title: Hippocampal CRF, NE, and NMDA system interactions in memory processing in the rat.
abstract: In the present study, we investigated the neural mechanisms of corticotropin-releasing factor (CRF) and the interactions among CRF, norepinephrine (NE), and N-methyl-D-aspartate (NMDA) systems in the dentate gyrus (DG) of hippocampus in modulating the memory process of rats. One-way passive avoidance task was adopted. Results indicated that CRF (80 ng), when directly injected into the DG, consistently and significantly enhanced memory retention in rats. The noradrenergic neurotoxin DSP-4, at a high dose (4 micrograms), impaired memory. DSP-4 at a moderate dose (2 micrograms), which did not affect retention alone, antagonized the memory-enhancing effect of CRF. Similarly, the beta-adrenergic antagonist propranolol, at a high dose (8 micrograms), reduced retention. At a low dose (80 ng), which did not markedly affect retention by itself, propranolol also prevented the memory-improving effect of CRF. Moreover, direct NE infusions to the DG significantly improved retention performance in a dose-sensitive manner. Coadministration of CRF and NE did not further enhance retention. These results together suggest that CRF and NE facilitated memory probably through the same instead of independent mechanisms. In contrast, the selective NMDA receptor antagonists 2-amino-5-phosphonopentanoate (AP5) and MK801, at high doses markedly impaired memory retention (0.8 and 3.2 micrograms for AP5, 2 and 10 micrograms for MK801). At a dose of MK801 that did not significantly alter retention alone (80 ng), it completely blocked the memory-facilitating effect of CRF. These results indicate that CRF enhanced memory indirectly through NMDA receptor mediation also. Finally, MK801 at 80 ng also successfully antagonized the memory-facilitating effect of NE in the DG. We have demonstrated that MK801, at the dose chosen for interaction studies, did not markedly alter locomotor activity. These results together suggest that CRF, through a presynaptic facilitation mechanism, possibly facilitates NE release in the DG; increased NE release and stimulation of beta-adrenergic receptors in the DG result in NMDA receptor activations in the same area. This sequence of events enhance the memory consolidation process in the hippocampus and explained the neural mechanism of CRF in facilitating retention performance in rats. The same neuropeptide/neurotransmitter interactions may have other physiological and neuropathological implications.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China.
authors.forename: E H
authors.initials: EH
authors.lastname: Lee
authors.forename: C P
authors.initials: CP
authors.lastname: Lee
authors.forename: H I
authors.initials: HI
authors.lastname: Wang
authors.forename: W R
authors.initials: WR
authors.lastname: Lin
mesh_terms: D018663:Adrenergic Agents / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism* / Q000494:pharmacology; D004338:Drug Combinations; D004347:Drug Interactions; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D016202:N-Methylaspartate / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism* / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D017981:Receptors, Neurotransmitter / Q000502:physiology; D012153:Retention, Psychology / Q000187:drug effects / Q000502:physiology*
chemical_list: D018663:Adrenergic Agents; D001596:Benzylamines; D004338:Drug Combinations; D018019:Receptors, Corticotropin-Releasing Hormone; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D016202:N-Methylaspartate; D003346:Corticotropin-Releasing Hormone; D011433:Propranolol; C012102:DSP 4; D009638:Norepinephrine