Genotypic differences in brain dopamine receptor function in the DBA/2J and C57BL/6J inbred mouse strains.
The propensity for high ethanol preference and high ethanol consumption (herein referred to as ethanol abuse) may be a consequence of a congenital deficit in central dopaminergic activity. This hypothesis was examined in the ethanol-avoiding DBA/2J (DBA) and ethanol-preferring C57BL/6J (C57) inbred mouse strains. Endogenous dopamine D1 and D2 receptor functions differed between strains in the nigrostriatal/mesolimbic dopamine system. At the level of the forebrain, the C57 mouse exhibited higher dopamine D1 and D2 receptor mRNA abundance and elevated dopamine D1 and D2 receptor densities in the striatum compared to DBA mouse. A likely explanation for these observations might be that higher dopamine receptor gene expression could be a consequence of low synaptic dopamine activity. Accordingly, we found higher striatal dopamine-sensitive adenylyl cyclase activity in the C57 mouse. The C57 mouse exhibited an enhanced dopamine D1-D2 receptor link as suggested by an enhanced up-regulation of striatal dopamine D2 receptor mRNA following dopamine D1 receptor blockade with SCH-23390 compared to DBA mouse. At the level of the mesencephalon and hind brain, the C57 mouse had lower dopamine D2 receptor mRNA in the medulla pons, and correspondingly lower midbrain and medulla pons dopamine D2 receptor densities. Adenylyl cyclase activities in these regions were similar to the DBA mouse suggesting that the coupling of these dopamine D2 receptors could be a factor regulating their function. Strain differences in dopamine D2 receptor function were also observed in the diencephalic dopamine system. The C57 mouse exhibited lower dopamine D2 receptor density in the hippocampus and lower dopamine D2 receptor mRNA abundance and lower adenylyl cyclase activity in the hypothalamus. Changes in brain dopamine receptor gene expression following ethanol intake inferred an increase in the activities of central dopamine pathways in both the DBA and C57 mouse supporting an association between dopamine receptor function and ethanol drinking. These lines of evidence provide a basis for the hypothesis that a genetically determined brain dopaminergic deficit mediated by dopamine D1-D2 receptor mechanisms may be involved in at least a part of the risk for ethanol abuse in the C57 inbred mouse strain.
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Department of Pharmacology, University of Toronto, Ontario, Canada.
O'Dowd
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George
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D000262:Adenylyl Cyclases / Q000378:metabolism; D000437:Alcoholism / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D001552:Benzazepines / Q000378:metabolism; D015152:Blotting, Northern; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D000431:Ethanol / Q000097:blood* / Q000633:toxicity; D005786:Gene Expression Regulation / Q000235:genetics*; D005838:Genotype; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000378:metabolism; D011869:Radioligand Assay; D017447:Receptors, Dopamine D1 / Q000235:genetics* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000378:metabolism; D013045:Species Specificity; D013134:Spiperone / Q000378:metabolism; D015854:Up-Regulation
D001552:Benzazepines; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D000431:Ethanol; D013134:Spiperone; D000262:Adenylyl Cyclases