Accumbens Homer2 overexpression facilitates alcohol-induced neuroplasticity in C57BL/6J mice.
Homer proteins are integral components of the postsynaptic density that are necessary for alcohol-induced neuroplasticity within the nucleus accumbens (NAC). In this report, we describe the effects of chronic alcohol consumption upon NAC Homer expression and investigate the functional consequences of mimicking the alcohol-induced changes in Homer expression vis-à-vis alcohol-induced changes in NAC neurochemistry and behavior. Chronic alcohol consumption under continuous access (3 months; daily intake approximately 11.2+/-1.5 g/kg/day) produced a robust increase in NAC Homer2 protein levels that was apparent at 2 days, 2 weeks, and 2 months following withdrawal from alcohol drinking. The increased Homer2 expression was accompanied by a less enduring elevation in total mGluR1 and NR2b levels that were evident at 2 days and 2 weeks but not at the 2-month time point. Mimicking the alcohol-induced increase in Homer2 levels by viral transfection of NAC neurons in alcohol-preferring C57BL/6J inbred mice enhanced behavioral output for alcohol reinforcement and increased alcohol intake under both preprandial and postprandial conditions. Moreover, NAC Homer2 overexpression facilitated the expression of an alcohol-conditioned place preference, as well as the development of motor tolerance. Finally, NAC Homer2 overexpression facilitated NAC glutamate and dopamine release following an acute alcohol injection and augmented alcohol-induced dopamine and glutamate sensitization, but did not affect NAC gamma-aminobutyric acid levels. Thus, an upregulation in NAC mGluR-Homer2-N-methyl-D-aspartic acid receptor signaling appears to be an important molecular adaptation to alcohol that promotes neuroplasticity facilitating motivational drive for alcohol and the development of alcoholism-related behaviors.
Szumlinski
Karen K
KK
Department of Psychology, Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA 93106-9660, USA. szumlinski@psych.ucsb.edu
Ary
Alexis W
AW
Lominac
Kevin D
KD
Klugmann
Matthias
M
Kippin
Tod E
TE
D000428:Alcohol Drinking / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001522:Behavior, Animal; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage*; D005786:Gene Expression Regulation / Q000187:drug effects*; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D000072233:Homer Scaffolding Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects*; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism; D012054:Reinforcement, Psychology; D013997:Time Factors; D014161:Transduction, Genetic
D002352:Carrier Proteins; D002492:Central Nervous System Depressants; D000072233:Homer Scaffolding Proteins; C000606625:Homer2 protein, mouse; D018094:Receptors, Metabotropic Glutamate; D049452:Green Fluorescent Proteins; D000431:Ethanol