The antihypertensive drug pindolol attenuates long-term but not short-term binge-like ethanol consumption in mice


Autoria(s): 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.
Data(s)

2016

Resumo

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 to 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 in BLA principal neurons from long-term ethanol consuming mice but not naïve 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.

Identificador

http://eprints.qut.edu.au/92232/

Publicador

Wiley-Blackwell Publishing Ltd.

Relação

DOI:10.1111/adb.12359

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)

http://purl.org/au-research/grants/NHMRC/1061979

Direitos

Copyright 2016 Society for the Study of Addiction

Fonte

School of Clinical Sciences; Faculty of Health; Institute of Health and Biomedical Innovation

Palavras-Chave #alcohol #basolateral amygdala #long-term ethanol consumption #norepinephrine #pindolol #serotonin
Tipo

Journal Article