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.

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The selective I(2) receptor ligand BU224 reduces immobility of rats in the FST, indicative of antidepressant-like activity. This effect is accompanied by alterations in HPA axis and central monoaminergic activity.

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The trace amine b-phenylethylamine (PEA) is normally present in the body at low nanomolar concentrations but can reach micromolar levels after ingestion of drugs that inhibit monoamine oxidase and primary amine oxidase. In vivo, PEA elicits a robust pressor response, but there is no consensus regarding the underlying mechanism, with both vasodilation and constriction reported in isolated blood vessels. Using functional and biochemical approaches, we found that at low micromolar concentrations PEA (1-30 mM) enhanced nerve-evoked vasoconstriction in the perfused rat mesenteric bed but at a higher concentration (100 mM) significantly inhibited these responses. The a 2 -adrenoceptor antagonist rauwolscine (1 mM) also enhanced nerve-mediated vasoconstriction, but in the presence of both rauwolscine (1 mM) and PEA (30 mM) together, nerveevoked responses were initially potentiated and then showed time-dependent rundown. PEA (10 and 100 mM) significantly increased noradrenaline outflow from the mesenteric bed as determined by high-pressure liquid chromatography coupled with electrochemical detection. In isolated endothelium-denuded arterial segments, PEA (1 mM to 1 mM) caused concentrationdependent reversal of tone elicited by the a 1 -adrenoceptor agonists noradrenaline (EC 50 51.69 6 10.8 mM; n 5 5), methoxamine (EC 50 68.21 6 1.70 mM; n 5 5), and phenylephrine (EC 50 67.74 6 16.72 mM; n 5 5) but was ineffective against tone induced by prostaglandin F 2a or U46619 (9,11-dideoxy-9a,11a-methanoepoxyprostaglandin F 2a H]rauwolscine (K i % 1.2 mM), ligands for a 1 -and a 2 -adrenoceptors, respectively. These data provide the first demonstration that dual indirect sympathomimetic and a 1 -adrenoceptor blocking actions underlie the vascular effects of PEA in resistance arteries.