The α1 subunit-containing GABAA receptor-mediated inhibitory transmission in the lateral orbitofrontal cortex contributes to anxiety- and depression-like behaviors in Parkinsonian rats.

The lateral orbitofrontal cortex (LO) is critically involved in the modulation of anxiety and depression. However, the involvement of GABAA receptor-mediated inhibitory transmission within the LO in Parkinson's disease (PD)-associated anxiety and depression remains unclear. In this study, unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) in adult male Sprague-Dawley rats induced anxiety- and depression-like behaviors, accompanied by hyperactivity of glutamatergic neurons, decreased synthesis and release of GABA and increased release of glutamate, as well as down-regulation of the expression of α1 subunit-containing GABAA receptors in the LO. Intra-LO injection of GABAA receptor agonist muscimol elicited anxiety- and depression-like behaviors, while injection of GABAA receptor antagonist bicuculline exerted anti effects in both sham and the lesioned rats. The doses producing behavioral effects in the lesioned rats were higher than those in sham rats. Intra-LO injection of muscimol decreased the firing rate of glutamatergic neurons and reduced extracellular dopamine (DA) and serotonin (5-HT) levels in the LO; conversely, bicuculline increased the firing rate of the neurons and elevated DA and 5-HT levels in both groups. Notably, the duration of muscimol and bicuculline action on the firing rate of glutamatergic neurons and monoamine release was shortened in the lesioned rats compared to sham rats, which were attributed to down-regulation of the expression of α1 subunit-containing GABAA receptors. Collectively, our findings suggest that degeneration of the nigrostriatal pathway suppresses GABAA receptor-mediated inhibitory transmission in the LO, which is crucial for regulating PD-associated anxiety and depression.