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Abstract
Alcohol use disorders (AUD) often co-occur with anxiety and depressive disorders, and anxiety often drives relapse during alcohol abstinence. Optimal AUD pharmacotherapies may thus need to target both excessive alcohol intake and elevated anxiety. (−)-OSU6162 (OSU) is a monoamine stabilizer that attenuates alcohol-mediated behaviors in both preclinical and clinical settings. However, OSU’s effect on anxiety-like behavior following long-term drinking remains unknown. To this end, we utilized a genetic rat model that exhibits increased anxiety- and depression-like behaviors (Flinders Sensitive Line; FSL) and their controls (Flinders Resistant Line; FRL). Using the novelty suppressed feeding (NSF) test, we evaluated anxiety-like behaviors (1) at baseline, (2) following long-term voluntary drinking and after 24 h of alcohol deprivation, and (3) following OSU administration in the same animals. At baseline, FSL animals displayed significantly elevated anxiety-like characteristics compared to FRL. Compared to alcohol-naïve animals, long-term drinking significantly reduced anxiety-like behaviors in FSL, without any significant effects in FRL animals. Compared to vehicle, OSU administration significantly reduced anxiety-like behaviors in alcohol-naïve FSL and long-term drinking FRL animals. While there was no significant difference in alcohol intake between FSL and FRL, OSU attenuated alcohol intake in both strains. Conclusively, in addition to the compound’s previously identified ability to suppress alcohol-mediated behaviors, OSU may also possess anxiolytic properties, warranting further clinical evaluation in both AUD and anxiety disorder settings.
Highlights
A complex relationship exists between anxiety, stress and alcohol drinking, with alcohol having anxiolytic and stress-relieving effects and acting as a stressor[1]
We evaluated the effects of OSU on anxiety-like levels and voluntary alcohol intake in a preclinical genetic model: the Flinders Sensitive Line (FSL) and their controls, the Flinders Resistant Line (FRL)
In view of the above, we used the FSL/FRL model and, by evaluating anxiety-like behaviors using the novelty suppressed feeding (NSF) test, we formulated the following three questions, previously not explored: (1) Are there differences in anxiety-like behaviors and/or levels of voluntary alcohol intake in FSL compared to FRL animals? (2) Does long-term alcohol drinking affect anxiety-like behaviors in the FSL/FRL model? (3) Does the monoamine stabilizer OSU affect anxiety-like behaviors and voluntary alcohol intake in the FSL/FRL model? Data from the present study provide the first evidence, to our knowledge, of OSU’s anxiolyticlike properties, including OSU’s ability to reduce voluntary alcohol intake, in a genetic rat model of depression
Summary
A complex relationship exists between anxiety, stress and alcohol drinking, with alcohol having anxiolytic and stress-relieving effects and acting as a stressor[1]. It was found that OSU had no short-term negative effects on any of the cognitive domains assessed in patients with AUD, while improving certain higher order cognitive functions[19] These findings suggested that OSU may have beneficial treatment effects on both craving and cognition in AUDs. no studies to date have examined OSU’s effect both on anxiety and alcohol intake following a history of long-term drinking. No studies to date have examined OSU’s effect both on anxiety and alcohol intake following a history of long-term drinking To this end, we evaluated the effects of OSU on anxiety-like levels and voluntary alcohol intake in a preclinical genetic model: the Flinders Sensitive Line (FSL) and their controls, the Flinders Resistant Line (FRL). In view of the above, we used the FSL/FRL model and, by evaluating anxiety-like behaviors using the novelty suppressed feeding (NSF) test, we formulated the following three questions, previously not explored: (1) Are there differences in anxiety-like behaviors and/or levels of voluntary alcohol intake in FSL compared to FRL animals? (2) Does long-term alcohol drinking affect anxiety-like behaviors in the FSL/FRL model? (3) Does the monoamine stabilizer OSU affect anxiety-like behaviors and voluntary alcohol intake in the FSL/FRL model? Data from the present study provide the first evidence, to our knowledge, of OSU’s anxiolyticlike properties, including OSU’s ability to reduce voluntary alcohol intake, in a genetic rat model of depression
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