title: Central 5-HT1A receptor-mediated modulation of heart rate dynamics and its adjustment by conditioned and unconditioned fear in mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Behavioral Neuroscience Group, Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.
authors.forename: Jiun
authors.initials: J
authors.lastname: Youn
authors.forename: Torben
authors.initials: T
authors.lastname: Hager
authors.forename: Ilga
authors.initials: I
authors.lastname: Misane
authors.forename: Anton W
authors.initials: AW
authors.lastname: Pieneman
authors.forename: René F
authors.initials: RF
authors.lastname: Jansen
authors.forename: Sven Ove
authors.initials: SO
authors.lastname: Ogren
authors.forename: Michael
authors.initials: M
authors.lastname: Meyer
authors.forename: Oliver
authors.initials: O
authors.lastname: Stiedl
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003213:Conditioning, Psychological / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D004644:Emotions; D005239:Fear / Q000187:drug effects; D006321:Heart / Q000294:innervation*; D006339:Heart Rate / Q000187:drug effects; D008024:Ligands; D008297:Male; D011939:Mental Recall / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D017711:Nonlinear Dynamics; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D012815:Signal Processing, Computer-Assisted; D013997:Time Factors
chemical_list: D008024:Ligands; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D044282:Receptor, Serotonin, 5-HT1A
keywords: 5-Hydroxytryptamine; autonomic nervous system; fear conditioning; non-linear dynamics; novelty; radio-telemetry
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