Fig. 5: Pharmacological manipulation of ADORA2A, NPY5R, and RXR during behavior. | Translational Psychiatry

Fig. 5: Pharmacological manipulation of ADORA2A, NPY5R, and RXR during behavior.

From: Cell-type-specific interrogation of CeA Drd2 neurons to identify targets for pharmacological modulation of fear extinction

Fig. 5

Adora2a, Npy5r, and Rxrg were found to be increased following fear conditioning; therefore, the effect of pharmacological manipulation of ADORA2A, NPY5R, and RXR during fear extinction was examined to assess their utility as potential enhancers of exposure therapy. a List of pharmacological agents used, their targets and the effects of binding to target. b Schematic of experimental design for examination of ADORA2A antagonism by Istradefylline prior to or following fear extinction. c Three groups of animals were fear conditioned (5 CS/US, 0.65 mA foot shock). d Pre-extinction injection of Istradefylline (Istra/Veh group) causes significant decrease in freezing compared to vehicle injected controls (n = I/V 30, V/I 14, V/V 38) (two-way RM ANOVA F(2,71) = 10.26, p < .0001; Tukey’s multiple comparisons: I/V vs. V/I p = .0005, I/V vs. V/V p = .0017, V/I vs. V/V p = .517). e Animals that previously received Istradefylline prior to fear extinction (Istra/Veh) continue to express less freezing 24 h later during second extinction session (retention) compared to vehicle controls (Veh/Veh) and those that received Istradefylline following extinction (Veh/Istra) (two-way RM ANOVA F(2,69) = 5.381 (two animals removed b/c injuries from fighting, one from V/V, and one from I/V), p < .01; Tukey’s multiple comparisons: I/V vs. V/I p = .0236, I/V vs. V/V p = .0181, V/I vs. V/V p = .8988). f Schematic of experimental design for examination of the effect of ADORA2A antagonism following fear conditioning. g Two groups of mice were fear conditioned (5 CS/US, 0.65 mA foot shock) (n = 6 Veh, 6 Istra). h No effect of prior Istrafedylline treatment following fear conditioning was detected during first (two-way RM ANOVA F(1,10) = 1.22, p > .05) or (i) second extinction session (two-way RM ANOVA F(1,10) = 0.88, p > .05). j Schematic for experimental design of examination of effect of Istradefylline on locomotion, center-time, and acoustic startle. k Pre-session administration of vehicle (Veh) or Istradefylline (Istra). Day 2 Istradefylline treatment caused acute increase in distance traveled compared to day 1 vehicle that returned to baseline on day 3 with vehicle administration test (n = 6) (RM ANOVA F(1.443,8.656) = 60.77, p < .0001; Tukey’s Multiple Comparisons: Veh (D1) vs Istra p = .0009, Veh (D1) vs. Veh (D3) p = .0984, Veh (D3) vs. Istra p < .0001). l Pre-session administration of vehicle (Veh) or isradefylline (Istra). Day 2 Istradefylline treatment did not cause changes in anxiety-like behavior (time in center). Day 3 Veh did have reduced time in center compared to Day 2 Istra; however, this is likely due to habituation (n = 6) (RM ANOVA F(1.542, 9.253) = 6.602, p < .05; Tukey’s Multiple Comparisons Test Veh (D1) vs Istra p = .4570, Veh (D1) vs. Veh (D3), p = .0577, Veh (D3) vs. Istra, p = .0440). m Pre-session administration of vehicle (Veh) or isradefylline (Istra). Day 2 treatment with Istradefylline caused a decreased acoustic startle amplitude that did not persist into Day 3 vehicle treatment (n = 6) (RM ANOVA F(1.794,16.14) = 8.203, p = .0043; Tukey’s Multiple Comparisons Test Veh (D1) vs Istra, p = .0205, Veh (D1) vs. Veh (D3), p = .7924, Veh (D3) vs. Istra p = .0111)). n Schematic for experimental design of examination of effects of Venelperit and Bexarotene. o Cohorts of mice were fear conditioned (5 CS/US, 0.65 mA foot shock) (n = 20 Veh, 12 Vel, 12 Bex), no differences between groups was detected. p Pre-extinction injection of Velneperit caused increased freezing when compared to vehicle group. No difference between Bexarotene and vehicle group was detected (two-way RM ANOVA, F (2,41) = 3.325, p < .05, Dunnett’s Multiple Comparisons Test: Veh vs. Bex, p = .5712, Veh vs. Vel, p = .0255). q The next day, 24 h later, during a second extinction session, significant main effect of treatment was detected (two-way RM ANOVA, F (2,41) = 8.52, p < .001). Injection of Velneperit prior to first extinction session did not cause significant changes in behavior compared to vehicle; however, prior injection of Bexarotene caused a significant reduction in freezing (Dunnett’s Multiple Comparisons Test: Veh vs. Bex, p = .0148, Veh vs. Vel, p = .1491)

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