LAUSR

&NA; The lateral habenula (LHb) plays an important role in the regulation of depression. At present, it is not clear whether GABAA receptor‐mediated inhibitory transmission in the LHb is involved in Parkinson's disease (PD)‐associated depression. In this study, unilateral 6‐hydroxydopamine lesions of the substantia nigra in rats induced depressive‐like behaviors and led to hyperactivity of LHb neurons compared to sham‐operated rats, which attribute to depletion of dopamine, and decreased synthesis and release of GABA and increased release of glutamate in the LHb. Intra‐LHb injection of GABAA receptor agonist muscimol produced antidepressant‐like effects, while the injection of GABAA receptor antagonist picrotoxin induced or increased the expression of depressive‐like behaviors in sham‐operated and the lesioned rats. However, the doses producing these behavioral effects in the lesioned rats were lower than those in sham‐operated rats. Intra‐LHb injection of muscimol decreased the firing rate of LHb neurons and increased the medial prefrontal cortex serotonin (5‐HT) release; conversely, picrotoxin increased the firing rate of the neurons and decreased 5‐HT release in two groups of rats. Compared to sham‐operated rats, the duration of muscimol and picrotoxin action on the firing rate of the neurons and 5‐HT release was prolonged in the lesioned rats. These changes in the lesioned rats were associated with up‐regulation of the expression of &agr;1 subunit‐containing GABAA receptors and reduction of GABA release in the LHb. Collectively, our findings suggest that degeneration of the nigrostriatal pathway impairs GABAA receptor‐mediated inhibitory transmission in the LHb, and the transmission is important for regulating PD‐associated depression. HighlightsActivation and blockade of LHb GABAA receptors regulated depressive‐like behaviors.The doses producing the effects in lesioned rats were lower than that of sham rats.Lesioning of the SNc in rats decreased synthesis and release of GABA in the LHb.The lesion prolonged the neuronal activity and 5‐HT release to GABAA stimulation.The lesion increased protein expression of GABAA receptor &agr;1 subunit in the LHb.