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.
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| Parker, Jones G; Zweifel, Larry S; Clark, Jeremy J et al. (2010) Absence of NMDA receptors in dopamine neurons attenuates dopamine release but not conditioned approach during Pavlovian conditioning. Proc Natl Acad Sci U S A 107:13491-6 |
| Zweifel, Larry S; Parker, Jones G; Lobb, Collin J et al. (2009) Disruption of NMDAR-dependent burst firing by dopamine neurons provides selective assessment of phasic dopamine-dependent behavior. Proc Natl Acad Sci U S A 106:7281-8 |
| Zweifel, Larry S; Argilli, Emanuela; Bonci, Antonello et al. (2008) Role of NMDA receptors in dopamine neurons for plasticity and addictive behaviors. Neuron 59:486-96 |
