Genetic Dissection of Brain Reward Circuits

Summary

Principal Investigator: Larry S Zweifel
Abstract: One of the major pathways thought to be important for behavioral responses to natural rewards and drugs of abuse is the mesocorticolimbic dopamine (DA) circuit. Stable alterations within this circuit that lead to drug seeking behavior are thought to involve signaling through the NMDA-type glutamate receptor (NMDAR), however virtually nothing is known about the cell-specific requirements of this signal transduction cascade within DA neurons. To study the cell-specific requirements of NMDAR signaling mice which lack the functional subunit of NMDAR, NR1, within DA neurons will be studied. A new mouse model that will allow for the cell-specific, reversible inactivation of neural activity will also be generated. This approach, based on the chemical dimerization and inactivation of a protein critical for neurotransmitter release, will advance our understanding of the activity-dependence of neurons within reward pathways required for addiction. Attaining an enhanced understanding of the neural mechanisms and circuitry of addiction will hopefully lead to better treatments for individuals who suffer from addiction and lead to the design of Pharmaceuticalsto treat chronic severe pain and other debilitating illnesses without fear of developing dependence.
Funding Period: 2007-09-01 - 2009-08-31
more information: NIH RePORT

Top Publications

  1. pmc Role of NMDA receptors in dopamine neurons for plasticity and addictive behaviors
    Larry S Zweifel
    Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
    Neuron 59:486-96. 2008
  2. pmc Disruption of NMDAR-dependent burst firing by dopamine neurons provides selective assessment of phasic dopamine-dependent behavior
    Larry S Zweifel
    Department of Psychology, University of Washington, Seattle, WA 98195, USA
    Proc Natl Acad Sci U S A 106:7281-8. 2009
  3. pmc Absence of NMDA receptors in dopamine neurons attenuates dopamine release but not conditioned approach during Pavlovian conditioning
    Jones G Parker
    Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle WA 98195, USA
    Proc Natl Acad Sci U S A 107:13491-6. 2010
  4. pmc A behavioral genetics approach to understanding D1 receptor involvement in phasic dopamine signaling
    Valerie Z Wall
    Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA
    Mol Cell Neurosci 46:21-31. 2011

Detail Information

Publications4

  1. pmc Role of NMDA receptors in dopamine neurons for plasticity and addictive behaviors
    Larry S Zweifel
    Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
    Neuron 59:486-96. 2008
    ..These findings provide evidence for a role of NMDAR signaling in DA neurons for specific behavioral modifications associated with drug seeking behaviors...
  2. pmc Disruption of NMDAR-dependent burst firing by dopamine neurons provides selective assessment of phasic dopamine-dependent behavior
    Larry S Zweifel
    Department of Psychology, University of Washington, Seattle, WA 98195, USA
    Proc Natl Acad Sci U S A 106:7281-8. 2009
    ....
  3. pmc Absence of NMDA receptors in dopamine neurons attenuates dopamine release but not conditioned approach during Pavlovian conditioning
    Jones G Parker
    Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle WA 98195, USA
    Proc Natl Acad Sci U S A 107:13491-6. 2010
    ....
  4. pmc A behavioral genetics approach to understanding D1 receptor involvement in phasic dopamine signaling
    Valerie Z Wall
    Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA
    Mol Cell Neurosci 46:21-31. 2011
    ..However, the D1 receptor likely has additional roles beyond those of phasic dopamine detection, because D1 receptor knockout mice have deficits in addition to what has been observed in mice with reduced phasic dopamine release...