N⁶-substituated adenosine analog J4 attenuates anxiety-like behaviors in mice

Rationale: Withdrawal from chronic alcohol exposure produces various physical and mental withdrawal symptoms. Activation of adenosine receptors is known to inhibit withdrawal-induced excitation. However, limited studies investigate how adenosine analogs may prove helpful tools to alleviate alcohol withdrawal-related affective behaviors. Objectives: This study aimed to investigate the effects of J4 compared with saline using the mice vapor or voluntary ethanol drinking model on behavioral endpoints representing ethanol-withdrawal negative emotionality commonly observed during abstinence from chronic alcohol use. Methods: We subjected C57BL/6 J mice to chronic intermittent ethanol (CIE) exposure schedule to investigate how 72-h withdrawal from alcohol alters affective-like behavior. Next, we determined how treatment with J4, a second-generation adenosine analog, influenced affective behaviors produced by alcohol withdrawal. Finally, we determined how J4 treatment alters voluntary ethanol drinking using the two-bottle-choice drinking paradigm. Results: Our results show that 72-h withdrawal from chronic intermittent ethanol exposure produces limited affective-like disturbances in male C57BL/6 J mice exposed to 4 cycles ethanol vapor. Most importantly, J4 treatment irrespective of ethanol exposure decreases innate anxiety-like behavior in mice. Conclusions: Withdrawal from chronic intermittent ethanol exposure and subsequent behavioral testing 72 h later produces minimal affective-like behavior. J4 treatment did however reduce marble-burying behavior and increased time spent in open arms of the elevated plus maze, suggesting J4 may be useful as a general anxiolytic.