Homer proteins regulate sensitivity to cocaine.
Drug addiction involves complex interactions between pharmacology and learning in genetically susceptible individuals. Members of the Homer gene family are regulated by acute and chronic cocaine administration. Here, we report that deletion of Homer1 or Homer2 in mice caused the same increase in sensitivity to cocaine-induced locomotion, conditioned reward, and augmented extracellular glutamate in nucleus accumbens as that elicited by withdrawal from repeated cocaine administration. Moreover, adeno-associated virus-mediated restoration of Homer2 in the accumbens of Homer2 KO mice reversed the cocaine-sensitized phenotype. Further analysis of Homer2 KO mice revealed extensive additional behavioral and neurochemical similarities to cocaine-sensitized animals, including accelerated acquisition of cocaine self-administration and altered regulation of glutamate by metabotropic glutamate receptors and cystine/glutamate exchange. These data show that Homer deletion mimics the behavioral and neurochemical phenotype produced by repeated cocaine administration and implicate Homer in regulating addiction to cocaine.
Szumlinski
Karen K
KK
Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, SC 29425, USA. szumlink@musc.edu
Dehoff
Marlin H
MH
Kang
Shin H
SH
Frys
Kelly A
KA
Lominac
Kevin D
KD
Klugmann
Matthias
M
Rohrer
Jason
J
Griffin
William
W
Toda
Shigenobu
S
Champtiaux
Nicolas P
NP
Berry
Thomas
T
Tu
Jian C
JC
Shealy
Stephanie E
SE
During
Matthew J
MJ
Middaugh
Lawrence D
LD
Worley
Paul F
PF
Kalivas
Peter W
PW
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000235:genetics / Q000378:metabolism*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000378:metabolism; D000072233:Homer Scaffolding Proteins; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D012646:Self Administration
D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; C000606623:Homer1 protein, mouse; C000606625:Homer2 protein, mouse; D018698:Glutamic Acid; D003042:Cocaine