Stanson Toshok Center for Brain Function and Repair, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA.
Department of Psychological and Brain Sciences, Institute for Neuroscience, Texas A&M University, College Station, TX, 77843, USA.
Mol Neurobiol. 2024 Apr;61(4):1907-1919. doi: 10.1007/s12035-023-03688-y. Epub 2023 Oct 9.
Selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, are frequently combined with medical psychostimulants such as methylphenidate (Ritalin), for example, in the treatment of attention-deficit hyperactivity disorder/depression comorbidity. Co-exposure to these medications also occurs with misuse of methylphenidate as a recreational drug by patients on SSRIs. Methylphenidate, a dopamine reuptake blocker, produces moderate addiction-related gene regulation. Findings show that SSRIs such as fluoxetine given in conjunction with methylphenidate potentiate methylphenidate-induced gene regulation in the striatum in rats, consistent with a facilitatory action of serotonin on addiction-related processes. These SSRIs may thus increase methylphenidate's addiction liability. Here, we investigated the effects of a novel SSRI, vilazodone, on methylphenidate-induced gene regulation. Vilazodone differs from prototypical SSRIs in that, in addition to blocking serotonin reuptake, it acts as a partial agonist at the 5-HT1A serotonin receptor subtype. Studies showed that stimulation of the 5-HT1A receptor tempers serotonin input to the striatum. We compared the effects of acute treatment with vilazodone (10-20 mg/kg) with those of fluoxetine (5 mg/kg) on striatal gene regulation (zif268, substance P, enkephalin) induced by methylphenidate (5 mg/kg), by in situ hybridization histochemistry combined with autoradiography. We also assessed the impact of blocking 5-HT1A receptors by the selective antagonist WAY-100635 (0.5 mg/kg) on these responses. Behavioral effects of these drug treatments were examined in parallel in an open-field test. Our results show that, in contrast to fluoxetine, vilazodone did not potentiate gene regulation induced by methylphenidate in the striatum, while vilazodone enhanced methylphenidate-induced locomotor activity. However, blocking 5-HT1A receptors by WAY-100635 unmasked a potentiating effect of vilazodone on methylphenidate-induced gene regulation, thus confirming an inhibitory role for 5-HT1A receptors. Our findings suggest that vilazodone may serve as an adjunct SSRI with diminished addiction facilitating properties and identify the 5-HT1A receptor as a potential therapeutic target to treat addiction.
选择性 5-羟色胺再摄取抑制剂（SSRIs），包括氟西汀，常与医学上的精神兴奋剂如哌醋甲酯（利他林）联合使用，例如在治疗注意力缺陷多动障碍/抑郁共病中。这些药物的共同暴露也发生在 SSRIs 患者滥用哌醋甲酯作为娱乐药物时。哌醋甲酯，一种多巴胺再摄取阻滞剂，产生适度的与成瘾相关的基因调节。研究结果表明，氟西汀等 SSRIs 与哌醋甲酯联合使用可增强大鼠纹状体中哌醋甲酯诱导的基因调节，这与 5-羟色胺对与成瘾相关过程的促进作用一致。因此，这些 SSRIs 可能会增加哌醋甲酯的成瘾性。在这里，我们研究了一种新型 SSRI 维拉佐酮对哌醋甲酯诱导的基因调节的影响。维拉佐酮与典型的 SSRIs 不同，除了阻断 5-羟色胺再摄取外，它还作为 5-HT1A 血清素受体亚型的部分激动剂。研究表明，刺激 5-HT1A 受体可以调节 5-羟色胺对纹状体的输入。我们比较了急性给予维拉佐酮（10-20mg/kg）与氟西汀（5mg/kg）对哌醋甲酯（5mg/kg）诱导的纹状体基因调节（zif268、物质 P、脑啡肽）的影响，通过原位杂交组织化学与放射自显影相结合的方法。我们还评估了选择性拮抗剂 WAY-100635（0.5mg/kg）阻断 5-HT1A 受体对这些反应的影响。在一个开阔场测试中，我们还平行地检查了这些药物治疗的行为效应。我们的结果表明，与氟西汀相反，维拉佐酮不会增强哌醋甲酯在纹状体中诱导的基因调节，而维拉佐酮增强了哌醋甲酯诱导的运动活性。然而，WAY-100635 阻断 5-HT1A 受体揭示了维拉佐酮对哌醋甲酯诱导的基因调节的增强作用，从而证实了 5-HT1A 受体的抑制作用。我们的发现表明，维拉佐酮可能作为一种辅助性 SSRI，具有降低成瘾促进特性，并确定 5-HT1A 受体作为治疗成瘾的潜在治疗靶点。
