Robert Messing
University of Texas at Austin, TX·Neuroscience
People who feel less of alcohol's effects are more likely to develop alcohol use disorder (AUD). Much of this reduced response comes from acute tolerance, the body's rapid adjustment to a single intoxicating dose.
- Fields
Neuroscience
Pharmacology
- Topics
alcohol use disorder
alcohol tolerance
alcohol consumption
- Grants
- 1 known grant, through Jun 2027
What they work on
- Test whether the PDE4 inhibitor apremilast increases PKA-driven phosphorylation of the β3 and β1 subunits of GABAA receptors, the brain's main inhibitory receptors, in hippocampal slices from wild-type mice.
- Determine how PKA phosphorylation affects alcohol tolerance and drinking, using knock-in mice whose GABAA β3 (S408A/S409A) or β1 (S409A) subunits lack the PKA target sites.
- Identify which brain PDE4 isozymes control alcohol-related behaviors, using isozyme-selective inhibitors and knockout mice, and find which PDE4 isoforms associate with receptor subunits using Blue Native PAGE and mass spectrometry.
- Screen 10 new compounds on GABAA receptors expressed in Xenopus oocytes to find a β1-selective positive allosteric modulator, then test it alone and with apremilast for effects on alcohol tolerance and drinking in mice.
More about the research
Tolerance can push drinking up in two ways. People drink more to reach the pleasant effects, and the unpleasant effects that would normally discourage drinking become weaker. Drugs called phosphodiesterase 4 (PDE4) inhibitors, including apremilast, reduce alcohol drinking in rodents. In the team's hands, apremilast also reduced alcohol tolerance. This project asks how these two effects are linked in the brain, with the goal of finding better drug targets for AUD.
Why it matters
Alcohol use disorder is common and harmful, and better medications are needed. By pinpointing which PDE4 enzyme and which GABAA receptor subunit control alcohol tolerance and drinking, this work could identify specific drug targets for treating the disorder. It may also support combining the existing drug apremilast with a new β1-selective compound.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Hyung Nam
Louisiana State University Health Sciences Center-Shreveport, LA·Neuroscience
Determine how chronic alcohol lowers neurogranin, a synaptic protein that tunes glutamate signaling, in the mouse medial prefrontal cortex, and test tolerance in mice with mPFC-specific Ng knockout or overexpression.
Marina Picciotto
Yale University, CT·Neuroscience
Define the role of nicotinic acetylcholine receptors in a ventral tegmental area to ventral pallidum GABA circuit and a medial septum to basolateral amygdala acetylcholine circuit that boost responding for rewards and reward-paired cues in mice.
Johannes W Hell
University of California-Davis, CA·Neuroscience
Test whether norepinephrine taken into neurons by the transporters OCT3 and PMAT activates internal β2ARs to drive GluA1 phosphorylation, AMPAR surface delivery and LTP, using inhibitors, knockout mice, immunoblotting and immunofluorescence.
The school
University of Texas at Austin: 49 labs on PI Pages, $1.1B a year on research, 871 research doctorates a year.
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