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Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive.

Lemos JC, Wanat MJ, Smith JS, Reyes BA, Hollon NG, Van Bockstaele EJ, Chavkin C, Phillips PE - Nature (2012)

Bottom Line: Remarkably, severe-stress exposure completely abolished this effect without recovery for at least 90 days.This loss of CRF's capacity to regulate dopamine release in the nucleus accumbens is accompanied by a switch in the reaction to CRF from appetitive to aversive, indicating a diametric change in the emotional response to acute stressors.Thus, the current findings offer a biological substrate for the switch in affect which is central to stress-induced depressive disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, USA.

ABSTRACT
Stressors motivate an array of adaptive responses ranging from 'fight or flight' to an internal urgency signal facilitating long-term goals. However, traumatic or chronic uncontrollable stress promotes the onset of major depressive disorder, in which acute stressors lose their motivational properties and are perceived as insurmountable impediments. Consequently, stress-induced depression is a debilitating human condition characterized by an affective shift from engagement of the environment to withdrawal. An emerging neurobiological substrate of depression and associated pathology is the nucleus accumbens, a region with the capacity to mediate a diverse range of stress responses by interfacing limbic, cognitive and motor circuitry. Here we report that corticotropin-releasing factor (CRF), a neuropeptide released in response to acute stressors and other arousing environmental stimuli, acts in the nucleus accumbens of naive mice to increase dopamine release through coactivation of the receptors CRFR1 and CRFR2. Remarkably, severe-stress exposure completely abolished this effect without recovery for at least 90 days. This loss of CRF's capacity to regulate dopamine release in the nucleus accumbens is accompanied by a switch in the reaction to CRF from appetitive to aversive, indicating a diametric change in the emotional response to acute stressors. Thus, the current findings offer a biological substrate for the switch in affect which is central to stress-induced depressive disorders.

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CRF increases dopamine release in the nucleus accumbens through co-activation of CRF R1 and R2a, Representative dopamine release evoked by electrical stimulation (dashed lines) before (left) and after (right) application of 100-nM CRF (mean ± s.e.m. for 5 consecutive stimulations, top) and corresponding two-dimensional plots depicting changes in peak dopamine oxidation current (pseudocolor) with time as the abscissa and applied potential as the ordinate (bottom). b, Concentration response to CRF, n = 11-18. c, Effect of antagonists for CRF R1 (antalarmin, 1000 nM) or CRF R2 (anti-sauvagine 30, 250 nM; ASVG 30), n = 18-20. d, CRF in mice lacking gene encoding the CRF R1 (left) or CRF R2 (right) receptor, n = 7-13. e-g, Effect of CRF R1 agonist, stressin 1, n = 9-15 (e), CRF R2 agonist, urocortin 3 (100 or 300 nM), n = 5-8 (f) or their co-application, n = 8-15 (g). Data on bar graphs are mean + s.e.m.; ns p > 0.05, * p < 0.05, ** p < 0.01 vs vehicle.
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Figure 2: CRF increases dopamine release in the nucleus accumbens through co-activation of CRF R1 and R2a, Representative dopamine release evoked by electrical stimulation (dashed lines) before (left) and after (right) application of 100-nM CRF (mean ± s.e.m. for 5 consecutive stimulations, top) and corresponding two-dimensional plots depicting changes in peak dopamine oxidation current (pseudocolor) with time as the abscissa and applied potential as the ordinate (bottom). b, Concentration response to CRF, n = 11-18. c, Effect of antagonists for CRF R1 (antalarmin, 1000 nM) or CRF R2 (anti-sauvagine 30, 250 nM; ASVG 30), n = 18-20. d, CRF in mice lacking gene encoding the CRF R1 (left) or CRF R2 (right) receptor, n = 7-13. e-g, Effect of CRF R1 agonist, stressin 1, n = 9-15 (e), CRF R2 agonist, urocortin 3 (100 or 300 nM), n = 5-8 (f) or their co-application, n = 8-15 (g). Data on bar graphs are mean + s.e.m.; ns p > 0.05, * p < 0.05, ** p < 0.01 vs vehicle.

Mentions: To directly test the functional effects of CRF on dopamine release in the nucleus accumbens, we selectively monitored dopamine release evoked by a single biphasic electrical pulse (2 ms/phase, 100-500 μA delivered once per minute) in acute coronal brain slices using fast-scan cyclic voltammetry at carbon-fiber microelectrodes (Fig. 2a and Supplementary Fig. 4). Vehicle or CRF (10, 100 or 1000 nM) was applied to the slice for 15 minutes following five minutes of stable baseline and the resultant effect was quantified by averaging the evoked dopamine current in the last ten minutes. Following application of vehicle, there was a modest decrease (~7 %) in dopamine release (Fig. 2b), whereas CRF increased dopamine release in a concentration-dependent manner eliciting effects significantly greater than vehicle at 100 and 1000 nM (27.8 ± 6.7 and 30.0 ± 8.4 % respectively, mean ± s.e.m.; F3, 49 = 5.026, p < 0.01, one-way ANOVA with Dunnett’s post-hoc t-tests; Fig. 2b and Supplementary Fig. 5). Interestingly, this effect could be blocked by application of either the selective CRF R1 antagonist, antalarmin (1 μM), or the selective CRF R2 antagonist, anti-sauvagine 30 (ASVG 30; 250 nM) to the slice beginning 20 minutes before CRF application (F2, 50 = 5.142, p < 0.01, one-way ANOVA with Dunnett’s post-hoc t-tests; Fig. 2c) indicating that co-activation of both receptors is required. Consistently, CRF (10, 100, 1000 nM) failed to increase dopamine release in the nucleus accumbens of mice with deletion of either the CRF R114 or R215 gene (Fig. 2d). Application of the selective CRF R1 agonist Stressin 1 (100 or 300 nM) or the selective CRF R2 agonist Urocortin 3 (100 or 300 nM) failed to significantly increase dopamine release when applied individually (p > 0.05 compared to respective vehicles; Fig. 2e and f), but significantly increased dopamine release when co-applied (F3,36 = 3.528, p < 0.05 vs vehicle, one-way ANOVA with Dunnett’s post-hoc t-tests). The effect of the agonists together could be blocked by pre-treatment with Antalarmin and ASVG 30 (unpaired t-test, p > 0.05; Fig. 2g). Together these data provide convergent evidence that CRF increases dopamine release in the nucleus accumbens through co-activation of CRF R1 and R2.


Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive.

Lemos JC, Wanat MJ, Smith JS, Reyes BA, Hollon NG, Van Bockstaele EJ, Chavkin C, Phillips PE - Nature (2012)

CRF increases dopamine release in the nucleus accumbens through co-activation of CRF R1 and R2a, Representative dopamine release evoked by electrical stimulation (dashed lines) before (left) and after (right) application of 100-nM CRF (mean ± s.e.m. for 5 consecutive stimulations, top) and corresponding two-dimensional plots depicting changes in peak dopamine oxidation current (pseudocolor) with time as the abscissa and applied potential as the ordinate (bottom). b, Concentration response to CRF, n = 11-18. c, Effect of antagonists for CRF R1 (antalarmin, 1000 nM) or CRF R2 (anti-sauvagine 30, 250 nM; ASVG 30), n = 18-20. d, CRF in mice lacking gene encoding the CRF R1 (left) or CRF R2 (right) receptor, n = 7-13. e-g, Effect of CRF R1 agonist, stressin 1, n = 9-15 (e), CRF R2 agonist, urocortin 3 (100 or 300 nM), n = 5-8 (f) or their co-application, n = 8-15 (g). Data on bar graphs are mean + s.e.m.; ns p > 0.05, * p < 0.05, ** p < 0.01 vs vehicle.
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Figure 2: CRF increases dopamine release in the nucleus accumbens through co-activation of CRF R1 and R2a, Representative dopamine release evoked by electrical stimulation (dashed lines) before (left) and after (right) application of 100-nM CRF (mean ± s.e.m. for 5 consecutive stimulations, top) and corresponding two-dimensional plots depicting changes in peak dopamine oxidation current (pseudocolor) with time as the abscissa and applied potential as the ordinate (bottom). b, Concentration response to CRF, n = 11-18. c, Effect of antagonists for CRF R1 (antalarmin, 1000 nM) or CRF R2 (anti-sauvagine 30, 250 nM; ASVG 30), n = 18-20. d, CRF in mice lacking gene encoding the CRF R1 (left) or CRF R2 (right) receptor, n = 7-13. e-g, Effect of CRF R1 agonist, stressin 1, n = 9-15 (e), CRF R2 agonist, urocortin 3 (100 or 300 nM), n = 5-8 (f) or their co-application, n = 8-15 (g). Data on bar graphs are mean + s.e.m.; ns p > 0.05, * p < 0.05, ** p < 0.01 vs vehicle.
Mentions: To directly test the functional effects of CRF on dopamine release in the nucleus accumbens, we selectively monitored dopamine release evoked by a single biphasic electrical pulse (2 ms/phase, 100-500 μA delivered once per minute) in acute coronal brain slices using fast-scan cyclic voltammetry at carbon-fiber microelectrodes (Fig. 2a and Supplementary Fig. 4). Vehicle or CRF (10, 100 or 1000 nM) was applied to the slice for 15 minutes following five minutes of stable baseline and the resultant effect was quantified by averaging the evoked dopamine current in the last ten minutes. Following application of vehicle, there was a modest decrease (~7 %) in dopamine release (Fig. 2b), whereas CRF increased dopamine release in a concentration-dependent manner eliciting effects significantly greater than vehicle at 100 and 1000 nM (27.8 ± 6.7 and 30.0 ± 8.4 % respectively, mean ± s.e.m.; F3, 49 = 5.026, p < 0.01, one-way ANOVA with Dunnett’s post-hoc t-tests; Fig. 2b and Supplementary Fig. 5). Interestingly, this effect could be blocked by application of either the selective CRF R1 antagonist, antalarmin (1 μM), or the selective CRF R2 antagonist, anti-sauvagine 30 (ASVG 30; 250 nM) to the slice beginning 20 minutes before CRF application (F2, 50 = 5.142, p < 0.01, one-way ANOVA with Dunnett’s post-hoc t-tests; Fig. 2c) indicating that co-activation of both receptors is required. Consistently, CRF (10, 100, 1000 nM) failed to increase dopamine release in the nucleus accumbens of mice with deletion of either the CRF R114 or R215 gene (Fig. 2d). Application of the selective CRF R1 agonist Stressin 1 (100 or 300 nM) or the selective CRF R2 agonist Urocortin 3 (100 or 300 nM) failed to significantly increase dopamine release when applied individually (p > 0.05 compared to respective vehicles; Fig. 2e and f), but significantly increased dopamine release when co-applied (F3,36 = 3.528, p < 0.05 vs vehicle, one-way ANOVA with Dunnett’s post-hoc t-tests). The effect of the agonists together could be blocked by pre-treatment with Antalarmin and ASVG 30 (unpaired t-test, p > 0.05; Fig. 2g). Together these data provide convergent evidence that CRF increases dopamine release in the nucleus accumbens through co-activation of CRF R1 and R2.

Bottom Line: Remarkably, severe-stress exposure completely abolished this effect without recovery for at least 90 days.This loss of CRF's capacity to regulate dopamine release in the nucleus accumbens is accompanied by a switch in the reaction to CRF from appetitive to aversive, indicating a diametric change in the emotional response to acute stressors.Thus, the current findings offer a biological substrate for the switch in affect which is central to stress-induced depressive disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, USA.

ABSTRACT
Stressors motivate an array of adaptive responses ranging from 'fight or flight' to an internal urgency signal facilitating long-term goals. However, traumatic or chronic uncontrollable stress promotes the onset of major depressive disorder, in which acute stressors lose their motivational properties and are perceived as insurmountable impediments. Consequently, stress-induced depression is a debilitating human condition characterized by an affective shift from engagement of the environment to withdrawal. An emerging neurobiological substrate of depression and associated pathology is the nucleus accumbens, a region with the capacity to mediate a diverse range of stress responses by interfacing limbic, cognitive and motor circuitry. Here we report that corticotropin-releasing factor (CRF), a neuropeptide released in response to acute stressors and other arousing environmental stimuli, acts in the nucleus accumbens of naive mice to increase dopamine release through coactivation of the receptors CRFR1 and CRFR2. Remarkably, severe-stress exposure completely abolished this effect without recovery for at least 90 days. This loss of CRF's capacity to regulate dopamine release in the nucleus accumbens is accompanied by a switch in the reaction to CRF from appetitive to aversive, indicating a diametric change in the emotional response to acute stressors. Thus, the current findings offer a biological substrate for the switch in affect which is central to stress-induced depressive disorders.

Show MeSH
Related in: MedlinePlus