Dilip Verma1, Sara Jamil2, Ramon Osman Tasan3, Maren Denise Lange2, Hans-Christian Pape2. 1. Institute of Physiology 1, Westfälische Wilhelms-University, Robert-Koch-Str. 27 a, 48149, Münster, Germany. dilip.verma@ukmuenster.de. 2. Institute of Physiology 1, Westfälische Wilhelms-University, Robert-Koch-Str. 27 a, 48149, Münster, Germany. 3. Department of Pharmacology, Medical University Innsbruck, 6020, Innsbruck, Austria.
Abstract
RATIONALE: Return of fear by re-exposure to an aversive event is a major obstacle in the treatment of fear-related disorders. Recently, we demonstrated that local pharmacological stimulation of neuropeptide Y type 2 receptors (Y2R) in anteroventral bed nucleus of stria terminalis (BNSTav) facilitates fear extinction and attenuates retrieval of remote fear with or without concomitant extinction training. Whether Y2R activation could also protect against re-exposure to traumatic events is still unknown. OBJECTIVE: Therefore, we investigated reinstatement of remote fear following early Y2R manipulation in BNSTav in relation to concomitant extinction training in mice. METHODS: We combined local pharmacological manipulation of Y2Rs in BNSTav with or without extinction training and tested for reinstatement of remote fear 15 days later. Furthermore, we employed immediate early gene mapping to monitor related local brain activation. RESULTS: Y2R stimulation by local injection of NPY3-36 into BNSTav facilitated extinction, reduced fear reinstatement at remote stages, and mimicked the influence of extinction in groups without prior extinction training. In contrast, Y2R antagonism (JNJ-5207787) delayed extinction and increased reinstatement. Y2R treatment immediately before remote fear tests had no effect. Concomitantly, Y2R activation at early time points reduced the number of c-Fos positive neurons in BNSTav during testing of reinstated remote fear. CONCLUSION: Local Y2R stimulation in BNSTav promotes fear extinction and stabilizes suppression of reinstated fear through a long-term influence, even without extinction training. Thus, Y2Rs in BNST are crucial pharmacological targets for extinction-based remote fear suppression.
RATIONALE: Return of fear by re-exposure to an aversive event is a major obstacle in the treatment of fear-related disorders. Recently, we demonstrated that local pharmacological stimulation of neuropeptide Y type 2 receptors (Y2R) in anteroventral bed nucleus of stria terminalis (BNSTav) facilitates fear extinction and attenuates retrieval of remote fear with or without concomitant extinction training. Whether Y2R activation could also protect against re-exposure to traumatic events is still unknown. OBJECTIVE: Therefore, we investigated reinstatement of remote fear following early Y2R manipulation in BNSTav in relation to concomitant extinction training in mice. METHODS: We combined local pharmacological manipulation of Y2Rs in BNSTav with or without extinction training and tested for reinstatement of remote fear 15 days later. Furthermore, we employed immediate early gene mapping to monitor related local brain activation. RESULTS: Y2R stimulation by local injection of NPY3-36 into BNSTav facilitated extinction, reduced fear reinstatement at remote stages, and mimicked the influence of extinction in groups without prior extinction training. In contrast, Y2R antagonism (JNJ-5207787) delayed extinction and increased reinstatement. Y2R treatment immediately before remote fear tests had no effect. Concomitantly, Y2R activation at early time points reduced the number of c-Fos positive neurons in BNSTav during testing of reinstated remote fear. CONCLUSION: Local Y2R stimulation in BNSTav promotes fear extinction and stabilizes suppression of reinstated fear through a long-term influence, even without extinction training. Thus, Y2Rs in BNST are crucial pharmacological targets for extinction-based remote fear suppression.
Entities:
Keywords:
Fear extinction; Neuropeptide Y; Reinstatement; Remote fear memory; Y2 receptor
Authors: R Frederick Westbrook; Mihaela Iordanova; Gavan McNally; Rick Richardson; Justin A Harris Journal: J Exp Psychol Anim Behav Process Date: 2002-01
Authors: N Brunello; J R Davidson; M Deahl; R C Kessler; J Mendlewicz; G Racagni; A Y Shalev; J Zohar Journal: Neuropsychobiology Date: 2001 Impact factor: 2.328