors Regulate Drug-Seeking Behavior
DAVID W. SELF, PH.D. Associate Professor of
Psychiatry and Neuroscience The Seay Center for
Basic and Applied Research in Psychiatric
Illness Southwestern Medical Center
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Drug-Induced Neuroplasticity in the Mesolimbic
Dopamine System
DA
VTA
White et al., 1995 Zhang et al., 1997 Ungless et
al., 2001 Saal et al., 2003
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Herpes Simplex (HSV) Viral Vectorfor In Vivo
GluR1 Over-Expression
HSV-lacZ HSV-GluR1 WT HSV-GluR1 S845A HSV-GluR1
S831A HSV-GluR1 Q582E HSV-GluR2 WT
Adapted from Bredt and Nicoll, 2003
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NAc Glutamatergic Deficits in Cocaine Addiction

• Reduced Excitatory
• Input to NAc
• Hypofrontality in humans (Volkow et al., 1992,
  2000 London et al., 1999)
• Reduced basal extracellular glutamate (Keys
  et al., 1998 Bell et al., 2000)
• Reduced AMPA response
• (White et al., 1995)
• LTD in PfC-NAc synapses w/sensitization (Thomas
  et al., 2001)

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mRNA Levels
Sutton et al., 2003
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Cocaine-Seeking Behavior
Drug-paired lever responses
Sutton et al., 2003
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HSV-GluR1/R2 reduces cocaine only
Cocaine
Extinction
Sutton et al., 2003
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Acknowledgements
VTA Studies Kwang-Ho Choi Scott Edwards
Collaborators Southwestern Med. Ctr. Lisa
Monteggia Amelia Eisch Harvard
University Rachael Neve
NAc Studies Ryan Bachtell Kwang-Ho Choi Mike
Sutton Eric Schmidt Kim Whisler
Supported by NIDA grants DA 10460, DA 08227, DA
13796, and the Wesley Gilliland Professorship in
Biomedical Research