Elevated BDNF after cocaine withdrawal facilitates LTP in medial prefrontal cortex by suppressing GABA inhibition.
Medial prefrontal cortex (mPFC) is known to be involved in relapse after cocaine withdrawal, but the underlying cellular mechanism remains largely unknown. Here, we report that after terminating repeated cocaine exposure in rats, a gradual increase in the expression of brain-derived neurotrophic factor (BDNF) in the mPFC facilitates activity-induced long-term potentiation (LTP) of excitatory synapses on layer V pyramidal neurons. This enhanced synaptic plasticity could be attributed to BDNF-induced suppression of GABAergic inhibition in the mPFC by reducing the surface expression of GABA(A) receptors. The BDNF effect was mediated by BDNF-TrkB-phosphatase 2A signaling pathway. Downregulating TrkB expression bilaterally in the mPFC reduced the locomotor hypersensitivity to cocaine 8 days after cocaine withdrawal. Thus, elevated BDNF expression after cocaine withdrawal sensitizes the excitatory synapses in the mPFC to undergo activity-induced persistent potentiation that may contribute to cue-induced drug craving and drug-seeking behavior.
Lu
Hui
H
Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
Cheng
Pei-Lin
PL
Lim
Byung Kook
BK
Khoshnevisrad
Nina
N
Poo
Mu-Ming
MM
D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003975:Diazepam / Q000494:pharmacology; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D047468:Immunoprecipitation / Q000379:methods; D066298:In Vitro Techniques; D026121:Indole Alkaloids / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000235:genetics / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D017397:Prefrontal Cortex / Q000166:cytology* / Q000187:drug effects; D017966:Pyramidal Cells / Q000187:drug effects* / Q000502:physiology; D011724:Pyridazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D014162:Transfection / Q000379:methods; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D018756:GABA Antagonists; D018757:GABA Modulators; D026121:Indole Alkaloids; D018377:Neurotransmitter Agents; D011724:Pyridazines; D011963:Receptors, GABA-A; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D005680:gamma-Aminobutyric Acid; C049985:staurosporine aglycone; C049853:gabazine; D020813:Receptor, trkB; D003042:Cocaine; D003975:Diazepam
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