The role of beta1 adrenoceptors in the development of alcohol dependence

Klenowski, P. M., Holgate, J., Bellingham, M., Molenaar, P. and Bartlett, S. (2013). The role of beta1 adrenoceptors in the development of alcohol dependence. In: Neuroscience 2013: 43rd Annual Meeting of the Society for Neuroscience, San Diego, CA, USA, (). 9-13 November, 2013.

Author Klenowski, P. M.
Holgate, J.
Bellingham, M.
Molenaar, P.
Bartlett, S.
Title of paper The role of beta1 adrenoceptors in the development of alcohol dependence
Conference name Neuroscience 2013: 43rd Annual Meeting of the Society for Neuroscience
Conference location San Diego, CA, USA
Conference dates 9-13 November, 2013
Publication Year 2013
Sub-type Published abstract
Open Access Status
Language eng
Formatted Abstract/Summary
There is significant evidence supporting the hypothesis that stressors play an important role in the development of alcohol dependence. Many investigators are dissecting the molecular mechanisms that underpin the role of stress in the development of alcohol dependence to improve upon the current pharmotherapeutics. Compounds that block norepinephrine receptors such as alpha1-adrenergic receptors using prazosin (Walker et al., 2008) or beta-adrenoceptor using propranolol have all shown promise as potential therapeutic agents (Gilpin and Koob, 2010). We have extended these studies to characterize the role of the beta1-adrenoceptor (AR) in ethanol consumption using the drinking in the dark (DID) protocol in mice and using to radioligand binding experiments to characterize the receptor in the brain of naïve and ethanol consuming mice. Briefly, mice were housed individually in a reverse light-dark cycle room and given access to 1 bottle of 20% ethanol (v/v) and 1 bottle of filtered water for a 2 hour period, 5 days a week, 3 hours into the dark cycle. Bottles were weighed 30 min and 2 hours after presentation to determine daily ethanol consumption. The beta1-adrenoceptor contains two binding sites, beta1H and beta1L, corresponding to high and low-affinity binding sites respectively. Receptor activation can occur through both binding sites. Some beta-blockers typified by (-)-CGP 12177 block beta1AR and beta2ARs, but can also activate beta1LARs at higher concentrations than those required to cause blockade (Kaumann and Molenaar, 2008). The role of beta1LARs have been extensively characterized in the heart. The mammalian brain is also an area of high beta1AR expression, however it is unknown whether beta1LARs exist in this region nor its role in stress and ethanol consumption. We show that there is high beta1AR expression in mouse brain using radioligand binding studies with (-)-[3H]-CGP 12177 to label beta1AR binding sites in brains from C57BL/6 mice. We then show that (-)-CGP 12177 reduces ethanol consumption in mice consuming ethanol using the DID protocol. We are currently screening a series of compounds with activity at beta1HAR and beta1LARs to determine their effect on ethanol consumption using an adapted drinking-in-the-dark paradigm established in our lab. Of particular interest is our data showing that the beta1LAR partial agonist (-)-CGP 12177 decreases ethanol consumption in C57BL/6 mice. Activation of the beta1AR through the beta1L site may represent a novel therapeutic strategy for the management of alcohol addiction.
Q-Index Code EX
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Conference Paper
Collection: School of Biomedical Sciences Publications
 
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Created: Wed, 26 Mar 2014, 10:46:58 EST by Dr Mark Bellingham on behalf of School of Biomedical Sciences