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This Article Full Text Full Text (PDF) All Versions of this Article: 574/2/399    most recent jphysiol.2006.108266v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Xie, X. Articles by Kilduff, T. S. Search for Related Content PubMed PubMed Citation Articles by Xie, X. Articles by Kilduff, T. S. Related Collections Neuroscience

¹ Biosciences Division, SRI International, Menlo Park, CA, USA
² Institute of Basic Medical Sciences, University of Tsukuba, Ibaraki, Japan

Hypocretin/orexin (Hcrt) is a critical neurotransmitter for the maintenance of wakefulness and has been implicated in several other functions, including energy metabolism and reward. Using whole-cell patch-clamp recordings from transgenic mice in which enhanced green fluorescent protein was linked to the Hcrt promoter, we investigated GABAergic control of the Hcrt neurones in hypothalamic slices. Bath application of GABA or muscimol caused an early hyperpolarization mediated by Cl^– and a late depolarization mediated by the efflux of bicarbonate. These GABA_A receptor-mediated responses were blocked by picrotoxin and bicuculline. Under the GABA_A blockade condition, GABA produced consistent hyperpolarization, decreased firing rate and input resistance. The selective GABA_B agonist (R)-baclofen caused a similar response with an EC₅₀ of 7.1 µM. The effects of (R)-baclofen were blocked by the GABA_B antagonist CGP 52432 but persisted in the presence of tetrodotoxin, suggesting direct postsynaptic effects. The existence of GABA_B modulation was supported by GABA_B(1) subunit immunoreactivity on Hcrt cells colabelled with antisera to the Hcrt-2 peptide. Furthermore, GABA_B receptor activation inhibited the presynaptic release of both glutamate and GABA. (R)-Baclofen depressed the amplitude of evoked excitatory postsynaptic currents (EPSCs) and inhibitory synaptic currents (IPSCs), and also decreased the frequency of both spontaneous and miniature EPSCs and IPSCs with a modest effect on their amplitudes. These data suggest that GABA_B receptors modulate Hcrt neuronal activity via both pre- and postsynaptic mechanisms, which may underlie the promotion of non-rapid eye movement sleep and have implications for the use of GABA_B agonists in the treatment of substance addiction through direct interaction with the Hcrt system.

(Received 3 March 2006; accepted after revision 13 April 2006; first published online 20 April 2006)
Corresponding author X. Xie: Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA. Email: xinmin.xie{at}sri.com

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