Mutations in the Garb1 gene promote ethanol consumption: Exploring a genetic and physiological basis for alcoholism.

Alcohol addiction is difficult to study in humans due to genetic and environmental complexities. Two mouse lines have been identified that exhibit a greatly increased voluntary consumption of ethanol and harbour single but distinct nucleotide mutations of the GABAA receptor (GABAAR) β1 subunit gene. Importantly, in the nucleus accumbens, a region associated with reward/addiction, we found GABAAR inhibition to be greatly enhanced in these mice as the mutant receptors now open spontaneously i.e. without the neurotransmitter GABA. The project is multidisciplinary and will:

a) Investigate how GABAergic transmission is altered by alcohol consumption/withdrawal.

b) Assess the contribution of accumbal GABAARs in addiction by introducing a mutant β1 gene into specific neurons in the nucleus accumbens.

You will be trained in electrophysiology, stereotaxic viral technology and behavioural techniques. The project will reveal fundamental information on the mechanisms of addiction and may identify new targets for treating alcoholism.

Reference

Maguire, E.P., Macpherson, T., Swinny, J., Dixon, C.I., Herd, M.B., Belelli, D., Stephens, D.N., King, S.L., Lambert, J.J. (2014). Tonic inhibition of accumbal spiny neurons by extrasynaptic α4bδ GABAA receptors modulates the actions of psychostimulants. J. Neurosci., (34(3):823-838)

Dixon, C. I., Belelli, D., Lambert JJ. et al., (2010). Cocaine effects on mouse incentive-learning & human addiction are linked to α2-subunit containing GABAA receptors. Proc.Natl. Acad. Sci. USA. 107: 2289-2294.

Anstee, Q., Belelli, D., Lambert, J.J., et al., (2013). Mutations of the GABRB1 gene promote alcohol consumption through increased tonic inhibition. Nature Commun. 4: 2816 doi:10.1038/ncomms3816

Supervisor: 
Professor Jerry Lambert
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