A combined pharmacological and genetic approach to investigate the role of orphanin FQ in learning and memory.
Using a combination of the selective opioid receptor-like1 (ORL1) receptor agonist, Ro 64-6198, and orphanin FQ/nociceptin (OFQ/N) peptide knockout (KO) mice, the influence of OFQ/N on cognition has been studied in the rodent. In wild type, C57BL/6J mice, Ro 64-6198 (0.3-1 mg/kg i.p.) impaired the acquisition of spatial learning in the Morris water maze, although a mild neurological impairment was evident which complicated precise interpretation. In Lister hooded rats, Ro 64-6198 (6 mg/kg i.p.) produced delay dependent impairments in rats performing either a delayed matching or a delayed nonmatching to position task with only a modest (< 20%) effect on omissions - an effect consistent with a short-term memory impairment. Electrophysiological studies demonstrated an inhibitory effect of OFQ/N on LTP recorded from the CA1 region of wild type mice, but not in ORL1 receptor knockout mice. In contrast to the ORL1 agonist, mice deficient in the OFQ/N peptide showed some evidence of improved spatial learning, fear conditioning and passive avoidance retention. However, CA1 LTP was similar between OFQ/N peptide KO mice and wild type controls. Subsequent receptor radioautography studies demonstrated the presence of ORL1 receptors within various regions of the medial temporal lobe system: i.e. CA1, dentate gyrus molecular layer, subiculum, perirhinal cortex. Taken together, these results suggest a bi-directional effect of OFQ/N containing systems on aspects of cognitive behaviour, particularly those elements associated with hippocampal function. This is consistent with a likely modulatory role of OFQ/N on hippocampal and associated cortical circuitry.
Higgins
G A
GA
PRBN, F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland.
Kew
J N C
JN
Richards
J G
JG
Takeshima
H
H
Jenck
F
F
Adam
G
G
Wichmann
J
J
Kemp
J A
JA
Grottick
A J
AJ
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects* / Q000502:physiology; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018847:Opioid Peptides / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000819:agonists / Q000172:deficiency* / Q000378:metabolism; D013028:Space Perception / Q000187:drug effects / Q000502:physiology; D013141:Spiro Compounds / Q000494:pharmacology; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D014151:Anti-Anxiety Agents; D007093:Imidazoles; D018847:Opioid Peptides; D011957:Receptors, Opioid; D013141:Spiro Compounds; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C408068:Ro 64-6198