Department of Behavioral Neuroscience, School of Medicine, Oregon Health & Science University, Portland, OR, USA.
Laboratoire d'Innovation Thérapeutique, Faculté de Pharmacie, UMR7200 CNRS/Université de Strasbourg, Strasbourg, IL, France.
Transl Psychiatry. 2024 Jul 15;14(1):286. doi: 10.1038/s41398-024-02993-x.
There is much interest in targeting the activity in the oxytocin system to regulate social bonding. However, studies with exogenous administration of oxytocin face the caveats of its low stability, poor brain permeability and insufficient receptor specificity. The use of a small-molecule oxytocin receptor-specific agonist could overcome these caveats. Prior to testing the potential effects of a brain-penetrant oxytocin receptor agonist in clinical settings, it is important to assess how such an agonist would affect social bonds in animal models. The facultatively monogamous prairie voles (Microtus ochrogaster), capable of forming long-term social attachments between adult individuals, are an ideal rodent model for such testing. Therefore, in a series of experiments we investigated the effects of the recently developed oxytocin receptor-specific agonist LIT-001 on the acquisition and expression of partner preference, a well-established model of pair bonding, in prairie voles. LIT-001 (10 mg/kg, intraperitoneal), as expected, facilitated the acquisition of partner preference when administered prior to a 4hr cohabitation. In contrast, while animals injected with vehicle after the 4hr cohabitation exhibited significant partner preference, animals that were injected with LIT-001 did not show such partner preference. This result suggests that OXTR activation during expression of pair bonding can inhibit partner preference. The difference in effects of LIT-001 on acquisition versus expression was not due to basal differences in partner preference between the experiments, as LIT-001 had no significant effects on expression of partner preference if administered following a shorter (2hr-long) cohabitation. Instead, this difference agrees with the hypothesis that the activation of oxytocin receptors acts as a signal of presence of a social partner. Our results indicate that the effects of pharmacological activation of oxytocin receptors crucially depend on the phase of social attachments.
人们对靶向催产素系统的活性以调节社交联系非常感兴趣。然而，使用外源性催产素进行的研究面临着其低稳定性、脑通透性差和受体特异性不足的缺点。使用小分子催产素受体特异性激动剂可以克服这些缺点。在将穿透血脑屏障的催产素受体激动剂应用于临床之前，评估这种激动剂如何影响动物模型中的社交联系非常重要。草原田鼠（Microtus ochrogaster）是一种选择性一夫一妻制的动物，能够在成年个体之间形成长期的社交联系，是进行这种测试的理想啮齿动物模型。因此，在一系列实验中，我们研究了最近开发的催产素受体特异性激动剂 LIT-001 对草原田鼠伴侣偏好获得和表达的影响，伴侣偏好是一种已建立的配对结合模型。正如预期的那样，LIT-001（10mg/kg，腹腔内注射）在 4 小时共居前给药时促进了伴侣偏好的获得。相比之下，虽然在 4 小时共居后注射载体的动物表现出明显的伴侣偏好，但注射 LIT-001 的动物没有表现出这种伴侣偏好。这一结果表明，在配对结合表达过程中激活 OXTR 可以抑制伴侣偏好。LIT-001 对获得和表达的影响不同，并不是由于实验之间伴侣偏好的基础差异，因为如果在更短的（2 小时长）共居后给药，LIT-001 对伴侣偏好的表达没有显著影响。相反，这一差异与催产素受体激活作为社交伴侣存在的信号的假设一致。我们的研究结果表明，催产素受体的药理学激活的效果取决于社交联系的阶段。
