Bonauto S M, Brunke O R, Vassoler F M, Weera M M
Graduate School of Biomedical Sciences, Tufts University, Boston, MA.
Department of Psychology, Tufts University, Medford, MA.
bioRxiv. 2025 Mar 20:2025.03.20.644324. doi: 10.1101/2025.03.20.644324.
Traumatic stress leads to maladaptive avoidance behaviors and alcohol misuse in some people. In rats, predator odor ("traumatic") stress produces persistent avoidance of stress-paired contexts and escalated alcohol self-administration in some animals (Avoiders), but not others (Non-Avoiders). This mirrors the individual differences in stress responsivity and alcohol misuse seen in humans. Here, we used a quinine-adulterated alcohol drinking procedure to model compulsive-like alcohol drinking in humans. Male and female Wistar rats were given 12 weeks of intermittent access to 20% (v/v) alcohol, followed by three weeks of limited access. Rats were then indexed for avoidance using predator odor stress exposure, and limited access drinking resumed for three additional weeks after stress. During this period, the alcohol solution was adulterated twice weekly with increasing concentrations of quinine. More Avoidant males were more resistant to quinine adulteration and Avoider males increased in non-quinine alcohol drinking. Using ultrasonic vocalizations (USVs) as a measure of affective state, we found that Non-Avoider males emitted more lower frequency USVs (<32 kHz) preceding, during, and following predator odor stress. Finally, quantification of gene expression in the lateral hypothalamus revealed a strong positive correlation between greater transcripts and avoidance in males and a positive correlation between transcripts and less anxiety-like behaviors in females. Together, these results suggest that the intersection of stress and compulsive-like alcohol drinking is sex-specific and dependent on individual differences in stress outcomes. This work reinforces the importance of considering sex differences in stress and alcohol use disorder research.
创伤性应激会导致一些人出现适应不良的回避行为和酒精滥用。在大鼠中，捕食者气味（“创伤性”）应激会使一些动物（回避者）持续回避与应激相关的环境，并增加酒精的自我给药量，而另一些动物（非回避者）则不会。这反映了人类在应激反应性和酒精滥用方面的个体差异。在此，我们使用一种掺入奎宁的酒精饮用程序来模拟人类的强迫性饮酒行为。给雄性和雌性Wistar大鼠提供为期12周的间歇性20%（v/v）酒精摄入机会，随后是为期三周的限量摄入。然后，通过捕食者气味应激暴露对大鼠进行回避指标测定，并在应激后再进行为期三周的限量饮酒。在此期间，每周两次向酒精溶液中掺入浓度不断增加的奎宁。更多的回避型雄性大鼠对奎宁掺假更具抵抗力，且回避型雄性大鼠的非奎宁酒精饮用量增加。使用超声波发声（USV）作为情感状态的指标，我们发现非回避型雄性大鼠在捕食者气味应激之前、期间和之后发出更多低频USV（<32 kHz）。最后，对下丘脑外侧的基因表达进行定量分析发现，雄性大鼠中较高的转录本与回避之间存在强正相关，而雌性大鼠中转录本与较少的焦虑样行为之间存在正相关。总之，这些结果表明，应激与强迫性饮酒的交集具有性别特异性，且取决于应激结果的个体差异。这项工作强化了在应激和酒精使用障碍研究中考虑性别差异的重要性。
