Central 5-HT1A receptor-mediated modulation of heart rate dynamics and its adjustment by conditioned and unconditioned fear in mice.

BACKGROUND AND
PURPOSE: The beat-by-beat fluctuation (dynamics) of heart rate (HR) depends on centrally mediated control of the autonomic nervous system (ANS) reflecting the physiological state of an organism. 5-HT1A receptors are implicated in affective disorders,associated with ANS dysregulation which increases cardiac risk but their role in autonomic HR regulation under physiological conditions is insufficiently characterized. EXPERIMENTAL APPROACH: The effects of subcutaneously administered 5-HT1A receptor ligands on HR dynamics were investigated in C57BL/6 mice during stress-free conditions and emotional challenge (recall of fear conditioned to an auditory stimulus and novelty exposure) using time domain and non-linear HR analyses. KEY
RESULTS: Pre-training treatment with of 8-OH-DPAT (0.5 mg·kg(-1) , s.c.) prevented conditioned tachycardia in the retention test indicating impaired fear memory. Pretest 5-HT1A receptor activation by 8-OH-DPAT (0.5 but not 0.1 and 0.02 mg·kg(-1) ) caused bradycardia and increased HR variability. 8-OH-DPAT (0.5 mg·kg(-1) ) lowered the unconditioned and conditioned tachycardia from ∼750 to ∼550 bpm, without changing the conditioned HR response to the sound. 8-OH-DPAT induced profound QT prolongation and bradyarrhythmic episodes. Non-linear analysis indicated a pathological state of HR dynamics after 8-OH-DPAT (0.5 mg·kg(-1) ) with ANS hyperactivation impairing HR adaptability. The 5-HT1A receptor antagonist WAY-100635 (0.03 mg·kg(-1) ) blocked these effects of 8-OH-DPAT. CONCLUSIONS AND IMPLICATIONS: Pre-training 5-HT1A receptor activation by 8-OH-DPAT (0.5 mg·kg(-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.