The antihypertensive drug pindolol attenuates long-term but not short-term binge-like ethanol consumption in mice
Patkar, Omkar L., Belmer, Arnauld, Holgate, Joan Y., Tarren, Josephine R., Shariff, Masroor R., Morgan, Michael, Fogarty, Matthew J., Bellingham, Mark C., Bartlett, Selena E., & Klenowski, Paul M. (2016) The antihypertensive drug pindolol attenuates long-term but not short-term binge-like ethanol consumption in mice. Addiction Biology. (In Press)
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/1B partial 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 naive mice. Additionally, this effect was blocked by the 5-HT1A/1B receptor 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.
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|Item Type:||Journal Article|
|Keywords:||alcohol, basolateral amygdala, long-term ethanol consumption, norepinephrine, pindolol, serotonin|
|Divisions:||Current > Schools > School of Clinical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
|Copyright Owner:||Copyright 2016 Society for the Study of Addiction|
|Deposited On:||22 Jan 2016 01:27|
|Last Modified:||05 Oct 2016 01:45|
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