Activation and Blockade of Serotonin-4 Receptors in the Lateral Habenula Produce Antidepressant Effects in the Hemiparkinsonian Rat

Abstract

<b><i>Background:</i></b> The 5-hydroxytryptamine (5-HT) neurotransmitter system and lateral habenula (LHb) are involved in the regulation of depression, while the mechanisms remain to be clarified. <b><i>Objectives:</i></b> The effects and possible mecha-nism underlying activation or blockade of 5-HT₄ receptors (5-HT₄Rs) in the LHb in depression were investigated by behavioral and neurochemical methods based on a Parkinson’s disease (PD) rat model. <b><i>Method:</i></b> 6-Hydroxydopamine (6-OHDA) was injected unilaterally into the substantia nigra pars compacta to establish the PD rat model. The depressive-like behaviors were measured by the forced swimming test (FST) and sucrose preference test (SPT). The concentrations of dopamine (DA), noradrenaline (NA) and 5-HT in the related brain regions were measured by a neurochemical method. <b><i>Results:</i></b> The 6-OHDA lesions increased the immobility time in the FST and decreased the sucrose consumption in the SPT, suggesting the induction of depressive-like behaviors. Intra-LHb injection of BIMU-8 (5-HT₄R agonist) or GR113808 (5-HT₄R antagonist) produced antidepressant effects in the lesioned rats. Intra-LHb injection of BIMU-8 significantly increased the DA levels in the medial prefrontal cortex (mPFC) and ventral hippocampus (vHip), increased the 5-HT level in the mPFC and decreased the NA level in the vHip only in the lesioned rats, while intra-LHb injection of GR113808 changed DA, NA and 5-HT levels in the mPFC, LHb and vHip in both sham and the lesioned rats. <b><i>Conclusions:</i></b> All these results suggest that activation or blockade of the LHb 5-HT₄Rs produce antidepressant effects in the 6-OHDA-lesioned rats, which are related to the changes of monoamines in the limbic and limbic-related regions.