Enhanced adrenergic excitation of serotonergic dorsal raphe neurons in genetically obese rats

doi:10.1016/S0304-3940(02)00931-X

Neuroscience Letters

Volume 332, Issue 2, 31 October 2002, Pages 107-110

https://doi.org/10.1016/S0304-3940(02)00931-X Get rights and content

Abstract

Serotonergic neurons in the dorsal raphe nucleus (DRN) project to the ventromedial hypothalamus (VMH), where serotonin (5-HT) release modulates feeding. 5-HT release in the VMH is altered in genetically obese vs. lean Zucker rats. Serotonergic DRN neurons are subject to adrenergic and serotonergic neuromodulation. To determine if the difference in 5-HT release between lean and obese rats might be due to differences in these neuromodulatory pathways, we examined the effects of phenylephrine (PE) and 5-HT on serotonergic DRN neurons using current-clamp recording. Cells from lean and obese animals responded similarly to 5-HT, but cells from obese rats exhibited both a larger depolarization and increased firing rate in response to PE than did cells from lean rats. This indicates that DRN neurons of obese rats have an enhanced adrenergic drive.

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Acknowledgements

This study was supported by a grant from the NIH (DK 32907, B.H.). We gratefully acknowledge Z.Z. Pan for helpful discussions and advice, Jock Hamilton for his technical support, David Gavel and Robert Reeves for assistance in genotyping animals, and Earl Carstens and Dorothy Gietzen for comments on the manuscript.

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2010, Frontiers in Neuroendocrinology
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The neurotransmitter serotonin (5-HT) has been proposed to be involved in the mechanism by which ghrelin potentiates memory, since the peripheral administration of fluoxetine (a selective 5-HT reuptake inhibitor) decreased the effects of hippocampal ghrelin administration on food intake and memory retention, adding an exciting note on the discovery of new pathways of memory regulation [43]. Indeed the neurotransmitter 5-HT has been proposed to be involved in the mechanism of satiety [88], while drugs that inhibit serotonergic neurotransmission increase food intake and vice versa [206]. Besides its role in memory formation, ghrelin action has also been linked to anxiety and depression [11,44,41,42,141].
Ghrelin, a peptide hormone predominantly produced by the stomach, was isolated as the endogenous ligand for the growth hormone secretagogue receptor. Ghrelin is a potent stimulator of growth hormone (GH) secretion and is the only circulatory hormone known to potently enhance feeding and weight gain and to regulate energy homeostasis following central and systemic administration. Therapeutic intervention with ghrelin in catabolic situations may induce a combination of enhanced food intake, increased gastric emptying and nutrient storage, coupled with an increase in GH thereby linking nutrient partitioning with growth and repair processes. These qualities have fostered the idea that ghrelin-based compounds may have therapeutic utility in treating malnutrition and wasting induced by various sub-acute and chronic disorders. Conversely, compounds that inhibit ghrelin action may be useful for the prevention or treatment of metabolic syndrome components such as obesity, impaired lipid metabolism or insulin resistance. In recent years, the effects of ghrelin on glucose homeostasis, memory function and gastrointestinal motility have attracted considerable amount of attention and revealed novel therapeutic targets in treating a wide range of pathologic conditions. Furthermore, discovery of ghrelin O-Acyltransferase has also opened new research opportunities that could lead to major understanding of ghrelin physiology. This review summarizes the current knowledge on ghrelin synthesis, secretion, mechanism of action and biological functions with an additional focus on potential for ghrelin-based pharmacotherapies.
Patterns of fos activation in rat raphe nuclei during feeding behavior
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Serotonin appears to participate in the control of feeding behavior (Blundell, 1977; Simansky, 1996; Kaye et al., 1998; Schuhler et al., 2005) and maybe involved in the modulation of hunger and satiety (Blundell and Hill, 1987), depending on the receptor subtype involved (Bovetto and Richard, 1995; Lin and York, 2005; Somerville et al., 2007). Serotonergic transmission from the dorsal (DRN) (Fletcher and Coscina, 1993; Ohliger-Frerking et al., 2002) and median (MRN) (Wirtshafter, 2001) raphe nuclei to the ventromedial hypothalamus contributes to feeding regulation. Serotonergic neurons also exert facilitatory effect on the trigeminal motoneurons (Ribeiro-do-Valle, 1997; Ribeiro-do-Valle and Lucena, 2001).
To analyze the differential recruitment of the raphe nuclei during different phases of feeding behavior, rats were subjected to a food restriction schedule (food for 2 h/day, during 15 days). The animals were submitted to different feeding conditions, constituting the experimental groups: search for food (MFS), food ingestion (MFI), satiety (MFSa) and food restriction control (MFC). A baseline condition (BC) group was included as further control. The MFI and MFC groups, which presented greater autonomic and somatic activation, had more FOS-immunoreactive (FOS-IR) neurons. The MFI group presented more labeled cells in the linear (LRN) and dorsal (DRN) nuclei; the MFC group showed more labeling in the median (MRN), pontine (PRN), magnus (NRM) and obscurus (NRO) nuclei; and the MFSa group had more labeled cells in the pallidus (NRP). The BC exhibited the lowest number of reactive cells. The PRN presented the highest percentage of activation in the raphe while the DRN the lowest. Additional experiments revealed few double-labeled (FOS-IR + 5-HT-IR) cells within the raphe nuclei in the MFI group, suggesting little serotonergic activation in the raphe during food ingestion. These findings suggest a differential recruitment of raphe nuclei during various phases of feeding behavior. Such findings may reflect changes in behavioral state (e.g., food-induced arousal versus sleep) that lead to greater motor activation, and consequently increased FOS expression. While these data are consistent with the idea that the raphe system acts as gain setter for autonomic and somatic activities, the functional complexity of the raphe is not completely understood.
Gross mapping of α<inf>1</inf>-adrenoceptors that regulate behavioral activation in the mouse brain
2004, Behavioural Brain Research
Brain α₁-adrenoceptors that participate in behavioral activation were mapped in the mouse brain by determining where microinjection of the α₁-antagonist, terazosin, inhibited behavioral activity in a novel cage test. A total of 5 out of 23 tested regions were shown to be involved including the dorsal pons/locus coeruleus region (DP/LC), the dorsal raphe/periaqueductal gray area (DR/PAG), the vermis cerebellum (CER), the nucleus accumbens (ACC) and the medial preoptic area (MPOA). Injection in the 4th ventricle was also effective perhaps by acting on several of these regions simultaneously. A partial inhibition was obtained from the motor cortex. Coinjection of the α_1/2-agonist, 6-fluoronorepinephrine (6FNE) but not the α₂-agonist, dexmedetomidine (DMT) reversed the behavioral inhibition in all regions. It is hypothesized that brain motoric α₁-receptors elicit behavioral activation by coordinately exciting several monoaminergic, motor and motivational systems.
Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin
2004, Biochemical and Biophysical Research Communications
Citation Excerpt :
The fact that the magnitude of the increase in food intake was more remarkable at 24 h could probably be related to the fact that the rats eat mostly during the dark period. Previous reports have demonstrated that serotoninergic neurons in the DRN, project to the ventromedial hypothalamus, where serotonin (5-HT) release modulates feeding [25,26]. The neurotransmitter serotonin appears to be involved in the mechanism of satiety [27].
Ghrelin is a peptide hormone produced and secreted from the stomach. Hypothalamic injection of the peptide increases food intake but it is not known if the peptide affects other brain regions. We measured several behavioral parameters such as anxiety (elevated plus maze), memory retention (step down test), and food intake after injections of different doses of the peptide in the hippocampus, amygdala, and dorsal raphe nucleus (DRN). The injection of ghrelin in the hippocampus and DRN significantly and dose dependently increased food intake in relation to controls rats, while injections into the amygdala did not affect the food intake. We also show for the first time that ghrelin clearly and dose dependently increases memory retention in the hippocampus, amygdala, and DRN. Moreover, ghrelin at different potencies induced anxiogenesis in these brain structures while the highest dose of 3 nmol/μl was effective in all of them. The comparison of sensitivity of each brain structure indicates a specific role of them for each of the behaviors studied. The results provide new insight in to the anatomical substrate and the functional role of extrahypothalamic ghrelin targets in the CNS.
Serotonergic dorsal raphe neurons from obese Zucker rats are hyperexcitable
2003, Neuroscience
Release of serotonin (5-HT) from dorsal raphe nucleus (DRN) neurons projecting to the ventromedial hypothalamus (VMH) has a modulatory effect on the neural pathway involved in feeding, hunger, and satiety. The obese Zucker rat, an animal model of genetic obesity, exhibits differences in serotonin signaling as well as a mutated leptin receptor. To evaluate possible mechanisms underlying this difference in serotonin signaling, we have compared electrophysiological responses of DRN neurons from 14- to 25-day-old male lean (Fa/Fa) and obese (fa/fa) Zucker rats using the whole-cell patch clamp technique on cells in brain slices from these animals. We found that the resting properties of these neurons are not different, but the DRN neurons from obese rats are hyperexcitable in response to current injection. This hyperexcitability is not accompanied by an increase in the depolarization caused by current injection or by changes in the threshold for spiking. However, the hyperexcitability is accompanied by reduction in the size and time course of the afterhyperpolarization (AHP) following an action potential. DRN neurons of obese rats recover from the AHP faster due to a smaller amplitude AHP and a faster time constant (τ) of decay of the AHP. These deficits are not due to changes in the spike waveform, as the spike amplitude and duration do not differ between lean and obese animals.
In summary, we provide evidence that serotonergic DRN neurons from obese Zucker rats are intrinsically hyperexcitable compared with those from lean rats. These results suggest a potential mechanism for the reported increase in 5-HT release at the VMH of obese rats during feeding, and provide the first direct evidence of changes in the intrinsic activity of serotonergic neurons, which are crucial regulators of feeding behavior, in a genetic model of obesity.
The distributions and signaling directions of the cerebrospinal fluid contacting neurons in the parenchyma of a rat brain
2003, Brain Research
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These regions include the locus coeruleus nucleus, the solitary tract nucleus, the raphes magnus nucleus, the nigra substance, the thalamo-central medial nucleus, the parafascicular nucleus, the gigantocellular reticular nucleus, the preoptic area and the cortex. Many studies have indicated that the dorsal raphe nucleus is a nucleus which has many physiological functions including thermoregulation [15], sleep [14,32,43], cardiovascular functions [33], hormone-endocrine functions [18,26], multiple arousal systems [5], obesity [36], anxiety and depression [10,39], conditioned-fear and stress [22], sexual behaviors [23] and mood disorders [2]. It is important in pain modulation and anti-nociception function [9,48].
Many studies have been made on the distributions of CSF contacting neurons (CSF-CNs) in the parenchyma of the brain with horseradish peroxidase (HRP) or autoradiographics. A significant amount of data has shown that both HRP and autoradiographical substances could pass freely through the spaces of ependyma into the parenchyma of the brain. It is therefore possible that the results were not exact. We found that CB-HRP was a dependable tracer to CSF-CNs and studied the distributions and the signaling directions of cerebrospinal fluid contacting neurons (CSF-CNs) in the parenchyma of the brain with the cholera toxin subunit B with horseradish peroxidase (CB-HRP) tracing combined with transmission electron microscopy. The results were as follows: (1) CSF contacting tanycytes existed not only in the wall of the third ventricle (3V), but also in the walls of the lateral ventricle (LV), the fourth ventricle (4V) and the central canal (CC) of the spinal cord. (2) Some CSF contacting glia cells were observed in the lateral septal nucleus (LS). (3)The distal CSF-CNs in the parenchyma were found in LS, the anterodorsal thalamic nucleus (AD), the supramammillary nucleus (SuM), the dorsal raphe nucleus (DR), the floor of 4V and the lateral superior olive (LSO), but they were mainly found in DR and divided into groups A and B. (4) Axon terminals labeled by CB-HRP were found in the cavity of the brain ventricle. (5) The synaptic relationships between the neurons were labeled by CB-HRP in DR and no-labeled by CB-HRP in the parenchyma. Both synapses Gray I and II were found. It was significant that the presynaptic elements were formed by the neurons no-labeled CB-HRP and the postsynaptic elements labeled CB-HRP. Our results suggested firstly that the signaling directions of CSF-CNs in DR were only from the parenchyma to CSF.

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Enhanced adrenergic excitation of serotonergic dorsal raphe neurons in genetically obese rats

Abstract

Section snippets

Acknowledgements

Brain Res.

Brain Res.

Pharmacol. Biochem. Behav.

Physiol. Behav.

Modulation of a transient outward current in serotonergic neurons by alpha 1-adrenoceptors

Nature

Phenotype of fatty due to Gln269Pro mutation in the leptin receptor (Lepr)

Diabetes