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The Journal of Neuroscience, February 27, 2008, 28(9):2190-2198; doi:10.1523/JNEUROSCI.3711-07.2008
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Behavioral/Systems/Cognitive
Nociceptin Receptor Impairs Recognition Memory via Interaction with NMDA Receptor-Dependent Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Signaling in the Hippocampus
Celia Goeldner,1 David Reiss,1 Jürgen Wichmann,3 Hamid Meziane,2 Brigitte L. Kieffer,1 andAbdel-Mouttalib Ouagazzal1 1Institut de Génétique et de Biologie Moléculaire et Cellulaire and 2Institut Clinique de La Souris, 67404 Illkirch, France, and 3Pharmaceuticals Division, Discovery Chemistry, F. Hoffmann-La Roche, CH-4070 Basel, Switzerland
Correspondence should be addressed to Dr. Abdel-Mouttalib Ouagazzal, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 Rue Laurent Fries, BP 10142, 67404 Illkirch, France. E-mail address: Email: Abdel-Mouttalib.OUAGAZZAL{at}igbmc.u-strasbg.fr
Strong evidence suggests a role for nociceptin/orphanin FQ (N/OFQ) neuropeptide and its receptor (NOP) in cognition. However, the signaling mechanisms underlying N/OFQ modulation of memory are less understood. Here, we show that intracerebroventricular or intrahippocampal infusions of N/OFQ impair long-term memory formation in the mouse object recognition task. The synthetic NOP receptor agonist, (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (Ro64-6198), administered systemically, also produced amnesic effects that were blocked by coinfusion of the NOP receptor antagonist, [Nphe1,Arg14,Lys15]nociceptin-NH2 (UFP-101), into the dorsal hippocampus. In contrast, Ro64-6198 had no effect on short-term memory or recall performances. Immunoblotting analysis revealed a strong suppressive action of Ro64-6198 on learning-induced upregulation of hippocampal extracellular signal-regulated kinase (ERK) phosphorylation, which is crucial for long-term information storage. Accordingly, pharmacological inhibition of ERK activation after systemic injection of SL327 [
-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzene acetonitrile], a selective inhibitor of the upstream kinase MEK (mitogen-activated protein kinase kinase), abolished long-term recognition memory formation. The noncompetitive NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate (MK-801), given systemically, also suppressed ERK activation and disrupted recognition memory. In contrast, no effect of MK-801 was observed on recall, as for Ro64-6198. When administered concurrently at subthreshold doses, Ro64-6198 and MK-801 synergistically suppressed hippocampal ERK activation and impaired long-term memory formation. Under resting conditions, neither Ro64-6198 nor MK-801 affected spontaneous ERK activity in the hippocampus at the amnesic doses whereas at higher doses, only MK-801 had a suppressive effect. We conclude that N/OFQ-NOP receptor system negatively regulates long-term recognition memory formation through hippocampal ERK signaling mechanisms. This modulation may in part take place by inhibiting glutamatergic function at the NMDA receptor.
Key words: opioid; NOP receptor; NMDA receptor; hippocampus; recognition memory; ERK; mice
Received Aug. 15, 2007; revised Jan. 15, 2008; accepted Jan. 15, 2008.
Correspondence should be addressed to Dr. Abdel-Mouttalib Ouagazzal, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 Rue Laurent Fries, BP 10142, 67404 Illkirch, France. E-mail address: Email: Abdel-Mouttalib.OUAGAZZAL{at}igbmc.u-strasbg.fr
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