The suppressive effect of an intra-prefrontal cortical infusion of BDNF on cocaine-seeking is Trk receptor and extracellular signal-regulated protein kinase mitogen-activated protein kinase dependent.
Cocaine-mediated neuroadaptations in the prefrontal cortical-nucleus accumbens pathway underlie drug-seeking in animals with a cocaine self-administration (SA) history. Neuroplasticity in the cortico-accumbens pathway is regulated, in part, by the expression and availability of neurotrophic factors, such as BDNF. We have previously demonstrated that infusion of BDNF into the dorsomedial prefrontal cortex (dmPFC) immediately after the last of 10 cocaine SA sessions attenuates contextual, cue- and cocaine prime-induced reinstatement of cocaine-seeking (Berglind et al., 2007) and normalizes cocaine-induced disruption of glutamatergic transmission in the nucleus accumbens (Berglind et al., 2009). In the present study, the suppressive effect of intra-dmPFC BDNF on cocaine-seeking is shown to depend on Trk receptor-mediated activation of extracellular signal-regulated kinase (ERK) signaling in the dmPFC. The tyrosine kinase inhibitor, K252a, and the mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor, U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene), prevented BDNF's suppressive effects on cocaine-seeking. Vehicle-infused rats with a cocaine SA history showed significant decreases in ERK and cyclic AMP response element binding protein (CREB), but not Akt, phosphorylation after the final cocaine SA session that were reversed by intra-dmPFC BDNF. Additionally, BDNF's ability to normalize cocaine-mediated decreases in ERK and CREB phosphorylation was blocked by U0126, demonstrating that ERK/MAPK activation mediated the behavioral effects. This study elucidates a mechanism whereby BDNF/TrkB (tropomyosin receptor kinase B) activates ERK-regulated CREB phosphorylation in the dmPFC to counteract the neuroadaptations induced by cocaine SA and subsequent relapse to cocaine-seeking.
Department of Neurosciences and Neurobiology of Addiction Research Center, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Timothy W
TW
Whitfield
Xiangdang
X
Shi
Wei-Lun
WL
Sun
Jacqueline F
JF
McGinty
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D003042:Cocaine / Q000008:administration & dosage*; D003463:Cues; D058999:Drug-Seeking Behavior / Q000187:drug effects* / Q000502:physiology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009042:Motivation / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000378:metabolism*; D012646:Self Administration
D019208:Brain-Derived Neurotrophic Factor; D020813:Receptor, trkB; D020928:Mitogen-Activated Protein Kinases; D003042:Cocaine
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