Protein synthesis and the mechanisms of lasting change in anxiety induced by severe stress.
Brief, unprotected exposure of rats to cats (predator stress) may be lastingly anxiogenic in a variety of tests of rodent anxiety. Recent findings suggest that predator stress induced plasticity in neural circuitry implicated in fear learning underlies some of these anxiogenic effects. In addition, recent work implicates a consolidation-like process in the impact of predator stress on anxiety in that effects of predator stress may be interrupted by immediate post stressor pharmacological interventions. The present study tested whether "consolidation" of the anxiogenic effects of predator stress were dependent on protein synthesis. In addition, the study examined whether a protein synthesis dependent reconsolidation-like process was at work when rats were exposed to a cat twice. Anisomycin (210 mg/kg) or vehicle (Tween 80 in saline) was injected subcutaneously 1 min after a single cat exposure (consolidation test paradigm) or a 1 min after a second cat exposure (reconsolidation test paradigm) and behavior tested 7-8 days after predator stress. In the consolidation test paradigm, anisomycin blocked the anxiogenic effects of predator stress in the elevated plus maze (EPM) measured with open arm exploration. Moreover, anisomycin blocked the potentiation of startle by predator stress when rats were startled in the light, but not when startled in the dark. In contrast, the delay of habituation of startle produced by predator stress was unaffected by anisomycin. Suppression of risk assessment in the EPM by predator stress was not affected by anisomycin either. In startle testing, vehicle injection 1 min after predator stress led to a lasting suppression, rather than enhancement of startle response. Vehicle plus predator stress enhanced and prolonged corticosterone level changes sampled over 30-180 min after treatment when compared to handled or predator stressed only rats. In addition, predator stress plus vehicle suppression of startle was blocked by a benzodiazepine anxiolytic (chloradiazepoxide) or the glucorticoid receptor (GR) blocker RU486. Both drugs returned startle to the predator stressed only heightened levels. It is argued that an added anxiogenic effect of vehicle injection plus predator stress leads to a suppression, rather than enhancement of startle. Startle suppression appears to be mediated, in part, by activation of GR by corticosterone which engages a protein synthesis dependent process, since anisomycin blocked the startle suppressive effects of vehicle. Startle suppression also appeared to be independent of the startle enhancing effect of predator stress and in competition with it. Since predator stress may model aspects of hyperarousal associated with post traumatic stress disorder (PTSD), implications of these findings for understanding of mechanisms of initiation of the disorder and for treatment are discussed.
Adamec
Robert
R
Department of Psychology, Memorial University, 232 Elizabeth Avenue, St. John's, NF, A1B 3X9, Canada. radamec@mun.ca
Strasser
Kirby
K
Blundell
Jacqueline
J
Burton
Paul
P
McKay
Donald W
DW
D000704:Analysis of Variance; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001007:Anxiety / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D001245:Association Learning / Q000187:drug effects / Q000502:physiology*; D002415:Cats; D002707:Chlordiazepoxide / Q000494:pharmacology; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D006185:Habituation, Psychophysiologic / Q000187:drug effects / Q000502:physiology; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D015735:Mifepristone / Q000494:pharmacology; D011235:Predatory Behavior; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D020318:Rats, Long-Evans; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D012720:Severity of Illness Index; D013315:Stress, Psychological / Q000150:complications / Q000378:metabolism*
D014151:Anti-Anxiety Agents; D006727:Hormone Antagonists; D011500:Protein Synthesis Inhibitors; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D000841:Anisomycin; D002707:Chlordiazepoxide