Orexins alleviate motor deficits via increasing firing activity of pallidal neurons in a mouse model of Parkinson's disease.

Orexin is a peptide neurotransmitter released in the globus pallidus. Morphological evidence reveals that both orexin 1 receptor (OX ₁ R) and orexin 2 receptor (OX ₂ R) exist in the globus pallidus. Here we showed that bilateral microinjection of both orexin-A and orexin-B into the globus pallidus alleviated motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mice. Further in vivo extracellular single-unit recording revealed that the basal spontaneous firing rate of the globus pallidus neurons in MPTP parkinsonian mice was slower than that of normal mice. Application of orexin-A or orexin-B significantly increased the spontaneous firing rate of pallidal neurons. The influx of Ca ²⁺ through the L-type Ca ²⁺ channel is the major mechanism involved in orexin-induced excitation in the globus pallidus. Orexin-A-induced increase in firing rate of pallidal neurons in MPTP parkinsonian mice was stronger than that of normal mice. Orexin-A exerted both electrophysiological and behavioral effects mainly via OX ₁ R, and orexin-B exerted the effects via OX ₂ R. Endogenous orexins modulated the excitability of globus pallidus neurons mainly through OX ₁ R. The present behavioral and electrophysiological results suggest that orexins ameliorate parkinsonian motor deficits through increasing the spontaneous firing of globus pallidus neurons.