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

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Abstract

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 GABAA 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 GABAA 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 GABAA receptors may represent a novel therapeutic target for the treatment of motor symptoms of Parkinson's disease.

Original languageEnglish (US)
Pages (from-to)1896-1905
Number of pages10
JournalEuropean Journal of Neuroscience
Volume48
Issue number3
DOIs
StatePublished - Aug 2018

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Keywords

  • 6-OHDA rat
  • GABA
  • GABA receptor
  • Parkinson's disease
  • basal ganglia

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