title: Impaired escape performance and enhanced conditioned fear in rats following exposure to an uncontrollable stressor are mediated by glutamate and nitric oxide in the dorsal raphe nucleus.
abstract: Exposure to uncontrollable aversive events produces a variety of behavioral consequences that do not occur if the aversive event is controllable. Accumulating evidence suggests that exaggerated excitation of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) is sufficient to cause these same behaviors, such as poor shuttlebox escape performance and enhanced conditioned fear that occur 24 h after exposure to inescapable tailshock (IS). The aim of the present studies was to explore the possibility that N-methyl-D-aspartate (NMDA) receptor activation and nitric oxide (NO) formation within the DRN might be involved in mediating the behavioral consequences of IS. To this end, either the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (APV) or the nitric oxide synthase inhibitor Nw-nitro-L-arginine methyl ester (L-NAME), was microinjected into the DRN before IS or before testing 24 h later. Blocking NMDA receptors with APV in the DRN during IS prevented the usual impact of IS on escape responding and conditioned fear. However, injection of APV at the time of testing only reduced these effects. The DRN was shown to be the critical site mediating blockade of these behavioral changes since injection of APV lateral to the DRN did not alter the behavioral consequences of IS. Conversely, L-NAME was most effective in reversing the effects of IS when administered at the time of testing. These results suggest that there is glutamatergic input to the DRN at the time of IS that produces long-lasting changes in DRN sensitivity. This plasticity in the DRN is discussed as a possible mechanism by which IS leads to changes in escape performance and conditioned fear responding.
authors.affiliation: Department of Psychology, Connecticut College, Box 5275, 270 Mohegan Avenue, 06320-4196, New London, CT 06320-4196, USA. regra@conncoll.edu
authors.forename: R E
authors.initials: RE
authors.lastname: Grahn
authors.forename: L R
authors.initials: LR
authors.lastname: Watkins
authors.forename: S F
authors.initials: SF
authors.lastname: Maier
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000378:metabolism; D000818:Animals; D003213:Conditioning, Psychological; D004597:Electroshock; D004791:Enzyme Inhibitors / Q000378:metabolism; D004924:Escape Reaction / Q000502:physiology*; D005239:Fear / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism*; D006380:Helplessness, Learned; D008297:Male; D008959:Models, Neurological; D019331:NG-Nitroarginine Methyl Ester / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism*; D011897:Random Allocation; D011903:Raphe Nuclei / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D012701:Serotonin; D018698:Glutamic Acid; D015763:2-Amino-5-phosphonovalerate; D019331:NG-Nitroarginine Methyl Ester