Experimental neurologySep 10, 2019

Activating specific brain receptors in the lateral habenula may reduce depression-like behavior in a Parkinson's disease rodent model

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Updated Apr 3, 2026

Abstract

Unilateral 6-hydroxydopamine lesions in rats induced depressive-like behaviors and hyperactivity of LHb neurons compared to sham-lesioned controls.

Activation of AMPA receptors with (S)-AMPA in the LHb produced antidepressant-like effects in both lesioned and sham-lesioned rats.
Inhibition of AMPA receptors with NBQX led to depressive-like behaviors despite reducing LHb neuronal activity.
Intra-LHb injection of (S)-AMPA excited dopaminergic neurons in the anterior ventral tegmental area and serotonergic neurons in the dorsal raphe nucleus.
Increased release of dopamine and serotonin in the medial prefrontal cortex was observed following (S)-AMPA injection.
Lesions of the substantia nigra compacta reduced levels of a specific protein that enhances the activity of certain AMPA receptors in the LHb.

Simplified

Evidence indicates that depression is closely related to hyperactivity of the lateral habenula (LHb). However, it is not clear how activation and blockade of AMPA receptors (AMPARs) in the LHb affect depressive-like behaviors, particularly in Parkinson's disease-related depression. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) in rats induced depressive-like behaviors and led to hyperactivity of LHb neurons compared to SNc sham-lesioned rats. Interestingly, intra-LHb injection of AMPAR agonist (S)-AMPA produced antidepressant-like effects in the two groups of rats and antagonist NBQX induced depressive-like behaviors, although (S)-AMPA excited LHb neurons and NBQX inhibited these neurons. We further found that intra-LHb injection of (S)-AMPA excited dopaminergic neurons in the anterior ventral tegmental area (aVTA) and serotonergic neurons in the dorsal raphe nucleus (DRN), which increased release of DA and 5-HT in the medial prefrontal cortex (mPFC), while NBQX induced the opposite effects. Further, lesioning the GABAergic rostromedial tegmental nucleus did not alter the proportions of the responses of these neurons to AMPAR stimulation. Additionally, lesions of the SNc reduced the level of p-GluR2-S880 in the LHb, which can increase the surface expression of calcium-impermeable GluR2-containing AMPARs (CI-AMPARs). This change in SNc-lesioned rats enhanced effects of (S)-AMPA and NBQX on the behaviors, LHb neuronal firing and release of DA and 5-HT. Collectively, antidepressant-like effects produced by (S)-AMPA attribute to activation of LHb neurons expressing CI-AMPAR, which excites aVTA dopaminergic neurons and DRN serotonergic neurons via the direct projection, thereby increasing release of mPFC DA and 5-HT.

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Activating specific brain receptors in the lateral habenula may reduce depression-like behavior in a Parkinson's disease rodent model

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