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Cocaine- and Extinction-Induced Neuroplasticity in AMPA Receptors Regulate

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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Cocaine- and Extinction-Induced Neuroplasticity in AMPA Receptors Regulate

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  1. 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

  2. From PfC, hippocampus, amygdala, and thalamus From PfC and amygdala Glu Glu White et al., 1995 Thomas et al., 2001 AMPARs LTP AMPARs LTD NAc Propensity for Cocaine-Seeking Behavior? 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

  3. Prokaryotic sequences HSV-derived sequences GluR1-derived sequences packaging/ cleaving AmpR SV-40 Poly A Ori Ori S IE 4/5 Promoter Inserted Transgene Pore-dead Q582E PKC/CaMKII-resistant S831A PKA-resistant S845A 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

  4. NAc Glutamatergic Deficits in Cocaine Addiction Hipp PfC Behavioral Disinhibition DA NAc DA VTA DA Incentive Motivation • 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)

  5. mRNA Levels w/o levers Ctrl WD EXT Ctrl GluR1 50% 61% 78% GluR2 56% 57% 64% Sutton et al., 2003

  6. Cocaine-Seeking Behavior GluR1 Protein Levels *** p < 0.001 % ∆ from control p = 0.027 Extinction Level No EXT Partial EXT Full EXT *** p = 0.03 % ∆ from control Cue-Induced Reinstatement Low RSTMT High RSTMT Drug-paired lever responses Sutton et al., 2003

  7. HSV-GluR1/R2 reduces cocaine only Self-Administration Extinction Day 1 Extinction Latency Test days Cocaine injections/4 hrs Drug-paired lever Sham HSV-LacZ HSV-GluR1 HSV-GluR2 Intra-NAc HSV Infusions Hour Test day Sham (14) HSV-LacZ (13) HSV-GluR1 (14) HSV-GluR2 (11) Cocaine Extinction Sutton et al., 2003

  8. 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

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