Role of NMDA receptors in dopamine neurons for plasticity and addictive behaviors.
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.
Zweifel
Larry S
LS
Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. larryz@u.washington.edu
Argilli
Emanuela
E
Bonci
Antonello
A
Palmiter
Richard D
RD
D000818:Animals; D016739:Behavior, Addictive / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D001522:Behavior, Animal; D002352:Carrier Proteins / Q000235:genetics; D003042:Cocaine / Q000494:pharmacology; D004298:Dopamine / Q000172:deficiency / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011597:Psychomotor Performance / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000166:cytology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; C121673:Gprin1 protein, mouse; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C493215:Slc6a3 protein, mouse; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D014446:Tyrosine 3-Monooxygenase; D003042:Cocaine; D004298:Dopamine