Genotypic differences in mesolimbic enkephalin gene expression in DBA/2J and C57BL/6J inbred mice.
The DBA/2J and C57BL/6J (herein referred to as DBA and C57) inbred mouse strains exhibit low and high predispositions for voluntary ethanol consumption, respectively, but the neurobiological basis underlying this differential drug vulnerability remains poorly understood. Comparison of endogenous brain proenkephalin gene expression showed the C57 mouse, compared to the DBA mouse, had lower preproenkephalin mRNA abundance, proenkephalin concentration and processed [Met5]enkephalin-immunoreactive peptide levels in the mid brain. No strain differences in enkephalin gene expression was observed in the striatum, hypothalamus, or medulla pons. Neurochemical analysis of C57 mice, following high voluntary ethanol consumption (approximately 17 g/kg/day), revealed markedly higher enkephalin gene expression in the striatum and mid brain compared to ethanol-naive animals. These findings suggested that mesolimbic enkephalin is augmented following ethanol consumption, and that endogenous low enkephalin biosynthesis may be associated with an increased vulnerability for ethanol abuse. However, the neurobiological basis of this behaviour may not be quite this simple. C57 mice pretreated with the dopamine receptor agonist, bromocriptine, had reduced striatum and mid brain preproenkephalin mRNA levels, and showed a 41% lower voluntary ethanol consumption compared to controls. We conclude that functional connectivity exists between enkephalin and dopamine systems, and although low mesolimbic enkephalin may predispose to high ethanol preference, dopamine is a more important determinant than enkephalin in the hierarchy of neurotransmitter pathways that mediate the increased vulnerability for ethanol consumption in the C57 mouse.
Ng
G Y
GY
Department of Pharmacology, University of Toronto, Ontario, Canada.
O'Dowd
B F
BF
George
S R
SR
D000428:Alcohol Drinking / Q000235:genetics / Q000523:psychology; D000818:Animals; D015152:Blotting, Northern; D001971:Bromocriptine / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D004744:Enkephalin, Methionine / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D004745:Enkephalins / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D005838:Genotype; D008032:Limbic System / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D012333:RNA, Messenger / Q000096:biosynthesis; D011863:Radioimmunoassay; D017448:Receptors, Dopamine D2 / Q000819:agonists; D013045:Species Specificity
D018491:Dopamine Agonists; D004745:Enkephalins; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D001971:Bromocriptine; D004744:Enkephalin, Methionine