Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Youn J

PROVIDER: S-EPMC3799599 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Youn Jiun J Hager Torben T Misane Ilga I Pieneman Anton W AW Jansen René F RF Ogren Sven Ove SO Meyer Michael M Stiedl Oliver O

British journal of pharmacology 20131001 4

<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>The effects of subcutaneously ...[more]

PMID: 23902597

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Project description:Fibromyalgia (FM) patients have dysfunctional endogenous pain modulation, where opioid and serotonergic signaling is implicated. The aim of this study was to investigate whether genetic variants in the genes coding for major structures in the opioid and serotonergic systems can affect pain modulation in FM patients and healthy controls (HC). Conditioned pain modulation (CPM), evaluating the effects of ischemic pain on pressure pain sensitivity, was performed in 82 FM patients and 43 HC. All subjects were genotyped for relevant functional polymorphisms in the genes coding for the μ-opioid receptor (OPRM1, rs1799971), the serotonin transporter (5-HTT, 5-HTTLPR/rs25531) and the serotonin 1a receptor (5-HT1a, rs6295). Results showed the OPRM1 G-allele was associated with decreased CPM. A significant gene-to-gene interaction was found between the OPRM1 and the 5-HT1a gene. Reduced CPM scores were seen particularly in individuals with the OPRM1 G*/5-HT1a CC genotype, indicating that the 5-HT1a CC genotype seems to have an inhibiting effect on CPM if an individual has the OPRM1 G-genotype. Thus, regardless of pain phenotype, the OPRM1 G-allele independently as well as with an interaction with the 5-HT1a gene influenced pain modulation. FM patients had lower CPM than HC but no group differences were found regarding the genetic effects on CPM, indicating that the results reflect more general mechanisms influencing pain modulatory processes rather than underlying the dysfunction of CPM in FM. In conclusion, a genetic variant known to alter the expression of, and binding to, the my-opioid receptor reduced a subject's ability to activate descending pain inhibition. Also, the results suggest a genetically inferred gene-to-gene interaction between the main opioid receptor and a serotonergic structure essential for 5-HT transmission to modulate pain inhibition. The results in this study highlight the importance of studying joint synergistic and antagonistic effects of neurotransmittor systems in regard to pain modulation.

Dataset Information

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

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

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

Similar Datasets

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