Histamine H<sub>3</sub>Receptors Inhibit Serotonin Release in Substantia Nigra Pars Reticulata

Threlfell, Sarah; Cragg, Stephanie J.; Kalló, Imre; Túri, Gergely F.; Coen, Clive W.; Greenfield, Susan

doi:10.1523/jneurosci.2690-04.2004

Cited by 105 publications

(134 citation statements)

References 55 publications

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“…Furthermore, H 3 heteroreceptors are also located on non-histaminergic neurons, regulating release of neurotransmitters such as acetylcholine, serotonin and dopamine, and may also be involved in food intake regulation [78,42,80,81]. However, SGAs maintain a very weak antagonistic potency at histaminergic H 3 Rs in the brain [82,83].…”

Section: H 1 R H 3 R and Sga-induced Weight Gainmentioning

confidence: 99%

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

Lian

Huang

Pai

et al. 2016

Pharmacological Research

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Second generation antipsychotic drugs (SGAs) cause substantial body weight gain/obesity and other metabolic side-effects such as dyslipidaemia. Their antagonistic affinity to the histaminergic H1 receptor (H1R) has been identified as one of the main contributors to weight gain/obesity side-effects. The effects and mechanisms of betahistine (a histaminergic H1R agonist and H3 receptor antagonist) have been investigated for ameliorating SGA-induced weight gain/obesity in both animal models and clinical trials. It has been demonstrated that co-treatment with betahistine is effective in reducing weight gain, associated with olanzapine in drug-naïve patients with schizophrenia, as well as in the animal models of both drug-naïve rats and rats with chronic, repeated exposure to olanzapine. Betahistine co-treatment can reduce food intake and increase the effect of thermogenesis in brown adipose tissue by modulating hypothalamic H1R-NPY-AMPKα (NPY: neuropeptide Y; AMPKα: AMP-activated protein kinase α) pathways, and ameliorate olanzapineinduced dyslipidaemia through modulation of AMPKα-SREBP-1-PPARα-dependent pathways (SREBP-1: Sterol regulatory element binding protein 1; PPARα: Peroxisome proliferator-activated receptor-α) in the liver. Although reduced locomotor activity was observed from antipsychotic treatment in rats, betahistine did not affect locomotor activity. Importantly, betahistine co-treatment did not influence the effects of antipsychotics on serotonergic receptors in the key brain regions for antipsychotic therapeutic efficacy. However, betahistine co-treatment reverses the upregulated dopamine D2 binding caused by chronic olanzapine administration, which may be beneficial in reducing D2 supersensitivity often observed in chronic antipsychotic treatment. Therefore, these results provide solid evidence supporting further clinical trials in treating antipsychotics-induced weight gain using betahistine in patients with schizophrenia and other mental disorders.

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Section: H 1 R H 3 R and Sga-induced Weight Gainmentioning

confidence: 99%

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

Lian

Huang

Pai

et al. 2016

Pharmacological Research

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“…[32] Furthermore, H3 heteroreceptors are located on non-histaminergic neurons, regulating release of neurotransmitters such as acetylcholine, serotonin and dopamine, which may also be involved in food intake regulation. [6,[33][34][35][36] …”

Section: The Role Of Histamine and H1 Receptors In Food Intake Regulamentioning

confidence: 99%

The Role of Hypothalamic H1 Receptor Antagonism in Antipsychotic-Induced Weight Gain

Deng

Huang

2013

CNS Drugs

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Treatment with second generation antipsychotics (SGAs), notably olanzapine and clozapine, causes severe obesity side effects. Antagonism of histamine H1 receptors has been identified as a main cause of SGAinduced obesity, but the molecular mechanisms associated with this antagonism in different stages of SGAinduced weight gain remain unclear. This review aims to explore the potential role of hypothalamic histamine H1 receptors in different stages of SGA-induced weight gain/obesity and the molecular pathways related to SGA-induced antagonism of these receptors. Initial data have demonstrated the importance of hypothalamic H1 receptors in both short-and long-term SGA-induced obesity. Blocking hypothalamic H1 receptors by SGAs activates AMP-activated protein kinase (AMPK), a well-known feeding regulator. During short-term treatment, hypothalamic H1 receptor antagonism by SGAs may activate the AMPK-carnitine palmitoyltransferase 1 signaling to rapidly increase caloric intake and result in weight gain. During long-term SGA treatment, hypothalamic H1 receptor antagonism can reduce thermogenesis, possibly by inhibiting the sympathetic outflows to the brainstem rostral raphe pallidus and rostral ventrolateral medulla, therefore decreasing brown adipose tissue thermogenesis. Additionally, blocking of hypothalamic H1 receptors by SGAs may also contribute to fat accumulation by decreasing lipolysis but increasing lipogenesis in white adipose tissue. In summary, antagonism of hypothalamic H1 receptors by SGAs may time-dependently affect the hypothalamus-brainstem circuits to cause weight gain by stimulating appetite and fat accumulation but reducing energy expenditure. The H1 receptor and its downstream signaling molecules could be valuable targets for the design of new compounds for treating SGA-induced weight gain/obesity.

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“…[5] The histamine H 3 receptor has been described as a presynaptic autoreceptor [6][7][8] mainly expressed in the central nervous system (CNS), regulating histamine biosynthesis and release, as well as a heteroreceptor on non-histaminergic neurons, where it is capable of inhibiting the release of other important neurotransmitters, such as acetylcholine, noradrenaline, dopamine and serotonin. [9][10][11][12] The blockade of this negative feedback mechanism with histamine H 3 receptor antagonists/inverse agonists suggests that they would be useful for the treatment of a variety of CNS disorders affecting cognition, sleep and energy homeostasis. [13] Many classes of potent H 3 receptor antagonists have been reported in the reference literature.…”

Section: Introductionmentioning

confidence: 99%

Novel sulfonylurea derivatives as H3 receptor antagonists. Preliminary SAR studies

Ceras

Cirauqui

Pérez‐Silanes

et al. 2012

European Journal of Medicinal Chemistry

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Abstract:The combination of antagonism at histamine H 3 receptor and the stimulation of insulin secretion have been proposed as an approach to new dual therapeutic agents for the treatment of type 2 diabetes mellitus associated with obesity. We have designed and synthesized a new series of non-imidazole derivatives, based on a basic amine ring connected through an alkyl spacer of variable length to a phenoxysulfonylurea moiety. These compounds were initially evaluated for histamine H 3 receptor binding affinities, suggesting that a propoxy chain linker between the amine and the core ring could be essential for optimal binding affinity. Compound 56, 1-(naphthalen-1-yl)-3-[(p-(3-pyrrolidin-1-ylpropoxy)benzene)]sulfonylurea exhibited the best H 3 antagonism affinity. However, since all these derivatives failed to block K ATP channels, the link of these two related moieties should not be considered a good pharmacophore for obtaining new dual H 3 antagonists with insulinotropic activity, suggesting the necessity to propose a new chemical hybrid prototype.

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Histamine H₃Receptors Inhibit Serotonin Release in Substantia Nigra Pars Reticulata

Cited by 105 publications

References 55 publications

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

The Role of Hypothalamic H1 Receptor Antagonism in Antipsychotic-Induced Weight Gain

Novel sulfonylurea derivatives as H3 receptor antagonists. Preliminary SAR studies

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Histamine H3Receptors Inhibit Serotonin Release in Substantia Nigra Pars Reticulata

Cited by 105 publications

References 55 publications

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

The Role of Hypothalamic H1 Receptor Antagonism in Antipsychotic-Induced Weight Gain

Novel sulfonylurea derivatives as H3 receptor antagonists. Preliminary SAR studies

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Product

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Histamine H₃Receptors Inhibit Serotonin Release in Substantia Nigra Pars Reticulata