Activation and blockade of serotonin₄ receptors in the lateral habenula improve working memory in unilateral 6-hydroxydopamine-lesioned Parkinson's rats.

Abstract

<b>Objective</b>: 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. <b>Methods</b>: 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.<b>Results</b>: 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.<b>Conclusion</b>: 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. <b>Abbreviation:</b> 6-OHDA: 6-hydroxydopamine; serotonin:5-HT; LHb: lateral habenula; PD: Parkinson's disease; SNc: substantia nigra pars compacta; DA: dopamine; NA: noradrenaline.