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A mouse model of high trait anxiety shows reduced heart rate variability that can be reversed by anxiolytic drug treatment.

Gaburro S, Stiedl O, Giusti P, Sartori SB, Landgraf R, Singewald N - Int. J. Neuropsychopharmacol. (2011)

Bottom Line: Increasing evidence suggests that specific physiological measures may serve as biomarkers for successful treatment to alleviate symptoms of pathological anxiety.Studies of autonomic function investigating parameters such as heart rate (HR), HR variability and blood pressure (BP) indicated that HR variability is consistently reduced in anxious patients, whereas HR and BP data show inconsistent results.These findings indicate that assessment of autonomic response in addition to freezing might be a useful indicator of the efficacy of novel anxiolytic treatments.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Austria.

ABSTRACT
Increasing evidence suggests that specific physiological measures may serve as biomarkers for successful treatment to alleviate symptoms of pathological anxiety. Studies of autonomic function investigating parameters such as heart rate (HR), HR variability and blood pressure (BP) indicated that HR variability is consistently reduced in anxious patients, whereas HR and BP data show inconsistent results. Therefore, HR and HR variability were measured under various emotionally challenging conditions in a mouse model of high innate anxiety (high anxiety behaviour; HAB) vs. control normal anxiety-like behaviour (NAB) mice. Baseline HR, HR variability and activity did not differ between mouse lines. However, after cued Pavlovian fear conditioning, both elevated tachycardia and increased fear responses were observed in HAB mice compared to NAB mice upon re-exposure to the conditioning stimulus serving as the emotional stressor. When retention of conditioned fear was tested in the home cage, HAB mice again displayed higher fear responses than NAB mice, while the HR responses were similar. Conversely, in both experimental settings HAB mice consistently exhibited reduced HR variability. Repeated administration of the anxiolytic NK1 receptor antagonist L-822429 lowered the conditioned fear response and shifted HR dynamics in HAB mice to a more regular pattern, similar to that in NAB mice. Additional receiver-operating characteristic (ROC) analysis demonstrated the high specificity and sensitivity of HR variability to distinguish between normal and high anxiety trait. These findings indicate that assessment of autonomic response in addition to freezing might be a useful indicator of the efficacy of novel anxiolytic treatments.

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Chronic treatment with the NK1 receptor antagonist L-822429 caused a reduction in fear expression and a normalization of heart rate (HR) variability in high anxiety behaviour (HAB) mice. (a) The conditioned stimulus (CS) presentation produced significant increased fear expression in untreated (□) but not drug-treated (▪) HAB mice. (b) Both control and L-822429-treated HAB mice displayed a reduction in locomotor activity upon CS exposure, which was less pronounced in the treatment group. (c) CS presentation elicited elevated HR [beats per min (bpm)] in both groups. (d) Compared to HAB controls, L-822429-treated HAB mice displayed an increased HR variability (root mean square of successive RR interval differences; RMSSD) upon CS exposure. Data are means±s.e.m. (n=7/group). * p<0.05, *** p<0.001 L-822429-treated vs. untreated HAB groups; ## p<0.01, ### p<0.001 CS vs. pre-CS values.
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fig005: Chronic treatment with the NK1 receptor antagonist L-822429 caused a reduction in fear expression and a normalization of heart rate (HR) variability in high anxiety behaviour (HAB) mice. (a) The conditioned stimulus (CS) presentation produced significant increased fear expression in untreated (□) but not drug-treated (▪) HAB mice. (b) Both control and L-822429-treated HAB mice displayed a reduction in locomotor activity upon CS exposure, which was less pronounced in the treatment group. (c) CS presentation elicited elevated HR [beats per min (bpm)] in both groups. (d) Compared to HAB controls, L-822429-treated HAB mice displayed an increased HR variability (root mean square of successive RR interval differences; RMSSD) upon CS exposure. Data are means±s.e.m. (n=7/group). * p<0.05, *** p<0.001 L-822429-treated vs. untreated HAB groups; ## p<0.01, ### p<0.001 CS vs. pre-CS values.

Mentions: A significant CS×treatment interaction was observed for the freezing response (F1,24=29.47, p<0.001; Fig. 5 a). Post-hoc comparison showed lower freezing during CS exposure in drug-treated compared to untreated HAB mice. Furthermore, no significant CS×treatment interaction for locomotor activity was observed (F1,32=1.32, p>0.05; Fig. 5 b). However, a main treatment effect was found (F1,52=6.96, p<0.05; Fig. 5 b) indicating that NK1 receptor antagonist-treated HAB mice displayed higher locomotor activity than HAB control mice. Furthermore, Student's t test revealed similar locomotor pre-CS activity between drug-treated compared to untreated HAB mice (t14=−1.06, p>0.05).


A mouse model of high trait anxiety shows reduced heart rate variability that can be reversed by anxiolytic drug treatment.

Gaburro S, Stiedl O, Giusti P, Sartori SB, Landgraf R, Singewald N - Int. J. Neuropsychopharmacol. (2011)

Chronic treatment with the NK1 receptor antagonist L-822429 caused a reduction in fear expression and a normalization of heart rate (HR) variability in high anxiety behaviour (HAB) mice. (a) The conditioned stimulus (CS) presentation produced significant increased fear expression in untreated (□) but not drug-treated (▪) HAB mice. (b) Both control and L-822429-treated HAB mice displayed a reduction in locomotor activity upon CS exposure, which was less pronounced in the treatment group. (c) CS presentation elicited elevated HR [beats per min (bpm)] in both groups. (d) Compared to HAB controls, L-822429-treated HAB mice displayed an increased HR variability (root mean square of successive RR interval differences; RMSSD) upon CS exposure. Data are means±s.e.m. (n=7/group). * p<0.05, *** p<0.001 L-822429-treated vs. untreated HAB groups; ## p<0.01, ### p<0.001 CS vs. pre-CS values.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198175&req=5

fig005: Chronic treatment with the NK1 receptor antagonist L-822429 caused a reduction in fear expression and a normalization of heart rate (HR) variability in high anxiety behaviour (HAB) mice. (a) The conditioned stimulus (CS) presentation produced significant increased fear expression in untreated (□) but not drug-treated (▪) HAB mice. (b) Both control and L-822429-treated HAB mice displayed a reduction in locomotor activity upon CS exposure, which was less pronounced in the treatment group. (c) CS presentation elicited elevated HR [beats per min (bpm)] in both groups. (d) Compared to HAB controls, L-822429-treated HAB mice displayed an increased HR variability (root mean square of successive RR interval differences; RMSSD) upon CS exposure. Data are means±s.e.m. (n=7/group). * p<0.05, *** p<0.001 L-822429-treated vs. untreated HAB groups; ## p<0.01, ### p<0.001 CS vs. pre-CS values.
Mentions: A significant CS×treatment interaction was observed for the freezing response (F1,24=29.47, p<0.001; Fig. 5 a). Post-hoc comparison showed lower freezing during CS exposure in drug-treated compared to untreated HAB mice. Furthermore, no significant CS×treatment interaction for locomotor activity was observed (F1,32=1.32, p>0.05; Fig. 5 b). However, a main treatment effect was found (F1,52=6.96, p<0.05; Fig. 5 b) indicating that NK1 receptor antagonist-treated HAB mice displayed higher locomotor activity than HAB control mice. Furthermore, Student's t test revealed similar locomotor pre-CS activity between drug-treated compared to untreated HAB mice (t14=−1.06, p>0.05).

Bottom Line: Increasing evidence suggests that specific physiological measures may serve as biomarkers for successful treatment to alleviate symptoms of pathological anxiety.Studies of autonomic function investigating parameters such as heart rate (HR), HR variability and blood pressure (BP) indicated that HR variability is consistently reduced in anxious patients, whereas HR and BP data show inconsistent results.These findings indicate that assessment of autonomic response in addition to freezing might be a useful indicator of the efficacy of novel anxiolytic treatments.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Austria.

ABSTRACT
Increasing evidence suggests that specific physiological measures may serve as biomarkers for successful treatment to alleviate symptoms of pathological anxiety. Studies of autonomic function investigating parameters such as heart rate (HR), HR variability and blood pressure (BP) indicated that HR variability is consistently reduced in anxious patients, whereas HR and BP data show inconsistent results. Therefore, HR and HR variability were measured under various emotionally challenging conditions in a mouse model of high innate anxiety (high anxiety behaviour; HAB) vs. control normal anxiety-like behaviour (NAB) mice. Baseline HR, HR variability and activity did not differ between mouse lines. However, after cued Pavlovian fear conditioning, both elevated tachycardia and increased fear responses were observed in HAB mice compared to NAB mice upon re-exposure to the conditioning stimulus serving as the emotional stressor. When retention of conditioned fear was tested in the home cage, HAB mice again displayed higher fear responses than NAB mice, while the HR responses were similar. Conversely, in both experimental settings HAB mice consistently exhibited reduced HR variability. Repeated administration of the anxiolytic NK1 receptor antagonist L-822429 lowered the conditioned fear response and shifted HR dynamics in HAB mice to a more regular pattern, similar to that in NAB mice. Additional receiver-operating characteristic (ROC) analysis demonstrated the high specificity and sensitivity of HR variability to distinguish between normal and high anxiety trait. These findings indicate that assessment of autonomic response in addition to freezing might be a useful indicator of the efficacy of novel anxiolytic treatments.

Show MeSH
Related in: MedlinePlus