Abstract
Repeated episodes of binge-like alcohol consumption produce anxiety, depression and various deleterious effects including alterations in neurogenesis. While the involvement of the serotonin receptor 1 A (5-HT1A) in the regulation of anxiety-like behavior and neurogenesis is well documented, its contribution to alcohol withdrawal-induced anxiety and alcohol-induced deficits in neurogenesis is less documented. Using the Drinking-In-the-Dark (DID) paradigm to model chronic long-term (12 weeks) binge-like voluntary alcohol consumption in mice, we show that the selective partial activation of 5-HT1A receptors by tandospirone (3 mg/kg) prevents alcohol withdrawal-induced anxiety in a battery of behavioral tests (marble burying, elevated-plus-maze, open-field), which is accompanied by a robust decrease in binge-like ethanol intake (1 and 3 mg/kg). Furthermore, using triple immunolabelling of proliferation and neuronal differentiation markers, we show that long-term DID elicits profound deficits in neurogenesis and neuronal fate specification in the dorsal hippocampus that are entirely reversed by a 2-week chronic treatment with the 5-HT1A partial agonist tandospirone (3 mg/kg/day). Together, our results confirm previous observations that 5-HT1A receptors play a pivotal role in alcohol drinking behavior and the associated emotional and neurogenic impairments, and suggest that 5-HT1A partial agonists represent a promising treatment strategy for alcohol abuse.
Highlights
Alcoholism is regarded as a chronic relapsing disorder, with the development of alcohol addiction a progressive cycle involving extended periods of heavy alcohol use, with repeated episodes of binge-like consumption and abstinence[1]
To evaluate the contribution of 5-HT1A receptors in anxiety-like behavior following withdrawal from long-term binge-like drinking, we investigated the effects of the 5-HT1A partial agonist tandospirone (3 mg/kg) on mice experiencing a 24-h withdrawal from alcohol in a battery of behavioral tests (Fig. 1A)
In the marble burying test, we observed a significant increase in anxiety-related marble digging behavior in alcohol-withdrawn mice compared to naive mice, and this increase was prevented by tandospirone pre-treatment (Fig. 1B)
Summary
Alcoholism is regarded as a chronic relapsing disorder, with the development of alcohol addiction a progressive cycle involving extended periods of heavy alcohol use, with repeated episodes of binge-like consumption and abstinence[1]. 5-HT1A receptor activation by the non-selective partial agonists buspirone was shown to reduce alcohol drinking[17] and alcohol withdrawal-induced anxiety[18,19,20] in rodents These particular studies used a protocol in which animals are forced to consume alcohol by including ethanol in a liquid diet as the sole source of nutrient, making their motivation to drink ethanol in relation to emotional deficits questionable. We and others have demonstrated that buspirone has a complex action with both anxiolytic and anxiogenic, or motor effects in rodents[25,26,27,28,29,30], which could explain the inconsistent results on the benefit of buspirone reported in human alcoholics[31] Together, these data suggest that that further work is needed to clarify the specific contribution of 5-HT1A receptors in both alcohol drinking behaviour and alcohol-withdrawal induced anxiety
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