The histaminergic tuberomamillary nucleus (TMN) controls arousal and attention and the firing of TMN neurons is state-dependent, active during waking, silent during sleep. Thyrotropin-releasing hormone (TRH) promotes arousal and combats sleepiness associated with narcolepsy. Single-cell RT-PCR (scRT-PCR) demonstrated variable expression of the two known TRH receptors in the majority of TMN neurons. TRH increased the firing rate of most (ca 70%) TMN neurons. This excitation was abolished in the presence of the TRH receptor antagonist chlordiazepoxide (50 μM). In the presence of tetrodotoxin TRH depolarized TMN neurons without changing their input resistance. This effect reversed at the potential typical for nonselective cation channels. The potassium channel blockers barium and cesium did not influence the TRH-induced depolarization. TRH effects were antagonized by inhibitors of the Na+/Ca2+ exchanger, KB-R7943 and benzamil. The frequency of spontaneous inhibitory GABAergic postsynaptic potentials was either increased (TTX-insensitive) or decreased (TTX-sensitive GABA release sites) by TRH, indicating a heterogeneous modulation of GABAergic inputs by TRH. Montirelin (TRH analogue, 1 mg/kg ip) induced waking in wild type mice but not in histidine decarboxylase knockout mice lacking histamine. Inhibition of histamine synthesis by (S)-α-fluoromethylhistidine blocked the arousal effect of montirelin in WT mice. We conclude, that direct excitation of rodent TMN neurons by TRH is receptor-mediated and demands activation of nonselective cation channels as well as electrogenic Na+/Ca2+ exchange. Our findings indicate a key role of histamine in TRH-induced arousal.
Parmentier, R., Kolbaev, S., Klyuch, B. P., Vandael, D., Lin, J. S., Selbach, O., ... & Sergeeva, O. A. (2009). Excitation of histaminergic tuberomamillary neurons by thyrotropin-releasing hormone. Journal of Neuroscience, 29(14), 4471-4483.
