Cook Jemma E, Platt Donna M, Rüedi-Bettschen Daniela, Rowlett James K
Department of Psychiatry and Human Behavior, Center for Innovation and Discovery in Addictions, University of Mississippi Medical Center, Jackson, MS, United States.
Front Psychiatry. 2023 May 12;14:1142531. doi: 10.3389/fpsyt.2023.1142531. eCollection 2023.
Benzodiazepines (BZs) are prescribed as anxiolytics, but their use is limited by side effects including abuse liability and daytime drowsiness. Neuroactive steroids are compounds that, like BZs, modulate the effects of GABA at the GABA receptor. In a previous study, combinations of the BZ triazolam and neuroactive steroid pregnanolone produced supra-additive (i.e., greater than expected effects based on the drugs alone) anxiolytic effects but infra-additive (i.e., lower than expected effects based on the drugs alone) reinforcing effects in male rhesus monkeys, suggestive of an improved therapeutic window.
Female rhesus monkeys (=4) self-administered triazolam, pregnanolone, and triazolam-pregnanolone combinations intravenously under a progressive-ratio schedule. In order to assess characteristic sedative-motor effects of BZ-neuroactive steroid combinations, female rhesus monkeys (n=4) were administered triazolam, pregnanolone, and triazolam-pregnanolone combinations. Trained observers, blinded to condition, scored the occurrence of species-typical and drug-induced behaviors.
In contrast to our previous study with males, triazolam-pregnanolone combinations had primarily supra-additive reinforcing effects in three monkeys but infra-additive reinforcing effects in one monkey. Scores for deep sedation (i.e., defined as atypical loose-limbed posture, eyes closed, does not respond to external stimuli) and observable ataxia (any slip, trip, fall, or loss of balance) were significantly increased by both triazolam and pregnanolone. When combined, triazolam-pregnanolone combinations had supra-additive effects for inducing deep sedation, whereas observable ataxia was attenuated, likely due to the occurrence of robust sedative effects.
These results suggest that significant sex differences exist in self-administration of BZ-neuroactive steroid combinations, with females likely to show enhanced sensitivity to reinforcing effects compared with males. Moreover, supra-additive sedative effects occurred for females, demonstrating a higher likelihood of this adverse effect when these drug classes are combined.
苯二氮䓬类药物（BZs）被用作抗焦虑药，但其使用受到包括滥用倾向和日间嗜睡等副作用的限制。神经活性甾体是一类化合物，与BZs一样，可在GABA受体处调节GABA的作用。在先前的一项研究中，BZ三唑仑与神经活性甾体孕烷醇酮的组合在雄性恒河猴中产生了超相加（即基于单独药物的预期效果更大）的抗焦虑作用，但产生了次相加（即基于单独药物的预期效果更低）的强化作用，提示治疗窗口有所改善。
4只雌性恒河猴在累进比率方案下静脉内自我给药三唑仑、孕烷醇酮以及三唑仑 - 孕烷醇酮组合。为了评估BZ - 神经活性甾体组合的特征性镇静 - 运动效应，给4只雌性恒河猴施用三唑仑、孕烷醇酮以及三唑仑 - 孕烷醇酮组合。对情况不知情的训练有素的观察者对物种典型行为和药物诱导行为的发生情况进行评分。
与我们先前对雄性恒河猴的研究不同，三唑仑 - 孕烷醇酮组合在三只猴子中主要产生超相加的强化作用，而在一只猴子中产生次相加的强化作用。三唑仑和孕烷醇酮均显著增加了深度镇静（即定义为非典型的四肢松弛姿势、闭眼、对外界刺激无反应）和明显共济失调（任何滑倒、绊倒、跌倒或失去平衡）的评分。当联合使用时，三唑仑 - 孕烷醇酮组合在诱导深度镇静方面具有超相加作用，而明显共济失调有所减轻，这可能是由于强烈镇静作用的出现。
这些结果表明，在BZ - 神经活性甾体组合的自我给药方面存在显著的性别差异，与雄性相比，雌性可能对强化作用表现出更高的敏感性。此外，雌性出现了超相加的镇静作用，表明当这些药物类别联合使用时，这种不良反应的可能性更高。
