Nociceptin receptor impairs recognition memory via interaction with NMDA receptor-dependent mitogen-activated protein kinase/extracellular signal-regulated kinase signaling in the hippocampus.
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 [alpha-[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.
Goeldner
Celia
C
Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France.
Reiss
David
D
Wichmann
Jürgen
J
Meziane
Hamid
H
Kieffer
Brigitte L
BL
Ouagazzal
Abdel-Mouttalib
AM
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects*; D008297:Male; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009483:Neuropsychological Tests; D018847:Opioid Peptides / Q000494:pharmacology*; D010364:Pattern Recognition, Visual / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000097629:Nociceptin
D004791:Enzyme Inhibitors; D018683:Excitatory Amino Acid Agents; D048049:Extracellular Signal-Regulated MAP Kinases; D018847:Opioid Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D000097629:Nociceptin