Strain differences in urocortin expression in the Edinger-Westphal nucleus and its relation to alcohol-induced...

The Edinger-Westphal nucleus is the primary source of urocortin in rodent brain. Mapping of inducible transcription factors has shown that the Edinger-Westphal nucleus is preferentially sensitive to ethanol self-administration. In the present study we have immunohistochemically compared expression of urocortin and c-Fos in naive and ethanol-treated C57BL/6J and DBA/2J mouse inbred strains. We found that C57BL/6J mice possess significantly higher numbers of urocortin-expressing cells in the Edinger-Westphal compared to DBA/2J mice. Subsequent histological analysis confirmed a lower number of large neurons in the DBA/2J Edinger-Westphal nucleus. Surprisingly, despite the differences in structure, no strain differences were observed in the number of c-Fos-containing cells after acute (0.6-4.8 g/kg, i.p.) and repeated (2.4 g/kg, 14 days, one injection/day) administration of ethanol. Double-label immunohistochemistry showed that ethanol-induced c-Fos expression is present in different sets of Edinger-Westphal cells between the strains. Specifically, expression of c-Fos in C57BL/6J mice is preferentially induced in urocortin cells, while c-Fos in DBA/2J mice occurs in a mixed population of cells. Behavioral analysis of the B6D2 F2 intercross, a heterogeneous mouse strain, showed that the number of urocortin cells is positively correlated with basal temperatures and ethanol-induced hypothermia. Involvement of the Edinger-Westphal in alcohol-induced hypothermia is further confirmed by analysis of urocortin cells in the HOT/COLD selected lines. These results provide evidence that C57BL/6J and DBA/2J mice have structural differences in the Edinger-Westphal that can result in activation of different populations of neurons upon alcohol intoxication contributing to differential thermoregulation between these inbred strains.