The involvement of other 5-HT receptor subtypes in HR regulation is discussed in the Supporting Information. Central 5-HT1A receptor involvement and the brain areas implicated 5-HT1A receptors are found predominantly in the CNS (brain and spinal cord) and parasympathetic control is exerted via direct outputs from the brain stem. to 550 bpm, without changing the conditioned HR response to the sound. 8-OH-DPAT induced profound QT prolongation and bradyarrhythmic episodes. nonlinear analysis indicated a pathological state of HR dynamics DMAT after 8-OH-DPAT (0.5 mgkg?1) with ANS hyperactivation impairing HR adaptability. The 5-HT1A receptor antagonist WAY-100635 (0.03 mgkg?1) blocked these effects of 8-OH-DPAT. CONCLUSIONS AND IMPLICATIONS Pre-training 5-HT1A receptor activation by 8-OH-DPAT (0.5 mgkg?1) impaired memory of conditioned auditory fear based on an attenuated HR increase, whereas pretest administration did not prevent the fear-conditioned HR increase but induced pathological HR dynamics through central ANS dysregulation with cardiac effects similar to acute SSRI overdose. comparisons were performed by Tukey HSD or Dunnett’s T3 when the Levene’s test was significant. An error probability of 0.05 was accepted as statistically significant in all tests. Results Behavioural effects of 8-OH-DPAT All mice injected subcutaneously with 8-OH-DPAT at 0.5 mgkg?1 showed the typical signs of the 5-HT syndrome (see Behavioural observations above). Pre-injection of WAY-100635 (0.03 mgkg?1) or NAD-299 (0.3 mgkg?1) prevented DMAT the 5-HT syndrome caused by 8-OH-DPAT. Effects of pre-training 8-OH-DPAT on HR responses during expression of cued fear Because the effect of pre-training 8-OH-DPAT (0.5 mgkg?1) on conditioned HR responses had not been investigated, experiments were performed with injections 15 min before training and testing 24 h later. Two-way anova with factors of training sequence and drug treatment indicated a significant effect of training sequence ( 0.05), drug treatment ( 0.0001) and a significant training DMAT sequence drug treatment interaction ( 0.05) for the sound-induced HR increase in the first 60 s of CS presentation indicative of conditioned fear. The same effect was observed for the whole (180 s) CS period training sequence ( 0.05), drug treatment ( 0.0001) and training sequence drug treatment interaction ( 0.05). Under both experimental conditions, pre-training injection of 8-OH-DPAT (0.5 mgkg?1) prevented the conditioned tachycardia to the auditory CS that was observed in saline-injected controls (Figure ?(Figure1).1). The HR increase elicited by the auditory CS reached maximum physiological levels [800 beats per min (bpm)] in saline-injected mice starting from pre-CS (baseline) HR (583 15 bpm) that did not differ significantly between drug-treated groups (data not shown). In addition, 24 h after 8-OH-DPAT administration, none of the HR effects that are described below, were observed after pretest injection of 8-OH-DPAT. Open in a separate window Figure 1 Effects of 8-OH-DPAT (0.5 mgkg?1) injected subcutaneously 15 min before training on fear-conditioned heart rate changes (HR). Mice were subjected to either paired CS/US or CS separated from US by a 30 s trace interval during training. Heart rate was determined during the retention test in the home cage 24 h after training. HR denotes changes from baseline values [180 s pre-CS phase; mean HR (0 bpm) = 583 15 bpm]. CS1: the first 60 s of CS presentation; CSall: throughout the 180 s CS presentation; values represent means SEM; = 6 per group; * 0.05; *** 0.001 versus saline control. Effects of 5-HT1A receptor ligands on HR responses CCND2 during expression of cued fear Baseline HR and its fear-induced adjustment was measured 24 h after training in the home cage during exposure to the sound serving as the conditioned fear stimulus. Typical HR responses of a saline- and an 8-OH-DPAT-injected mouse show substantial differences (Figure ?(Figure2A).2A). anova for repeated measures indicated significant HR differences as a function of drug treatment (F4,29 = 17.95, 0.0001; Figure ?Figure2B).2B). In addition, there was a significant effect of time on HR (F4,12 = 34.75, 0.0001). There was no significant interaction between time and drug treatment (F4,48 = 1.17, = 0.325). The test showed a significant difference between 0.5 mgkg?1 8-OH-DPT and the saline control group ( 0.002). Open in a separate window Figure 2 Effects of 5-HT1A receptor ligands on heart rate responses during expression of conditioned fear to the auditory cue. Typical instantaneous heart rate responses of mice injected subcutaneously with saline and 8-OH-DPAT (A), and mean heart rate responses in 30 s bins (B) after injection of mice with either saline, 8-OH-DPAT or NAD-299 at the given dose 15 min before the cue-dependent memory test. CS: conditioned stimulus (sound); values represent DMAT means SEM; = 12 (saline), = 7 (8-OH-DPAT 0.5.