Abstract
Long-term binge alcohol consumption alters the signaling of numerous neurotransmitters in the brain including noradrenaline (NE) and serotonin (5-HT). Alterations in the signaling of these neuronal pathways result in dysfunctional emotional states like anxiety and depression which are typically seen during alcohol withdrawal. Interestingly, studies have demonstrated that the development of alcohol-induced negative affective states is linked to disrupted neurogenesis in the dentate gyrus (DG) region of the hippocampus in alcohol-dependent animals. We have previously shown that modulation of NE and 5-HT activity by pharmacological targeting of β-adrenoreceptors (β-ARs) and 5-HT1A/1B receptors with pindolol reduces consumption in long-term alcohol-consuming mice. Since these receptors are also involved in emotional homeostasis and hippocampal neurogenesis, we investigated the effects of pindolol administration on emotional and neurogenic deficits in mice consuming long-term alcohol (18 weeks). We report that acute administration of pindolol (32 mg/kg) reduces anxiety-like behavior in mice at 24 h withdrawal in the marble-burying test (MBT) and the elevated plus-maze (EPM). We also show that chronic (2 weeks) pindolol treatment (32 mg/kg/day) attenuates alcohol-induced impairments in the density of immature neurons (DCX+) but not newborn cells (BrdU+) in the hippocampal DG. Pindolol treatment also restores the normal proportion of newborn proliferating cells (BrdU+/Ki67+/DCX−), newborn proliferating immature neurons (BrdU+/Ki67+/DCX+) and newborn non-proliferating immature neurons (BrdU+/Ki67−/DCX+) following long-term alcohol intake. These results suggest that pindolol, through its unique pharmacology may rescue some but not all deficits of long-term alcohol abuse on the brain, adding further value to its properties as a strong pharmaceutical option for alcohol use disorders (AUDs).
Highlights
Alcohol abuse is highly prevalent in society with significantly higher rates of co-occurrence with mood disorders including depression and anxiety (Penick et al, 1988; Ross, 1995; Hall et al, 1999)
Since studies robustly implicate 5-HT1 and β-adrenergic receptors in emotional regulation and hippocampal neurogenesis, coupled with other studies that show changes in these receptors with long-term alcohol intake and withdrawal (Nevo et al, 1995; Gilpin and Koob, 2010; Sari, 2013; Patkar et al, 2017; Belmer et al, 2018), we investigated the effects of pindolol, a drug with a dual mechanism of action of 5-HT1A/1B receptors and β1/β2 adrenoreceptors on anxiety-like behavior and neurogenic deficits in mice
To evaluate the effects of pindolol on emotional deficits following long-term alcohol exposure, we tested it on withdrawal-induced anxiety-like behavior in the marble-burying test (MBT) and the elevated plus-maze test (EPM) following 12 and 13 weeks of alcohol intake respectively (Figures 1C–F)
Summary
Alcohol abuse is highly prevalent in society with significantly higher rates of co-occurrence with mood disorders including depression and anxiety (Penick et al, 1988; Ross, 1995; Hall et al, 1999). There is an abundance of literature suggesting that dysregulation in noradrenaline (NE) and serotonin (5-HT) signaling in the brain contributes to altered affective states including anxiety and depression (Gorelick, 1989; Gallant, 1993; George, 1994; Gilpin and Koob, 2010; Petrakis et al, 2012; Silberman et al, 2012). Studies with animal models of alcohol intake and human alcoholics implicate dysfunctional NE (Smith and Aston-Jones, 2008; Gilpin and Koob, 2010; Becker, 2012) and 5-HT (Gallant, 1993; Lê et al, 2002; Commons et al, 2003) signaling in the development of negative affective states during withdrawal. Pharmacological blockade of altered NE and 5-HT function remediated withdrawal-induced emotional dysregulation, and facilitated a reduction in alcohol consumption (Walker et al, 2008; Gilpin and Koob, 2010; Patkar et al, 2017; Belmer et al, 2018)
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