Obesity is associated with high serotonin 4 receptor availability in the brain reward circuitry

Haahr, Mette E.; Rasmussen, Peter Mondrup; Madsen, Karine; Marner, Lisbeth; Ratner, Cecilia; Gillings, Nic; Baaré, William F.C.; Knudsen, Gitte M.

doi:10.1016/j.neuroimage.2012.03.050

Cited by 61 publications

(36 citation statements)

References 45 publications

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“…These findings are substantiated by fMRI reports of visually perceived foods showing increased VP activity that correlats with the degree of food ‘pleasantness’ (Rudenga et al, 2010; Simmons et al, 2014). Underscoring the role of the VP in dysregulated food reward processes is the positive correlation of positron emission tomography (PET) for 5HT 4 receptor density in this region with body mass index indicative of obesity in humans (Haahr et al, 2012). PET for mu opioid receptors indicate that increases in negative affect ratings by healthy human volunteers, which are associated with sustained sadness (Zubieta et al, 2003), or sustained muscle pain (Zubieta et al, 2002), correlate with deactivation of these receptors in the VP.…”

Section: 0 Drugs Of Abuse; Influences On Vp Function and Behaviormentioning

confidence: 99%

The ventral pallidum: Subregion-specific functional anatomy and roles in motivated behaviors

Root

Meléndez

Záborszky

et al. 2015

Progress in Neurobiology

297

362

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The ventral pallidum (VP) plays a critical role in the processing and execution of motivated behaviors. Yet this brain region is often overlooked in published discussions of the neurobiology of mental health (e.g., addiction, depression). This contributes to a gap in understanding the neurobiological mechanisms of psychiatric disorders. This review is presented to help bridge the gap by providing a resource for current knowledge of VP anatomy, projection patterns and subregional circuits, and how this organization relates to the function of VP neurons and ultimately behavior. For example, ventromedial (VPvm) and dorsolateral (VPdl) VP subregions receive projections from nucleus accumbens shell and core, respectively. Inhibitory GABAergic neurons of the VPvm project to mediodorsal thalamus, lateral hypothalamus, and ventral tegmental area, and this VP subregion helps discriminate the appropriate conditions to acquire natural rewards or drugs of abuse, consume preferred foods, and perform working memory tasks. GABAergic neurons of the VPdl project to subthalamic nucleus and substantia nigra pars reticulata, and this VP subregion is modulated by, and is necessary for, drug-seeking behavior. Additional circuits arise from nonGABAergic neuronal phenotypes that are likely to excite rather than inhibit their targets. These subregional and neuronal phenotypic circuits place the VP in a unique position to process motivationally-relevant stimuli and coherent adaptive behaviors.

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Section: 0 Drugs Of Abuse; Influences On Vp Function and Behaviormentioning

confidence: 99%

The ventral pallidum: Subregion-specific functional anatomy and roles in motivated behaviors

Root

Meléndez

Záborszky

et al. 2015

Progress in Neurobiology

297

362

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“…The intensity of signals coming from these two regions 11 correlated with the body mass index [118]. No evidence exists that that 5-HT5 and 5-HT 7 receptors are involved in satiety.…”

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confidence: 99%

Serotonin controlling feeding and satiety

Voigt

Fink

2015

Behavioural Brain Research

257

167

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Serotonin has been implicated in the control of satiety for almost four decades. Historically, the insight that the appetite suppressant effect of fenfluramine is linked to serotonin has stimulated interest in and research into the role of this neurotransmitter in satiety. Various rodent models, including transgenic models, have been developed to identify the involved 5-HT receptor subtypes. This approach also required the availability of receptor ligands of different selectivity, and behavioural techniques had to be developed simultaneously which allow differentiating between unspecific pharmacological effects of these ligands and 'true' 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 IntroductionWhat are the behavioural and physiological mechanisms that promote satiety? How is satiety defined? Satiety can be seen as a behavioural state which arises from food consumption and suppresses the initiation of eating for a particular period of time [1]. This description alone suggests a high degree of complexity as peripheral post-ingestive and post-absorptive signals need to be relayed to the brain where they are integrated with other signals to produce (or not) the behavioural state called satiety. The state of satiety is brought about a process called satiation, where sensory, cognitive and early post-ingestive mechanisms bring feeding to a halt and thus stopping a meal. Promoting satiation alone must not necessarily lead to reduced total food intake as the frequency of meals could be increased subsequently. Many peripheral and brain mechanisms have been identified that are involved in the expression satiety and it has been suggested that serotonin accelerates satiation and prolongs satiety [2]. In the following, we will review the role of serotonin in satiety in more detail 1 . The reader will see that, despite immense progress made during the last years, the field is still far from being resolved.As serotonin (5-Hydroxytryptamine; 5-HT) is a phylogenetically old neurotransmitter, various functions had time to evolve in different phyla, but maybe also in different species. 5-HT receptors exist in animal cells for millions of years and they are as old as adrenoreceptors ore some peptide receptors, possibly even older [5,6]. Even in invertebrates such as molluscs (Aplysia californica) and annelids (Hirudo medicinalis), 5-HT might functionally be related to food intake [7]. 5-HT is involved in feeding even in the honeybee where it has separate effects in the gut and in the insect brain [8]. In general, however, 5-HT seems rather to be involved in appetitive behaviours in invertebrates whereas it has more of a satiating effect in vertebrates [9]. In general, 5-HT neurons seem to be more extensively distributed throughout the body in lower animals than in higher animals including mammals where 5-HT neurones...

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“…High densities of 5HT4R are detected in the basal ganglia and limbic structures in the brain, whereas low densities are measured in the neocortex and negligible levels of binding are found in the cerebellum (4)(5)(6)(7). The 5HT4Rs are involved in different brain functions and dysregulation of these receptors has been implicated in depression (8)(9)(10), attention-deficit/hyperactivity disorder (11,12), anorexia and obesity (12,13). Furthermore, autoradiographic examinations of brain tissue from Alzheimer disease subjects have shown a marked loss of 5HT4R in hippocampal and cortical regions, which is consistent with a role of 5HT4R in cognition; and brain tissue from Huntington disease subjects demonstrated a reduction of 5HT4R in the putamen (7).…”

mentioning

confidence: 99%

In Vivo Evaluation of ¹⁸F-MNI698: An ¹⁸F-Labeled Radiotracer for Imaging of Serotonin 4 Receptors in Brain

et al. 2014

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Serotonin 4 receptors (5-hydroxytryptamine receptor 4 [5HT4R]) hold promise as a novel therapeutic approach to multiple brain disorders, including Alzheimer and Huntington disease. In vivo imaging of these receptors with selective 5HT4R radiotracers and PET would be valuable to investigate alterations in 5HT4R in different brain disorders and to assist drug discovery. In this study, 18 F-MNI698 was evaluated as a potential PET radiotracer for imaging of 5HT4R in the brain. Methods: Eighteen PET studies were performed in 3 adult rhesus monkeys. The radiotracer was administered as a bolus intravenous injection or bolus plus constant infusion (time that would be required to inject the bolus at the infusion rate 5 60 min), and arterial blood was collected for data quantification. Kinetic models were used to estimate distribution volumes and binding potentials, for which the cerebellum was used as a reference region. 18 F-MNI698 test-retest variability and upper mass dose limits were determined. Preblocking studies using several doses of SB204070, a selective 5HT4R antagonist, were performed. Results: 18 F-MNI698 avidly entered the monkey brain (peak percentage injected dose of ∼6.6%), and its brain distribution was consistent with known 5HT4R densities. At 120 min after bolus injection and after the start of radiotracer infusion, only less than 5% and approximately 10% parent compound was present in blood, respectively. Measured binding potentials were underestimated by 22%-36% when noninvasive methods were used for data quantification in comparison with invasive methods. A good agreement was found between test-retest measurements. The radiotracer upper mass dose limit (,5% occupancy) was determined to be 13.1 μg per 70 kg of body weight. SB204070 blocked the radiotracer binding in a dose-dependent manner. Conclusion: Data indicate that 18 F-MNI698 is a promising PET radiotracer for imaging of 5HT4R in the brain, and human studies are warranted based on these study results.

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Obesity is associated with high serotonin 4 receptor availability in the brain reward circuitry

Cited by 61 publications

References 45 publications

The ventral pallidum: Subregion-specific functional anatomy and roles in motivated behaviors

The ventral pallidum: Subregion-specific functional anatomy and roles in motivated behaviors

Serotonin controlling feeding and satiety

In Vivo Evaluation of ¹⁸F-MNI698: An ¹⁸F-Labeled Radiotracer for Imaging of Serotonin 4 Receptors in Brain

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Obesity is associated with high serotonin 4 receptor availability in the brain reward circuitry

Cited by 61 publications

References 45 publications

The ventral pallidum: Subregion-specific functional anatomy and roles in motivated behaviors

The ventral pallidum: Subregion-specific functional anatomy and roles in motivated behaviors

Serotonin controlling feeding and satiety

In Vivo Evaluation of 18F-MNI698: An 18F-Labeled Radiotracer for Imaging of Serotonin 4 Receptors in Brain

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In Vivo Evaluation of ¹⁸F-MNI698: An ¹⁸F-Labeled Radiotracer for Imaging of Serotonin 4 Receptors in Brain