Blockade of GABA transporter-1 and GABA transporter-3 in the lateral habenula improves depressive-like behaviors in a rat model of Parkinson's disease

The hyperactivity of the lateral habenula (LHb) is closely associated with depression. At present, it is unknown how GABA transporter (GAT) in the LHb affects depressive-like behaviors, particularly in Parkinson's disease (PD)-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 sham-lesioned rats. Intra-LHb injection of GAT-1 inhibitor NO-711 produced antidepressant-like responses, decreased firing rate of LHb neurons, and increased levels of LHb extracellular GABA in sham-lesioned and the lesioned rats. Further, the dose producing behavioral effects in the lesioned rats was lower than that of sham-lesioned rats. In the lesioned rats, the duration of inhibitory effect on the firing rate and increased levels of the GABA induced by NO-711 was longer than those in sham-lesioned rats, respectively. Intra-LHb injection of GAT-3 inhibitor SNAP-5114 improved depressive-like behaviors and decreased firing rate of LHb neurons in the lesioned rats, but not in sham-lesioned rats. SNAP-5114 increased LHb GABA levels in the lesioned rats, whereas did not alter that in sham-lesioned rats. These changes were involved in the down-regulated expression of LHb GAT-1 and GAT-3 after lesioning the SNc. These findings suggest that GAT-1 plays a major role in transporting LHb GABA under physiological conditions, and depletion of dopamine increases the transport capacity of GAT-3 in the LHb. Further, the study provides evidence that GAT-1 and GAT-3 in the LHb are involved in the regulation of PD-related depression.