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. 2023 Oct 13;49(2):443–454. doi: 10.1038/s41386-023-01739-5

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 4 — A Male DREADD+ mice (n = 5) had an elevated HPA axis response to 15 min of restraint stress following 9 weeks of CNO (2-way RM ANOVA; F_genotype(1,14) = 3.904, p = 0.068, F_time(1.671,23.39) = 77.76, p < 0.0001; F_{time*genotype}(3,42) = 5.130, p = 0.004) with a significant elevation in corticosterone levels 15 mins (p = 0.009) and 30 mins (p = 0.020) after restraint onset compared to controls (n = 11). B Area under the curve analysis did not show a significant difference in total corticosterone released in DREADD+ males following 9 weeks of chronic CNO (unpaired t-test; t₍₁₄₎ = 1.921, p = 0.075). C 9 weeks of chronic CNO did not alter the HPA axis response to acute restraint stress in DREADD+ females (n = 8) compared to controls (n = 7) (2-way RM ANOVA; F_genotype(1,13) = 0.529, p = 0.480; F_time(2.096,27.27) = 78.92, p < 0.0001; F_{time*genotype}(3,39) = 0.167, p = 0.918) and (D) did not affect total corticosterone released (unpaired t-test; t_(g13)=0.729, p = 0.479). E Using the von Frey filament test to measure tactile sensitivity, DREADD+ males (n = 7) showed a leftward shift of the paw withdrawal curve compared to controls (n = 11) (2-way RM ANOVA; F_genotype(1,16) = 4.034, p = 0.062; F_force(14,224) = 169.8, p < 0.0001; F_{genotype*force}(14, 224) = 2.658, p = 0.001) with DREADD+ males having significantly more paw withdrawals at 1.0 g (p = 0.021), 1.4 g (p = 0.006), and 2.0 g (p = 0.001) of force. F DREADD+ males had a lower average force required for 50% paw withdrawal (VF50) compared to controls (unpaired t-test; t₍₁₆) = 2.489, p = 0.024). G DREADD+ females (n = 8) also showed a leftward shift of the paw withdrawal curve compared to controls (n = 8) (2-way RM ANOVA; F_genotype(1,14) = 14.93, p = 0.002; F_force(4.396,61.55) = 371.2, p < 0.0001; F_{genotype*force}(14,196) = 5.182, p < 0.0001) with significantly more paw withdrawals at 1.4 g of force (p = 0.014), and (H) had lower VF50 (unpaired t-test; t₍₁₄₎ = 4.235, p = 0.0008) compared to controls. I Freezing behavior during auditory fear conditioning. Male DREADD+ mice (n = 7) showed no differences in freezing behavior during conditioning (2-way RM ANOVA; F_genotype(1,16) = 0.287, p = 0.600; F_trial(2.114,33.82) = 12.26, p < 0.0001; F_{genotype*trial}(3,48) = 0.085, p = 0.968) or extinction (2-way RM ANOVA; F_genotype(1,16) = 0.129, p = 0.725; F_trial(2.441,39.05) = 5.210, p = 0.007; F_{trial*genotype}(4,64) = 1.073, p = 0.377) compared to controls (n = 11) following 9 weeks of CNO. J Chronic CNO significantly elevated freezing behavior in female DREADD+ mice during conditioning (n = 8 per group; 2-way RM ANOVA; F_genotype(1,14) = 23.36, p = 0.0003, F_trial(2.170, 30.38) = 25.24, p < 0.0001; F_{genotype*trial}(3,42) = 4.20, p = 0.011), with DREADD+ females freezing more at baseline (p = 0.003) and conditioning trials 1 (p = 0.002) and 3 (p = 0.0004). Chronic CNO also increased female DREADD+ freezing behavior (n = 6 per group) during the extinction trials (2-way RM ANOVA; F_genotype(1,10) = 16.23, p = 0.002; F_trial(2.092, 20.92) = 2.324, p = 0.121; F_{genotype*trial}(4,40) = 0.780, p = 0.545), with significantly higher levels of freezing compared to controls during extinction trials 1 (p = 0.022) and 4 (p = 0.034). (***p < 0.001, **p < 0.01, *p < 0.05, @ main effect of genotype).