5-HT6 Receptors in the Lateral Habenula: A Potential Regulator of Anxiety in Parkinsonian Rats

Objectives: Anxiety represents one of the most frequently observed non-motor manifestations in patients diagnosed with Parkinson’s disease (PD), yet its neurobiological mechanisms remain largely unclear. The lateral habenular nucleus (LHb), an essential part of the limbic-monoaminergic system, plays a vital role in emotional regulation and houses serotonin 5-HT6 receptors, which are considered promising candidates for anxiolytic therapies. This research aimed to clarify the role of LHb 5-HT6 receptors in modulating anxiety-like behaviors within Parkinsonian contexts. Methods: To model PD, rats underwent unilateral 6-hydroxydopamine (6-OHDA) lesions targeting the medial forebrain bundle (MFB), while control animals received sham operations. Anxiety-related responses were examined utilizing the open field test (OFT) and elevated plus maze (EPM). Pharmacological modulation of LHb 5-HT6 receptors was achieved via microinjection of either the agonist WAY208466 or the antagonist SB258585. To account for potential locomotor confounds, spontaneous locomotor activity was measured. Results: Animals subjected to MFB lesions exhibited pronounced anxiety-related behaviors. This was evidenced by a reduction in center zone occupancy in the OFT, along with fewer entries into and less time spent within the open arms of the EPM. In the sham-operated rats, administering WAY208466 into the LHb induced anxiety-like behaviors, whereas SB258585 exhibited anxiolytic effects. Interestingly, lesioned rats responded to WAY208466 with anxiolytic effects, while SB258585 elicited anxiety-like behaviors. Notably, both compounds showed efficacy at lower doses among the lesioned rats compared to the sham controls. These behavioral changes occurred without notable alterations in locomotor activity. Conclusion: This study demonstrates that 5-HT6 receptors in the LHb exert bidirectional modulatory effects on anxiety-like behavior. In the PD model, the pharmacological actions of 5-HT6 receptor agents diverged from those observed in intact animals, suggesting that PD pathology may alter LHb 5-HT6 receptor function or sensitivity. These findings indicate that LHb 5-HT6 receptors may represent a promising therapeutic target for managing anxiety symptoms in PD.