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

• Published in: Addiction biology Vol. 22; no. 3; pp. 679 - 691
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-05-2017
• Subjects: alcohol; Animals; Antihypertensive Agents - pharmacology; basolateral amygdala; Behavior, Animal - drug effects; Binge Drinking - drug therapy; Disease Models, Animal; Ethanol - administration & dosage; long‐term ethanol consumption; Male; Mice; Mice, Inbred C57BL; norepinephrine; pindolol; Pindolol - pharmacology; serotonin; Time; alcohol; norepinephrine; long-term ethanol consumption; serotonin; basolateral amygdala; pindolol
• ISSN: 1355-6215; 1369-1600
• DOI: 10.1111/adb.12359

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 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.
In this study, we show that the antihypertensive drug pindolol reduces ethanol consumption in mice following long‐term binge‐like intake. Pindolol did not have non‐specific effects on locomotor activity, ethanol sensitivity or consumption of the natural reward sucrose. We also show that pindolol reduces excitatory post‐synaptic current frequency in naïve mice but increases excitatory post‐synaptic current frequency in long‐term ethanol consuming mice. Combined, these results demonstrate that pindolol represents a novel treatment option of the management of alcohol use disorders. Figure 1 highlights the key finding of the study.