CREB modulates the functional output of nucleus accumbens neurons: a critical role of N-methyl-D-aspartate glutamate receptor (NMDAR) receptors.
Nucleus accumbens (NAc) medium spiny neurons cycle between two states, a functionally inactive downstate and a functionally active upstate. Here, we show that activation of the transcription factor cAMP-response element-binding protein (CREB), a common molecular response to several drugs of abuse, increases both duration of the upstate and action potential firing during the upstate. This effect of CREB is mediated by enhanced N-methyl-d-aspartate glutamate receptor (NMDAR) function: increased CREB activity increases both NMDAR-mediated synaptic currents and surface level of NMDARs, while inhibition of NMDARs abolishes the effect of CREB on upstate duration. Furthermore, mimicking the effect of CREB by pharmacological enhancement of NMDAR function in the NAc in vivo suppressed novelty- and cocaine-elicited locomotor activity. These findings suggest that by enhancing NMDAR-mediated synaptic transmission, CREB activation promotes the proportion of time NAc neurons spend in the upstate. This effect, along with the CREB enhancement of NAc membrane excitability (Dong, Y., Green, T., Saal, D., Marie, H., Neve, R., Nestler, E. J., and Malenka, R. C. (2006) Nat. Neurosci. 9, 475-477), may counteract drug-induced maladaptations in the NAc and thus ameliorate the addictive state.
Program in Neuroscience, Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Wegner 205, Pullman, WA 99164, USA.
Yanhua H
YH
Huang
Ying
Y
Lin
Travis E
TE
Brown
Ming-Hu
MH
Han
Daniel B
DB
Saal
Rachael L
RL
Neve
R Suzanne
RS
Zukin
Barbara A
BA
Sorg
Eric J
EJ
Nestler
Robert C
RC
Malenka
Yan
Y
Dong
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004594:Electrophysiology; D019706:Excitatory Postsynaptic Potentials; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000378:metabolism; D009714:Nucleus Accumbens / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D046509:Tissue Culture Techniques; D014162:Transfection
C508137:Creb1 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins