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Activation and blockade of serotonin 4 receptors in the lateral habenula improve working memory in unilateral 6-hydroxydopamine-lesioned Parkinson's rats

Yuan Guo, Li Zhang, Jin Zhang, Cheng-Xue Du, Shu-Xuan Lv, Tao Wang, Hui-Sheng Wang, Wen Xie, Jian Liu
Neurological Research 2019 March 30, : 1-9

OBJECTIVE: The aim of the present study was to investigate the effects and mechanism of 6-hydroxydopamine (6-OHDA) lesions and serotonin 4  (5-HT4 ) receptors in the lateral habenula (LHb) on Parkinson's disease (PD) related working memory.

METHODS: The working memory was measured by the T-maze rewarded alternation test in sham rats and rats with unilateral 6-OHDA lesions of substantia nigra pars compacta (SNc). The concentrations of dopamine (DA), noradrenaline (NA) and 5-HT in the related brain regions were measured by neurochemistry.

RESULTS: The results showed that 6-OHDA lesions of the SNc induced working memory impairment. Intra-LHb injection of 5-HT4  receptor agonist BIMU-8 (2, 4 or 8 μg) and antagonist GR113808 (1, 3.3 or 10 μg) improved the working memory only in the lesioned rats. Intra-LHb injection of BIMU-8 (8 μg) significantly increased DA levels in the medial prefrontal cortex, dorsal hippocampus and amygdala in the lesioned rats but not in sham rats. BIMU-8 did not change NA and 5-HT levels in the related brain regions in both sham and lesioned rats. Intra-LHb injection of GR113808 (10 μg) changed DA, NA and 5-HT levels in related brain regions in both sham and the lesioned rats. In addition, the 5-HT4  receptor-positive neurons in the LHb increased significantly in the lesioned rats.

CONCLUSION: These findings suggested that unilateral lesions of the SNc induced working memory impairment and up-regulation of 5-HT4  receptors in the LHb. Activation and blockade of LHb 5-HT4  receptors improved working memory, that were related to the change of monoamines levels. Abbreviation: 6-OHDA: 6-hydroxydopamine; serotonin:5-HT; LHb: lateral habenula; PD: Parkinson's disease; SNc: substantia nigra pars compacta; DA: dopamine; NA: noradrenaline.


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