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Link to original content: http://pubmed.ncbi.nlm.nih.gov/31599481/
Systemic serotonin inhibits brown adipose tissue sympathetic nerve activity via a GABA input to the dorsomedial hypothalamus, not via 5HT1A receptor activation in raphe pallidus - PubMed Skip to main page content
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. 2020 Mar;228(3):e13401.
doi: 10.1111/apha.13401. Epub 2019 Nov 1.

Systemic serotonin inhibits brown adipose tissue sympathetic nerve activity via a GABA input to the dorsomedial hypothalamus, not via 5HT1A receptor activation in raphe pallidus

Clarissa M D Mota  1   2 , Luiz G S Branco  2   3 , Shaun F Morrison  1 , Christopher J Madden  1
Affiliations

Systemic serotonin inhibits brown adipose tissue sympathetic nerve activity via a GABA input to the dorsomedial hypothalamus, not via 5HT1A receptor activation in raphe pallidus

Clarissa M D Mota et al. Acta Physiol (Oxf). 2020 Mar.

Abstract

Aim: Serotonin (5-hydroxytryptamine, 5-HT), an important neurotransmitter and hormone, modulates many physiological functions including body temperature. We investigated neural mechanisms involved in the inhibition of brown adipose tissue (BAT) sympathetic nerve activity (SNA) and BAT thermogenesis evoked by 5-HT.

Methods: Electrophysiological recordings, intravenous (iv) injections and nanoinjections in the brains of anaesthetized rats.

Results: Cooling-evoked increases in BAT SNA were inhibited by the intra-rostral raphé pallidus (rRPa) and the iv administration of the 5-HT1A receptor agonist, 8-OH-DPAT or 5-HT. The intra-rRPa 5-HT, the intra-rRPa and the iv 8-OH-DPAT, but not the iv 5-HT-induced inhibition of BAT SNA were prevented by nanoinjection of a 5-HT1A receptor antagonist in the rRPa. The increase in BAT SNA evoked by nanoinjection of NMDA in the rRPa was not inhibited by iv 5-HT, indicating that iv 5-HT does not inhibit BAT SNA by acting in the rRPa or in the sympathetic pathway distal to the rRPa. In contrast, under a warm condition, blockade of 5HT1A receptors in the rRPa increased BAT SNA and BAT thermogenesis, suggesting that endogenous 5-HT in the rRPa contributes to the suppression of BAT SNA and BAT thermogenesis. The increases in BAT SNA and BAT thermogenesis evoked by nanoinjection of NMDA in the dorsomedial hypothalamus (DMH) were inhibited by iv 5-HT, but those following bicuculline nanoinjection in the DMH were not inhibited.

Conclusions: The systemic 5-HT-induced inhibition of BAT SNA requires a GABAergic inhibition of BAT sympathoexcitatory neurones in the DMH. In addition, during warming, 5-HT released endogenously in rRPa inhibits BAT SNA.

Keywords: 5-hydroxytryptamine; brown adipose tissue; hypothalamus; raphé pallidus; thermoregulation.

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Conflict of interest statement

Conflict of interest

The authors have no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1
8-OH-DPAT-induced inhibition of skin cooling-evoked brown adipose tissue (BAT) sympathetic nerve activity (SNA) and thermogenesis requires the activation of serotonin (5-HT)1A receptors in the rostral raphé pallidus nucleus (rRPa). A, Intravenous (iv) administration of 8-OH-DPAT (100 εg, 500 εl) decreased BAT SNA, BAT temperature (TBAT), expired CO2 (Exp CO2), heart rate (HR), and arterial pressure (AP). Nanoinjection of WAY100635 in the rRPa increased BAT SNA and TBAT and prevented the iv 8-OH-DPAT-evoked inhibition of BAT SNA and BAT thermogenesis. B, D, Histologic sections illustrating representative rRPa injection sites (arrows) and rRPa nanoinjection sites plotted on a histological schematic of a partial coronal section about −12 mm caudal to bregma. py: pyramidal tract, 7: facial motor nucleus. C, Nanoinjection of 8-OH-DPAT (10 mM, 60 nl) in the rRPa decreased BAT SNA, TBAT, Exp CO2, and HR. Pre-treatment of the rRPa with WAY100635 prevented the 8-OH-DPAT in rRPa-induced inhibition of BAT thermogenesis. Vertical dotted lines represent a gap of 23 minutes.
Fig. 2
Fig. 2
Blockade of 5-HT1AR in the rostral raphé pallidus nucleus (rRPa) increases brown adipose tissue (BAT) sympathetic nerve activity (SNA) and thermogenesis in naïve (no previous 5-HT agonist treatment) rats with a warm skin/core and in non-naïve (previous 5-HT or 8-OH-DPAT iv or into rRPa) rats with a cool skin/core. A, Nanoinjection of WAY100635 (10 mM, 100 nl) in the rRPa in a naïve rat with a warm skin/core increased BAT SNA, BAT temperature (TBAT), and expired CO2 (Exp CO2). B, D, and F, Histologic sections illustrating a representative rRPa injection site (arrow) and rRPa nanoinjection sites plotted on histological schematics of a partial coronal section about −12 mm caudal to bregma. py: pyramidal tract, 7: facial motor nucleus. C, Nanoinjection of WAY100635 (10 mM, 100 nl) in the rRPa (D) of a naïve rat did not affect cool skin/core-activated BAT SNA or BAT thermogenesis. E, Nanoinjection of WAY100635 (10 mM, 100 nl) in the rRPa (F) of a non-naïve rat with cool skin/core increased BAT SNA, TBAT, and Exp CO2. TCORE: core temperature, TSKIN: skin temperature, py: pyramidal tract, 7: facial motor nucleus.
Fig. 3
Fig. 3
Inhibition of the skin/core cooling-evoked (TSKIN=35.7±0.2°C, TCORE= 35.9±0.2°C) increases in brown adipose tissue (BAT) sympathetic nerve activity (SNA) and thermogenesis evoked by the nanoinjection of 5-HT in the rostral raphé pallidus nucleus (rRPa) depends on 5-HT1AR in the rRPa, but a similar inhibition of BAT by iv infusion of 5-HT does not. A, Nanoinjection of 5-HT (33 mM, 60 nl) in the rRPa decreased BAT SNA, BAT temperature (TBAT), expired CO2 (Exp CO2), and heart rate (HR). Pre-treatment of the rRPa with the 5-HT1AR antagonist, WAY100635, prevented the effects of nanoinjection of 5-HT in the rRPa. B, D, Histologic sections illustrating representative rRPa injection sites (arrows) and rRPa nanoinjection sites plotted on a histological schematic of a partial coronal section about −12 mm caudal to bregma. C, Intravenous (iv) administration of 5-HT (500 εg/ml/h) decreased BAT SNA, TBAT, Exp CO2, and arterial pressure (AP). Pre-treatment of the rRPa with WAY100635 had no effect on the inhibition of BAT SNA or BAT thermogenesis from iv 5-HT. py: pyramidal tract, 7: facial motor nucleus.
Fig. 4
Fig. 4
Intravenous (iv) serotonin (5-HT) attenuates brown adipose tissue (BAT) sympathetic nerve activity (SNA) and thermogenesis evoked by blockade of GABAA receptors, but not that by activation of NMDA receptors in the rostral raphé pallidus nucleus (rRPa) A, Nanoinjection of NMDA (0.2 mM, 60 nl) in the rRPa increased BAT SNA, BAT temperature (TBAT), expired CO2 (Exp CO2), heart rate (HR), and arterial pressure (AP). Iv 5-HT decreased baseline AP, but did not affect any of the activations evoked by nanoinjection of NMDA in rRPa. B, D, Histologic sections illustrating representative rRPa injection sites (arrows) and rRPa nanoinjection sites plotted on a histological schematic of a partial coronal section about −12 mm caudal to bregma. C, Under warm conditions (TSKIN=37.0±0.1°C, TCORE=37.1±0.1°C), nanoinjection of bicuculline (BIC, 500 εM, 100 nl) in the rRPa increased BAT SNA, TBAT, Exp CO2, and HR. Iv 5-HT attenuated the BIC in rRPa-evoked increases in BAT SNA and in BAT thermogenesis. py: pyramidal tract, 7: facial motor nucleus.
Fig. 5
Fig. 5
Inhibition of neurons in the dorsomedial hypothalamus (DMH) attenuates brown adipose tissue (BAT) sympathetic nerve activity (SNA) and thermogenesis evoked by blockade of GABAA receptors, but not by activation of glutamate receptors, in the rostral raphé pallidus nucleus (rRPa). A, Nanoinjection of bicuculline (BIC, 500 εM, 100 nl) in the rRPa increased BAT SNA, BAT temperature (TBAT), expired CO2 (Exp CO2), and heart rate (HR). Nanoinjection of NMDA (0.2 mM, 60 nl) in the rRPa increased BAT SNA, TBAT, Exp CO2, and arterial pressure (AP). B, Continued recording (5 minutes between dotted vertical line at the end of record in A and vertical dotted line at the beginning of record in B) from the experiment in A, showing that after nanoinjection of muscimol (2 mM, 60 nl) bilaterally in the DMH, the amplitudes of the increases in BAT SNA, Exp CO2, and AP evoked by nanoinjection of NMDA in the rRPa were unchanged. In contrast, after nanoinjection of muscimol in the DMH, the amplitudes of the increases in BAT SNA, TBAT, Exp CO2, and HR evoked by nanoinjection of BIC in rRPa were attenuated. C, Histologic sections illustrating representative rRPa and DMH nanoinjection sites (arrows), and rRPa and DMH nanoinjection sites plotted on histological schematics of a partial coronal section through the brainstem between −10.5 to −12 mm caudal to bregma and of a coronal section through the hypothalamus at −3.2 mm caudal to bregma. py: pyramidal tract, 7: facial motor nucleus, DA: dorsal hypothalamic area, mt: mammillothalamic tract, f: fornix, 3V: third ventricle.
Fig. 6
Fig. 6
Intravenous (iv) serotonin (5-HT) attenuates brown adipose tissue (BAT) sympathetic nerve activity (SNA) and thermogenesis evoked by activation of glutamate receptors, but not that by blockade of GABAA receptors in the dorsomedial hypothalamus (DMH). A, Nanoinjection of NMDA (0.2 mM, 60 nl) in the DMH increased BAT SNA, BAT temperature (TBAT), and heart rate (HR). Infusion of 5-HT decreased AP and inhibited NMDA-evoked increases in BAT SNA and in BAT thermogenesis. B, D, Histologic sections illustrating representative DMH nanoinjection sites (arrows), and DMH nanoinjection sites plotted on histological schematics of a coronal section through the hypothalamus at −3.2 mm caudal to bregma. C, Nanoinjection of bicuculline (BIC, 500 εM, 100 nl) in the DMH increased BAT SNA. Infusion of 5-HT did not inhibit BIC-evoked increases in BAT SNA or BAT thermogenesis. DA: dorsal hypothalamic area, mt: mammillothalamic tract, f: fornix, 3V: third ventricle.
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