Zolpidem ameliorates motor impairments in the unilaterally 6-hydroxydopamine-lesioned rat

Nuclei within the basal ganglia-such as the globus pallidus external segment, subthalamic nucleus, and substantia nigra pars reticulata-have been shown to exhibit synchronous bursting activity entrained to excessive cortical beta oscillations following dopamine depletion. Zolpidem binds to GABA_A receptors with selectivity for those expressing the α₁ subunit, potentiating inhibitory postsynaptic currents and increasing the time decay of channel opening. Interestingly, zolpidem-sensitive nuclei within the basal ganglia circuitry are also those that have been shown to exhibit hyperexcitation in a dopamine-depleted state. We hypothesized that a drug with selectivity for these nuclei may improve motor impairments associated with Parkinson's disease. In order to determine the threshold dose at which zolpidem might encumber motor behavior, a dose-response experiment was performed in intact rats using rotarod. Next, we tested whether subthreshold doses (0.1, 0.25, 0.5 mg/kg; i.p.) of zolpidem improved volitional motor behavior/coordination using the rotarod balance beam and cylinder/paw preference tests in unilaterally 6-hydroxydopamine-lesioned rats. It was found that 0.1 mg/kg zolpidem significantly improved rotarod performance and significantly reduced forelimb use asymmetry compared to undrugged post-lesion conditions. Here, we present the first translational evidence for a role of zolpidem-sensitive GABA_A receptors in the treatment of PD motor symptoms. Our data show that zolpidem improves both motor coordination and volitional forelimb use in the unilateral 6-hydroxydopamine lesion model of PD, and thus suggest that zolpidem-sensitive GABA_A receptors may represent a novel therapeutic target for the treatment of motor symptoms of Parkinson's disease.