Abstract
A single exposure to drugs of abuse produces an NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) of AMPA receptor (AMPAR) currents in DA neurons; however, the importance of LTP for various aspects of drug addiction is unclear. To test the role of NMDAR-dependent plasticity in addictive behavior, we genetically inactivated functional NMDAR signaling exclusively in DA neurons (KO mice). Inactivation of NMDARs results in increased AMPAR-mediated transmission that is indistinguishable from the increases associated with a single cocaine exposure, yet locomotor responses to multiple drugs of abuse were unaltered in the KO mice. The initial phase of locomotor sensitization to cocaine is intact; however, the delayed sensitization that occurs with prolonged cocaine withdrawal did not occur. Conditioned behavioral responses for cocaine-testing environment were also absent in the KO mice. These findings provide evidence for a role of NMDAR signaling in DA neurons for specific behavioral modifications associated with drug seeking behaviors.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Behavior, Addictive / chemically induced
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Behavior, Addictive / genetics
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Behavior, Addictive / physiopathology*
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Behavior, Animal
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Carrier Proteins / genetics
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Cocaine / pharmacology
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Dopamine / deficiency
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Dopamine / metabolism*
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Dopamine Plasma Membrane Transport Proteins / genetics
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Exploratory Behavior / drug effects
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Exploratory Behavior / physiology
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In Vitro Techniques
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Locomotion / drug effects
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Locomotion / genetics
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Luminescent Proteins / genetics
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Luminescent Proteins / metabolism
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Membrane Potentials / radiation effects
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Mice
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Mice, Transgenic
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N-Methylaspartate / pharmacology
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Nerve Tissue Proteins / genetics
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Neuronal Plasticity / physiology*
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Neurons / physiology*
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Patch-Clamp Techniques
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Psychomotor Performance / physiology
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Receptors, N-Methyl-D-Aspartate / physiology*
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Tyrosine 3-Monooxygenase / metabolism
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Ventral Tegmental Area / cytology
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology
Substances
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Carrier Proteins
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Dopamine Plasma Membrane Transport Proteins
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Gprin1 protein, mouse
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Luminescent Proteins
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Nerve Tissue Proteins
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Receptors, N-Methyl-D-Aspartate
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Slc6a3 protein, mouse
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N-Methylaspartate
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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Tyrosine 3-Monooxygenase
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Cocaine
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Dopamine