Y. Yanovsky, S. Li and B. P. Klyuch contributed equally to the study.
l-Dopa activates histaminergic neurons
Article first published online: 14 MAR 2011
© 2011 The Authors. Journal compilation © 2011 The Physiological Society
The Journal of Physiology
Volume 589, Issue 6, pages 1349–1366, March 2011
How to Cite
Yanovsky, Y., Li, S., Klyuch, B. P., Yao, Q., Blandina, P., Passani, M. B., Lin, J.-S., Haas, H. L. and Sergeeva, O. A. (2011), l-Dopa activates histaminergic neurons. The Journal of Physiology, 589: 1349–1366. doi: 10.1113/jphysiol.2010.203257
- Issue published online: 14 MAR 2011
- Article first published online: 14 MAR 2011
- (Received 27 November 2010; accepted after revision 11 January 2011; first published online 17 January 2011)
Non-technical summary L-Dopa is an effective medication for Parkinson's disease (PD), but loses efficiency with time. This can be delayed by treatment with histamine antagonists. We show histaminergic neurons in the hypothalamus controlling wakefulness are excited by L-Dopa, which they can take up and transform to dopamine. They innervate the whole brain, in particular the striatum which is deficient of dopamine in PD. We revealed mechanisms of excitation of histaminergic neurons by L-Dopa and dopamine opening new avenues for the treatment of PD and sleep disorders.
Abstract l-Dopa is the most effective treatment of early and advanced stages of Parkinson's disease (PD), but its chronic use leads to loss of efficiency and dyskinesia. This is delayed by lower dosage at early stages, made possible by additional treatment with histamine antagonists. We present here evidence that histaminergic tuberomamillary nucleus (TMN) neurons, involved in the control of wakefulness, are excited under l-Dopa (EC50 15 μm), express Dopa decarboxylase and show dopamine immunoreactivity. Dopaergic excitation was investigated with patch-clamp recordings from brain slices combined with single-cell RT-PCR analysis of dopamine receptor expression. In addition to the excitatory dopamine 1 (D1)-like receptors, TMN neurons express D2-like receptors, which are coupled through phospholipase C (PLC) to transient receptor potential canonical (TRPC) channels and the Na+/Ca2+ exchanger. D2 receptor activation enhances firing frequency, histamine release in freely moving rats (microdialysis) and wakefulness (EEG recordings). In histamine deficient mice the wake-promoting action of the D2 receptor agonist quinpirole (1 mg kg−1, i.p.) is missing. Thus the histamine neurons can, subsequent to l-Dopa uptake, co-release dopamine and histamine from their widely projecting axons. Taking into consideration the high density of histaminergic fibres and the histamine H3 receptor heteromerization either with D1 or with D2 receptors in the striatum, this study predicts new avenues for PD therapy.