Excitation of histaminergic tuberomamillary neurons by thyrotropin-releasing hormone.
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 reverse-transcription-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 by the TRH receptor antagonist chlordiazepoxide (CDZ; 50 mum). In the presence of tetrodotoxin (TTX), TRH depolarized TMN neurons without obvious change of 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(+)/Ca(2+) exchanger, KB-R7943 and benzamil. The frequency of GABAergic spontaneous IPSCs was either increased (TTX-insensitive) or decreased [TTX-sensitive spontaneous IPSCs (sIPSCs)] by TRH, indicating a heterogeneous modulation of GABAergic inputs by TRH. Facilitation but not depression of sIPSC frequency by TRH was missing in the presence of the kappa-opioid receptor antagonist nor-binaltorphimine. Montirelin (TRH analog, 1 mg/kg, i.p.) induced waking in wild-type mice but not in histidine decarboxylase knock-out mice lacking histamine. Inhibition of histamine synthesis by (S)-alpha-fluoromethylhistidine blocked the arousal effect of montirelin in wild-type mice. We conclude that direct receptor-mediated excitation of rodent TMN neurons by TRH demands activation of nonselective cation channels as well as electrogenic Na(+)/Ca(2+) exchange. Our findings indicate a key role of the brain histamine system in TRH-induced arousal.
Department of Neurophysiology, Heinrich Heine University, Duesseldorf, Germany.
Regis
R
Parmentier
Sergej
S
Kolbaev
Boris P
BP
Klyuch
David
D
Vandael
Jian-Sheng
JS
Lin
Oliver
O
Selbach
Helmut L
HL
Haas
Olga A
OA
Sergeeva
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism / Q000502:physiology; D002413:Cations, Divalent / Q000378:metabolism; D006632:Histamine / Q000172:deficiency / Q000502:physiology*; D007026:Hypothalamic Area, Lateral / Q000378:metabolism / Q000502:physiology*; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology; D012894:Sleep Stages / Q000502:physiology; D015222:Sodium Channels / Q000378:metabolism / Q000502:physiology; D013973:Thyrotropin-Releasing Hormone / Q000502:physiology*
D015220:Calcium Channels; D002413:Cations, Divalent; D018025:Receptors, Thyrotropin-Releasing Hormone; D015222:Sodium Channels; D013973:Thyrotropin-Releasing Hormone; D006632:Histamine