Liu Kun-Cheng, Li Jun-Yi, Tan Hui-Hui, Du Cheng-Xue, Xie Wen, Zhang Yu-Ming, Ma Wei-Lin, Zhang Li
Department of Clinical Medicine, School of Medicine, Xi'an Jiaotong University, Xi'an 710061, China.
Department of Rehabilitation Medicine, the Second Hospital, Xi'an Jiaotong University, Xi'an 710004, China.
Neuropharmacology. 2015 Aug;95:290-8. doi: 10.1016/j.neuropharm.2015.03.031. Epub 2015 Apr 9.
Preclinical studies indicate both activation and blockade of serotonin6 (5-HT6) receptors may produce antidepressant-like effects. Depression is a common symptom in Parkinson's disease (PD); however, its pathophysiology is unclear. Here we examined whether 5-HT6 receptors in the dorsal hippocampus (DH) involve in the regulation of PD-associated depression. Unilateral 6-hydroxydopamine lesions of the medial forebrain bundle in rats induced depressive-like responses as measured by the sucrose preference and forced swim tests when compared to sham-operated rats. In sham-operated rats, intra-DH injection of 5HT6 receptor agonist WAY208466 or antagonist SB258585 increased sucrose consumption and decreased immobility time, indicating the induction of antidepressant effects. In the lesioned rats, WAY208466 also produced antidepressant effects, whereas SB258585 decreased sucrose consumption and increased immobility time, indicating the induction of depressive-like behaviors. Neurochemical results showed that WAY208466 did not change dopamine (DA) levels in the medial prefrontal cortex (mPFC), DH and habenula, and noradrenaline (NA) levels in the DH and habenula in sham-operated rats, and SB258585 increased DA and NA levels in these structures. Further, WAY208466 increased DA levels in the mPFC, DH and habenula, and NA level in the habenula in the lesioned rats, and SB258585 decreased DA levels in the mPFC and habenula. Additionally, the lesion did not change the density of neuronal glutamate transporter EAAC1/5-HT6 receptor co-expressing neurons in the DH. Compared to sham-operated rats, these findings suggest that the effects of 5-HT6 receptors in PD-associated depression may be mediated through different neurochemical mechanisms, and the DH is an important site involved in these effects.
临床前研究表明，血清素6（5-HT6）受体的激活和阻断都可能产生类抗抑郁作用。抑郁症是帕金森病（PD）的常见症状；然而，其病理生理学尚不清楚。在这里，我们研究了背侧海马体（DH）中的5-HT6受体是否参与PD相关抑郁症的调节。与假手术大鼠相比，大鼠内侧前脑束的单侧6-羟基多巴胺损伤通过蔗糖偏好和强迫游泳试验测量诱导出抑郁样反应。在假手术大鼠中，向DH内注射5-HT6受体激动剂WAY208466或拮抗剂SB258585可增加蔗糖消耗并减少不动时间，表明诱导了抗抑郁作用。在损伤大鼠中，WAY208466也产生了抗抑郁作用，而SB258585则降低了蔗糖消耗并增加了不动时间，表明诱导了抑郁样行为。神经化学结果表明，在假手术大鼠中，WAY208466不会改变内侧前额叶皮质（mPFC）、DH和缰核中的多巴胺（DA）水平，以及DH和缰核中的去甲肾上腺素（NA）水平，而SB258585会增加这些结构中的DA和NA水平。此外，WAY208466增加了损伤大鼠mPFC、DH和缰核中的DA水平，以及缰核中的NA水平，而SB258585降低了mPFC和缰核中的DA水平。此外，损伤并未改变DH中神经元谷氨酸转运体EAAC1/5-HT6受体共表达神经元的密度。与假手术大鼠相比，这些发现表明5-HT6受体在PD相关抑郁症中的作用可能通过不同的神经化学机制介导，并且DH是参与这些作用的重要部位。
