The antihypertensive drug pindolol attenuates long-term but not short-term binge-like ethanol consumption in mice.
Alcohol dependence is a debilitating disorder with current therapies displaying limited efficacy and/or compliance. Consequently, there is a critical need for improved pharmacotherapeutic strategies to manage alcohol use disorders (AUDs). Previous studies have shown that the development of alcohol dependence involves repeated cycles of binge-like ethanol intake and abstinence. Therefore, we used a model of binge-ethanol consumption (drinking-in-the-dark) in mice to test the effects of compounds known to modify the activity of neurotransmitters implicated in alcohol addiction. From this, we have identified the FDA-approved antihypertensive drug pindolol, as a potential candidate for the management of AUDs. We show that the efficacy of pindolol to reduce ethanol consumption is enhanced following long-term (12 weeks) binge-ethanol intake, compared with short-term (4 weeks) intake. Furthermore, pindolol had no effect on locomotor activity or consumption of the natural reward sucrose. Because pindolol acts as a dual beta-adrenergic antagonist and 5-HT1A/1Bpartial agonist, we examined its effect on spontaneous synaptic activity in the basolateral amygdala (BLA), a brain region densely innervated by serotonin and norepinephrine-containing fibres. Pindolol increased spontaneous excitatory post-synaptic current frequency of BLA principal neurons from long-term ethanol-consuming mice but not naïve mice. Additionally, this effect was blocked by the 5-HT1A/1Breceptor antagonist methiothepin, suggesting that altered serotonergic activity in the BLA may contribute to the efficacy of pindolol to reduce ethanol intake following long-term exposure. Although further mechanistic investigations are required, this study demonstrates the potential of pindolol as a new treatment option for AUDs that can be fast-tracked into human clinical studies.
Translational Research Institute, Queensland University of Technology, Brisbane, Australia.|Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology, Brisbane, Australia.
Omkar L
OL
Patkar
Translational Research Institute, Queensland University of Technology, Brisbane, Australia.|Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology, Brisbane, Australia.
Arnauld
A
Belmer
Translational Research Institute, Queensland University of Technology, Brisbane, Australia.|Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology, Brisbane, Australia.
Joan Y
JY
Holgate
Translational Research Institute, Queensland University of Technology, Brisbane, Australia.|Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology, Brisbane, Australia.
Josephine R
JR
Tarren
Translational Research Institute, Queensland University of Technology, Brisbane, Australia.|Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology, Brisbane, Australia.
Masroor R
MR
Shariff
Translational Research Institute, Queensland University of Technology, Brisbane, Australia.|Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology, Brisbane, Australia.
Michael
M
Morgan
School of Biomedical Sciences, The University of Queensland, Brisbane, Australia.
Matthew J
MJ
Fogarty
School of Biomedical Sciences, The University of Queensland, Brisbane, Australia.
Mark C
MC
Bellingham
Translational Research Institute, Queensland University of Technology, Brisbane, Australia.|Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology, Brisbane, Australia.
Selena E
SE
Bartlett
Translational Research Institute, Queensland University of Technology, Brisbane, Australia.|Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology, Brisbane, Australia.
Paul M
PM
Klenowski
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D063425:Binge Drinking / Q000188:drug therapy*; D004195:Disease Models, Animal; D000431:Ethanol / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010869:Pindolol / Q000494:pharmacology*; D013995:Time
D000959:Antihypertensive Agents; D000431:Ethanol; D010869:Pindolol
alcohol; basolateral amygdala; long-term ethanol consumption; norepinephrine; pindolol; serotonin