The Edinger-Westphal-lateral septum urocortin pathway and its relationship to alcohol consumption.
Identifying and characterizing brain regions regulating alcohol consumption is beneficial for understanding the mechanisms of alcoholism. To this aim, we first identified brain regions changing in expression of the inducible transcription factor c-Fos in the alcohol-preferring C57BL/6J (B6) and alcohol-avoiding DBA/2J (D2) mice after ethanol consumption. Drinking a 5% ethanol/10% sucrose solution in a 30 min limited access procedure led to induction of c-Fos immunoreactivity in urocortin (Ucn)-positive cells of the Edinger-Westphal nucleus (EW), suppression of c-Fos immunoreactivity in the dorsal portion of the lateral septum (LS) of both strains of mice, and strain-specific suppression in the intermediate portion of the LS and the CA3 hippocampal region. Because the EW sends Ucn projections to the LS, and B6 and D2 mice differ dramatically in EW Ucn expression, we further analyzed the Ucn EW-LS pathway using several genetic approaches. We find that D2 mice have higher numbers of Ucn-immunoreactive processes than B6 mice in the LS and that consumption of ethanol/sucrose in the F2 offspring of a B6D2 intercross positively correlates with Ucn immunoreactivity in the EW and negatively correlates with Ucn immunoreactivity in the LS. In agreement with these findings, we find that alcohol-avoiding male B6.D2 Alcp1 line 2.2 congenic mice have lower Ucn immunoreactivity in the EW than male B6.B6 mice. Finally, we also find that HAP mice, selectively bred for high alcohol preference, have higher Ucn immunoreactivity in EW, than LAP mice, selectively bred for low alcohol preference. Taken together, these studies provide substantial evidence for involvement of the EW-LS Ucn pathway in alcohol consumption.
Bachtell
Ryan K
RK
Department of Behavioral Neuroscience, Oregon Health and Science University and Portland Alcohol Research Center, Portland, Oregon 97239, USA.
Weitemier
Adam Z
AZ
Galvan-Rosas
Agustin
A
Tsivkovskaia
Natalia O
NO
Risinger
Fred O
FO
Phillips
Tamara J
TJ
Grahame
Nicholas J
NJ
Ryabinin
Andrey E
AE
D000428:Alcohol Drinking / Q000503:physiopathology*; D000437:Alcoholism / Q000503:physiopathology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002452:Cell Count; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D003433:Crosses, Genetic; D000431:Ethanol / Q000008:administration & dosage; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D009434:Neural Pathways / Q000503:physiopathology*; D010641:Phenotype; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D012646:Self Administration; D020665:Septum of Brain / Q000473:pathology / Q000503:physiopathology*; D012737:Sex Factors; D054832:Urocortins
D016760:Proto-Oncogene Proteins c-fos; D054832:Urocortins; D000431:Ethanol; D003346:Corticotropin-Releasing Hormone