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Histamine excites subthalamic nucleus neurons and improves motor behavior in normal and Parkinsonian rats

【摘要】:正The subthalamic nucleus(STN),one of the key structures in the basal ganglia(BG),is a critical target for Parkinson's disease(PD) treatment with deep brain stimulation.On the other hand,it has been well known that histamine concentration in the brain of PD patients rises and the STN receives direct histaminergic projections. However,little is known about the effect of histamine on the STN neurons and the role of central histaminergic nervous system in PD.In this study,using rat brain slice preparations and extracellular recordings,we found that histamine concentration-dependently excited the STN neurons,which was not blocked by low-Ca~(2+)/high-Mg~(2+) medium,indicating a direct postsynaptic action of histamine.Ranitidine(selective H_2 receptor antagonist),but not mepyramine and JNJ7777120(selective H_1 and H_4 receptor antagonist,respectively),blocked the histamine-in-duced excitation.Dimaprit(selective H-2 receptor agonist),rather than 2-pyridylethylamine and UVF8430(selective H_1 and H_4 receptor agonist,respectively),mimicked the excitatory effect of histamine on the STN neurons. Additionally,the dimaprit-induced STN neuronal excitation was effectively antagonized by ranitidine.The results demonstrate that histamine excites STN neurons via H_2 receptors,which is consistent with our immunostaining results that only H_2 receptors presented in the STN.Behavioral tests showed that bilateral microinjection of histamine into the STN promotes rat motor performances in rota-rod and balance beam.Furthermore,unilateral microinjection of histamine to the STN ipsilateral to the lesioning side of the 6-hydroxydopamine-lesioned rat considerably reduced apomorphine-induced animal's rotation,whereas unilateral microinjecting ranitidine rather than mepyramine remarkably augmented the apomorphine-induced rotation.Interestingly,in the 6-hydroxydopamine-induced rat models of PD rather than normal rats,histamine not only increased neuronal firing rates but decreased coefficient of variation of interspike intervals,indicating that histamine regularizes the firing pattern of STN neurons. These results demonstrate that by activating H_2 receptors,histamine excites and regularizes neuronal firing in the STN and subsequently restores motor performances of PD rats.Considering that histamine also excites the substantia nigra,neostriatum and globus pallidus,we speculate that the central histaminergic nervous system may actively modulate the activity of BG circuits through its direct parallel innervations on the those structures as well as STN and consequently regulate motor initiation and performance.Presumably,histamine H_2 receptor in the BG is a potential target for clinical treatment of PD.

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