RATIONALE: Alcohol addiction is a major psychiatric disease, and yet, the underlying molecular adaptations in the brain remain unclear. Recent evidence suggests a functional role for the ras-specific guanine-nucleotide releasing factor 2 (Rasgrf2) in alcoholism. Rasgrf2(-/-) mice consume less alcohol and show entirely absent dopamine responses to an alcohol challenge compared to wild types (WT). OBJECTIVE: In order to further investigate how Rasgrf2 modifies the acute and subchronic effects of alcohol in the brain, we investigated its effects on the noradrenergic and serotonergic systems. METHODS: We measured noradrenaline and serotonin activity in the brain by in vivo microdialysis and RNA expression by chip analysis and RT-PCR after acute and sub-chronic alcohol exposure in Rasgrf2(-/-) and WT mice. RESULTS: In vivo microdialysis showed a significantly reduced noradrenergic response and an absent serotonergic response in the nucleus accumbens (NAcc) and caudate putamen (CPu) after an alcohol challenge in Rasgrf2(-/-) mice. A co-expression analysis showed that there is a high correlation between Rasgrf2 and α2 adrenoceptor RNA expression in the ventral striatum in naïve animals. Accordingly, we further assessed the role of Rasgrf2 in the response of the noradrenergic system to subchronic alcohol exposure. A decrease in β1 adrenoceptor gene expression was seen in Rasgrf2(+/+), but not Rasgrf2(-/-) mice following alcohol exposure. Conversely, alcohol resulted in a decrease in both β2 and α2 adrenoceptor gene expression in knockout but not WT Rasgrf2 mice. CONCLUSIONS: These findings suggest that adaptations in the noradrenergic system contribute to the Rasgrf2 enhanced risk of alcoholism.
RATIONALE: Alcohol addiction is a major psychiatric disease, and yet, the underlying molecular adaptations in the brain remain unclear. Recent evidence suggests a functional role for the ras-specific guanine-nucleotide releasing factor 2 (Rasgrf2) in alcoholism. Rasgrf2(-/-) mice consume less alcohol and show entirely absent dopamine responses to an alcohol challenge compared to wild types (WT). OBJECTIVE: In order to further investigate how Rasgrf2 modifies the acute and subchronic effects of alcohol in the brain, we investigated its effects on the noradrenergic and serotonergic systems. METHODS: We measured noradrenaline and serotonin activity in the brain by in vivo microdialysis and RNA expression by chip analysis and RT-PCR after acute and sub-chronic alcohol exposure in Rasgrf2(-/-) and WT mice. RESULTS: In vivo microdialysis showed a significantly reduced noradrenergic response and an absent serotonergic response in the nucleus accumbens (NAcc) and caudate putamen (CPu) after an alcohol challenge in Rasgrf2(-/-) mice. A co-expression analysis showed that there is a high correlation between Rasgrf2 and α2 adrenoceptor RNA expression in the ventral striatum in naïve animals. Accordingly, we further assessed the role of Rasgrf2 in the response of the noradrenergic system to subchronic alcohol exposure. A decrease in β1 adrenoceptor gene expression was seen in Rasgrf2(+/+), but not Rasgrf2(-/-) mice following alcohol exposure. Conversely, alcohol resulted in a decrease in both β2 and α2 adrenoceptor gene expression in knockout but not WT Rasgrf2 mice. CONCLUSIONS: These findings suggest that adaptations in the noradrenergic system contribute to the Rasgrf2 enhanced risk of alcoholism.
Authors: Alanna C Easton; Walter Lucchesi; Anbarasu Lourdusamy; Bernd Lenz; Jalal Solati; Yulia Golub; Piotr Lewczuk; Cathy Fernandes; Sylvane Desrivieres; Ralph R Dawirs; Gunther H Moll; Johannes Kornhuber; Josef Frank; Per Hoffmann; Michael Soyka; Falk Kiefer; Gunter Schumann; K Peter Giese; Christian P Müller; Jens Treutlein; Sven Cichon; Monika Ridinger; Peter Mattheisen; Stefan Herms; Norbert Wodarz; Peter Zill; Wolfgang Maier; Rainald Mössner; Wolfgang Gaebel; Norbert Dahmen; Norbert Scherbaum; Christine Schmäl; Michael Steffens; Susanne Lucae; Marcus Ising; Bertram Müller-Myhsok; Markus M Nöthen; Karl Mann; Marcella Rietschel Journal: Neuropsychopharmacology Date: 2013-03-04 Impact factor: 7.853
Authors: Kenneth Blum; Mark S Brodie; Subhash C Pandey; Jean Lud Cadet; Ashim Gupta; Igor Elman; Panayotis K Thanos; Marjorie C Gondre-Lewis; David Baron; Shan Kazmi; Abdalla Bowirrat; Marcelo Febo; Rajendra D Badgaiyan; Eric R Braverman; Catherine A Dennen; Mark S Gold Journal: J Pers Med Date: 2022-06-20
Authors: Tianye Jia; Christine Macare; Sylvane Desrivières; Dante A Gonzalez; Chenyang Tao; Xiaoxi Ji; Barbara Ruggeri; Frauke Nees; Tobias Banaschewski; Gareth J Barker; Arun L W Bokde; Uli Bromberg; Christian Büchel; Patricia J Conrod; Rachel Dove; Vincent Frouin; Jürgen Gallinat; Hugh Garavan; Penny A Gowland; Andreas Heinz; Bernd Ittermann; Mark Lathrop; Hervé Lemaitre; Jean-Luc Martinot; Tomáš Paus; Zdenka Pausova; Jean-Baptiste Poline; Marcella Rietschel; Trevor Robbins; Michael N Smolka; Christian P Müller; Jianfeng Feng; Adrian Rothenfluh; Herta Flor; Gunter Schumann Journal: Proc Natl Acad Sci U S A Date: 2016-03-21 Impact factor: 12.779