Boehringer Ingelheim Pharma GmbH, Biberach an der Riss, Germany.
J Sex Med. 2010 May;7(5):1757-67. doi: 10.1111/j.1743-6109.2010.01763.x. Epub 2010 Feb 12.
Hypoactive sexual desire disorder (HSDD) is defined as persistent lack of sexual fantasies or desire marked by distress. With a prevalence of 10% it is the most common form of female sexual dysfunction. Recently, the serotonin-1A (5-HT(1A)) receptor agonist and the serotonin-2A (5-HT(2A)) receptor antagonist flibanserin were shown to be safe and efficacious in premenopausal women suffering from HSDD in phase III clinical trials.
The current study aims to assess the effect of flibanserin on neurotransmitters serotonin (5-HT), norepinephrine (NE), dopamine (DA), glutamate, and gamma-aminobutyric acid (GABA) in brain areas associated with sexual behavior.
Flibanserin was administered to female Wistar rats (280-350 g). Microdialysis probes were stereotactically inserted into the mPFC, NAC, or MPOA, under isoflurane anesthesia. The extracellular levels of neurotransmitters were assessed in freely moving animals, 24 hours after the surgery.
Dialysate levels of DA, NE, and serotonin from medial prefrontal cortex (mPFC), nucleus accumbens (NAC), and hypothalamic medial preoptic area (MPOA) from female rats.
Acute flibanserin administration decreased 5-HT and increased NE levels in all tested areas. DA was increased in mPFC and MPOA, but not in the NAC. Basal levels of NE in mPFC and NAC and of DA in mPFC were increased upon repeated flibanserin administration, when compared to vehicle-treated animals. The basal levels of 5-HT were not altered by repeated flibanserin administration, but basal DA and NE levels were increased in the mPFC. Glutamate and GABA levels remained unchanged following either repeated or acute flibanserin treatment.
Systemic administration of flibanserin to female rats differentially affects the monoamine systems of the brain. This may be the mechanistic underpinning of flibanserin's therapeutic efficacy in HSDD, as sexual behavior is controlled by an intricate interplay between stimulatory (catecholaminergic) and inhibitory (serotonergic) systems.
性欲低下障碍（HSDD）被定义为持续缺乏性幻想或欲望，伴有明显的痛苦。其患病率为 10%，是女性性功能障碍最常见的形式。最近，在 III 期临床试验中，血清素-1A（5-HT（1A））受体激动剂和血清素-2A（5-HT（2A））受体拮抗剂氟班色林被证明对患有 HSDD 的绝经前妇女安全且有效。
本研究旨在评估氟班色林对与性行为相关的大脑区域中神经递质血清素（5-HT）、去甲肾上腺素（NE）、多巴胺（DA）、谷氨酸和γ-氨基丁酸（GABA）的影响。
氟班色林给予雌性 Wistar 大鼠（280-350g）。在异氟烷麻醉下，立体定向插入微透析探针到 mPFC、NAC 或 MPOA。在手术后 24 小时，在自由活动的动物中评估神经递质的细胞外水平。
来自雌性大鼠的内侧前额叶皮质（mPFC）、伏隔核（NAC）和下丘脑内侧视前区（MPOA）的 DA、NE 和 5-HT 的透析液水平。
急性氟班色林给药降低了所有测试区域中的 5-HT 并增加了 NE 水平。DA 在 mPFC 和 MPOA 中增加，但在 NAC 中没有增加。与 vehicle 处理的动物相比，重复氟班色林给药后，mPFC 和 NAC 中的基础 NE 水平和 mPFC 中的基础 DA 水平增加。重复氟班色林给药不会改变 5-HT 的基础水平，但会增加 mPFC 中的基础 DA 和 NE 水平。谷氨酸和 GABA 水平在重复或急性氟班色林治疗后保持不变。
氟班色林在雌性大鼠中的系统给药会对大脑的单胺系统产生不同的影响。这可能是氟班色林在 HSDD 中的治疗疗效的机制基础，因为性行为受刺激（儿茶酚胺能）和抑制（血清素能）系统之间复杂的相互作用控制。
