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The Journal of Neuroscience, August 25, 2004, 24(34):7421-7426; doi:10.1523/JNEUROSCI.1587-04.2004

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Behavioral/Systems/Cognitive
Orexin-A Infusion in the Locus Ceruleus Triggers Norepinephrine (NE) Release and NE-Induced Long-Term Potentiation in the Dentate Gyrus

Susan G. Walling,¹ David J. Nutt,² Margaret D. Lalies,² and Carolyn W. Harley¹

¹Department of Psychology, Memorial University of Newfoundland, St. John's, Newfoundland, Canada A1B 3X9, and ²Psychopharmacology Unit, School of Medical Sciences, University of Bristol, BS8 1TD Bristol, United Kingdom

The orexins (ORX-A/ORX-B) are neuroactive peptides known to have roles in feeding and sleep. Evidence of dense, excitatory projections of ORX-A neurons to the noradrenergic pontine nucleus, the locus ceruleus (LC), suggests ORX-A also participates in attention and memory. Activation of LC neurons by glutamate produces a -adrenergic receptor-mediated long-term potentiation (LTP) of the perforant path-evoked potential in the dentate gyrus, a target structure of the LC that has been implicated in memory. We asked whether ORX-A also activates norepinephrine (NE)-induced LTP by initiating NE release in the hippocampus. Here, we show that ORX-A infusion (0.25-25 fmol) into the LC produces a robust, -adrenergic receptor-dependent, long-lasting potentiation of the perforant path-evoked dentate gyrus population spike in the anesthetized rat. Pharmacological inactivation of the LC with an ₂-adrenergic receptor agonist, before ORX-A infusion, prevents this potentiation. Analysis of NE concentrations in the hippocampus after ORX-A infusion into the LC reveals a transient, but robust, increase in NE release. Thus, this study demonstrates that the dense orexinergic projection to the LC promotes the induction of NE-LTP in the dentate gyrus. ORX-A modulation of LC activity may provide important support for the cognitive processes of attention and memory.

Key words: hypocretin; noradrenaline; noradrenergic; hippocampus; perforant; learning

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Received Nov 2, 2003; revised July 13, 2004; accepted July 15, 2004.

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