Homer isoforms differentially regulate cocaine-induced neuroplasticity.
Homer proteins modulate neuroplasticity in excitatory synapses and are dynamically regulated by cocaine. Whereas acute cocaine elevates immediate-early gene (short) isoforms of Homer1 in the nucleus accumbens, withdrawal from repeated cocaine administration downregulates the expression of constitutive Homer1 isoforms. The present study determined whether or not this downregulation in constitutive Homer expression in the accumbens is necessary for enduring alterations in cocaine-induced changes in the brain and behavior. The long vs short Homer isoforms were overexpressed in the rat nucleus accumbens during drug abstinence, and the adaptations elicited by repeated cocaine on glutamate transmission and motor behavior were measured. It was found that both chronic and acute overexpression of constitutive, but not short, Homer isoforms abolished cocaine-induced sensitization of locomotor hyperactivity and prevented the development of glutamate abnormalities in the accumbens, including the reduction in basal extracellular glutamate content and the sensitized glutamate response to a subsequent cocaine challenge injection. Together, these data indicate that the enduring reduction of long Homer isoforms in the nucleus accumbens of cocaine-withdrawn rats is necessary for the expression of cocaine-induced neuroplasticity.
Szumlinski
Karen K
KK
Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA. szumlinski@psych.ucsb.edu
Abernathy
Kenneth E
KE
Oleson
Erik B
EB
Klugmann
Matthias
M
Lominac
Kevin D
KD
He
Dao-Yao
DY
Ron
Dorit
D
During
Matthew
M
Kalivas
Peter W
PW
D000779:Anesthetics, Local / Q000008:administration & dosage*; D000818:Animals; D001522:Behavior, Animal; D002352:Carrier Proteins / Q000145:classification / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000378:metabolism* / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism; D000072233:Homer Scaffolding Proteins; D008297:Male; D051379:Mice; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000096:biosynthesis; D013997:Time Factors
D000779:Anesthetics, Local; D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; C000606623:Homer1 protein, mouse; C000606624:Homer1 protein, rat; D020033:Protein Isoforms; D011994:Recombinant Proteins; D018698:Glutamic Acid; D003042:Cocaine; D004298:Dopamine