title: Corticotrophin releasing factor-induced synaptic plasticity in the amygdala translates stress into emotional disorders.
abstract: The amygdala is involved in the associative processes for both appetitive and aversive emotions, and its function is modulated by stress hormones. The neuropeptide corticotrophin releasing factor (CRF) is released during stress and has been linked to many stress-related behavioral, autonomic, and endocrine responses. In the present study, nonanxiety-inducing doses of a potent CRF type 1 and 2 receptor agonist, urocortin (Ucn), was infused locally into the basolateral amygdala (BLA) of rats. After 5 daily injections of Ucn, the animals developed anxiety-like responses in behavioral tests. Intravenous administration of the anxiogenic agent sodium lactate elicited robust increases in blood pressure, respiratory rate, and heart rate. Furthermore, in the absence of any additional Ucn treatment, these behavioral and autonomic responses persisted for >30 d. Whole-cell patch-clamp recordings from BLA neurons of these hyper-reactive animals revealed a pronounced reduction in both spontaneous and stimulation-evoked IPSPs, leading to a hyperexcitability of the BLA network. This Ucn-induced plasticity appears to be dependent on NMDA receptor and subsequent calcium-calmodulin-dependent protein kinase II (CaMKII) activation, because it is blocked by pretreatment with NMDA receptor antagonists and by coadministration of CaMKII inhibitors. Our results show for the first time a stress peptide-induced behavioral syndrome that can be correlated with cellular mechanisms of neural plasticity, a novel mechanism that may explain the etiological role of stress in several chronic psychiatric and medical disorders.
authors.affiliation: Department of Psychiatry and Center for Behavioral Neuroscience, Emory University, Atlanta, Georgia 30322, USA. drainni@emory.edu
authors.forename: Donald G
authors.initials: DG
authors.lastname: Rainnie
authors.forename: Richard
authors.initials: R
authors.lastname: Bergeron
authors.forename: Tammy J
authors.initials: TJ
authors.lastname: Sajdyk
authors.forename: Madhvi
authors.initials: M
authors.lastname: Patil
authors.forename: Donald R
authors.initials: DR
authors.lastname: Gehlert
authors.forename: Anantha
authors.initials: A
authors.lastname: Shekhar
mesh_terms: D000342:Affective Symptoms / Q000503:physiopathology*; D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D019354:Sodium Lactate / Q000494:pharmacology; D013312:Stress, Physiological / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D054832:Urocortins; D000099052:CRF Receptor, Type 1
chemical_list: C101531:CRF receptor type 2; D018019:Receptors, Corticotropin-Releasing Hormone; D016194:Receptors, N-Methyl-D-Aspartate; D054832:Urocortins; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium; D019354:Sodium Lactate