Gender-dependent regulation of G-protein-gated inwardly rectifying potassium current in dorsal raphe neurons inknock-out mice devoid of the 5-hydroxytryptamine transporter

Loucif, Alexandre; Bonnavion, Patricia; Macri, Beatrice Mihaela; Golmard, Jean Louis; Boni, Claudette; Melfort, Maxette; Léonard, Grégoire; Lesch, Klaus‐Peter; Adrien, Joëlle; Jacquin, Thierry Didier

doi:10.1002/neu.20321

Cited by 15 publications

(13 citation statements)

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“…We were interested in gender effects as these may be particularly relevant in studies of the 5-HT system [77], [78], [79], [80]. We previously reported of an interaction between gender and inferred 5-HTT expression for cold-pain thresholds [32].…”

Section: Discussionmentioning

confidence: 99%

Serotonin-1A Receptor Polymorphism (rs6295) Associated with Thermal Pain Perception

et al. 2012

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BackgroundSerotonin (5-HT) is highly involved in pain regulation and serotonin-1A (5-HT1A) receptors are important in determining central 5-HT tone. Accordingly, variation in the 5-HT1A receptor gene (HTR1A) may contribute to inter-individual differences in human pain sensitivity. The minor G-allele of the HTR1A single nucleotide polymorphism (SNP) rs6295 attenuates firing of serotonergic neurons and reduces postsynaptic expression of the receptor. Experiments in rodents suggest that 5-HT1A-agonism modulates pain in opposite directions at mild compared to high noxious intensities. Based upon this and several other similar observations, we hypothesized that G-carriers would exhibit a relative hypoalgesia at mild thermal stimuli but tend towards hyperalgesia at higher noxious intensities.MethodsFourty-nine healthy individuals were selectively genotyped for rs6295. Heat- and cold-pain thresholds were assessed along with VAS-ratings of a range of suprathreshold noxious heat intensities (45°C–49°C). Nociceptive-flexion reflex (NFR) thresholds were also assessed.ResultsVolunteers did not deviate significantly from Hardy-Weinberg equilibrium. G-carriers were less sensitive to threshold-level thermal pain. This relative hypoalgesia was abolished at suprathreshold noxious intensities where G-carriers instead increased their ratings of heat-pain significantly more than C-homozygotes. No differences with regard to NFR-thresholds emerged.Conclusion/SignificanceTo the best of our knowledge this is the first study of human pain perception on the basis of variation in HTR1A. The results illustrate the importance of including a range of stimulus intensities in assessments of pain sensitivity. In speculation, we propose that an attenuated serotonergic tone may be related to a ‘hypo- to hyperalgesic’ response-pattern. The involved mechanisms could be of clinical interest as variation in pain regulation is known to influence the risk of developing pain pathologies. Further investigations are therefore warranted.

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Section: Discussionmentioning

confidence: 99%

Serotonin-1A Receptor Polymorphism (rs6295) Associated with Thermal Pain Perception

et al. 2012

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“…Other networks that profoundly affect striatal DA function include the mesocortical DA pathways, which themselves exhibit hormone responsiveness and sex differences in function and ER localization in their cells of origin (Kritzer and Creutz, 2008). The serotonergic system of the dorsal raphe is also an estrogen-sensitive major regulator of SNc DA neurons (Klink et al, 2002) that not only exhibits sex differences in G-protein signaling mechanisms (Loucif et al, 2006) but also has a sexually dimorphic ultrastructure in humans (Cordero et al, 2000). Together, these observations highlight the sexually dimorphic state and hormonal sensitivity of the networks interacting with and regulating the NSDA system.…”

Section: Sex-specific Estrogen Actions In the Brainmentioning

confidence: 99%

Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines

2010

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“…Interestingly, signaling to this pathway depends on the 5-HT1A agonist used [82,84,85]. In addition, the 5-HT1A autoreceptor also activates GIRK potassium channels to inhibit neuronal firing [86-89], and inhibits voltage-gated calcium channel activity to reduce calcium entry [90-92] (Figure 3). In post-synaptic cortical neurons, 5-HT1A-mediated inhibition of cAMP is thought to reduce CAMKII activity and to reduce AMPA receptor levels [93].…”

Section: -Ht1a Receptors and The 5-ht Systemmentioning

confidence: 99%

Transcriptional dysregulation of 5-HT1A autoreceptors in mental illness

2011

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The serotonin-1A (5-HT1A) receptor is among the most abundant and widely distributed 5-HT receptors in the brain, but is also expressed on serotonin neurons as an autoreceptor where it plays a critical role in regulating the activity of the entire serotonin system. Over-expression of the 5-HT1A autoreceptor has been implicated in reducing serotonergic neurotransmission, and is associated with major depression and suicide. Extensive characterization of the transcriptional regulation of the 5-HT1A gene (HTR1A) using cell culture systems has revealed a GC-rich "housekeeping" promoter that non-selectively drives its expression; this is flanked by a series of upstream repressor elements for REST, Freud-1/CC2D1A and Freud-2/CC2D1B factors that not only restrict its expression to neurons, but may also regulate the level of expression of 5-HT1A receptors in various subsets of neurons, including serotonergic neurons. A separate set of allele-specific factors, including Deaf1, Hes1 and Hes5 repress at the HTR1A C(-1019)G (rs6295) polymorphism in serotonergic neurons in culture, as well as in vivo. Pet1, an obligatory enhancer for serotonergic differentiation, has been identified as a potent activator of 5-HT1A autoreceptor expression. Taken together, these results highlight an integrated regulation of 5-HT1A autoreceptors that differs in several aspects from regulation of post-synaptic 5-HT1A receptors, and could be selectively targeted to enhance serotonergic neurotransmission.

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Gender-dependent regulation of G-protein-gated inwardly rectifying potassium current in dorsal raphe neurons inknock-out mice devoid of the 5-hydroxytryptamine transporter

Cited by 15 publications

References 51 publications

Serotonin-1A Receptor Polymorphism (rs6295) Associated with Thermal Pain Perception

Serotonin-1A Receptor Polymorphism (rs6295) Associated with Thermal Pain Perception

Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines

Transcriptional dysregulation of 5-HT1A autoreceptors in mental illness

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