Relationship between brain serotonin transporter binding, plasma concentration and behavioural effect of selective serotonin reuptake inhibitors

Hirano, Kazuyuki; Kimura, Ryohei; Sugimoto, Yukihiko; Yamada, Jun; Uchida, Shinya; Kato, Yasuhiro; Hashimoto, Hisakuni; Yamada, Shizuo

doi:10.1038/sj.bjp.0706108

Cited by 87 publications

(66 citation statements)

References 22 publications

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“…The present results support that notion as antidepressants have been shown to reduce marble burying [16,29]. The mechanism behind such an antidepressant-like profile remains unclear, but might include the localization of the receptors to areas such as the hippocampus and amygdala [12], and/or their possible regulation of the activity of serotonergic neurons by interactions with glutamatergic [9] or GABAergic [34] neurons in the raphe nuclei.…”

supporting

confidence: 86%

The 5-HT7 receptor influences stereotypic behavior in a model of obsessive-compulsive disorder

Hedlund

Sutcliffe

2007

Neuroscience Letters

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The 5-HT 7 receptor has been suggested as a new putative target for the treatment of neuropsychiatric disorders, especially depression. This hypothesis is based on the finding that antidepressant drugs have relatively high affinity for the 5-HT 7 receptor, and that inactivation or blockade of the receptor leads to an antidepressant-like profile in behavioral models and sleep parameters. Obsessivecompulsive disorder is also believed to involve the serotonergic system and is treated using antidepressants, thus it is of interest to study the possible role of the 5-HT 7 receptor in this disorder. We have evaluated the effect of inactivation or pharmacological blockade of the 5-HT 7 receptor in three mouse behavioral models that are believed to mimic some of the stereotypic aspects of obsessive-compulsive disorder. In the most well established behavioral model, marble burying, both inactivation and blockade of the 5-HT 7 receptor reduced stereotypic behavior in that the number of marbles buried decreased. In two newer, less well characterized models, head dipping and plasticmesh screen chewing, there was no difference between wild-type mice and mice lacking the 5-HT 7 receptor. Taken together the data confirms and expands on previous findings that the 5-HT 7 receptor is of importance for behaviors affected by antidepressants, and suggests that the 5-HT 7 receptor might be of relevance as a target for the treatment of obsessive-compulsive disorder. Keywordsserotonin; marble burying; head dipping; screen chewing; SB-269970The 5-HT 7 receptor, one of the most recently discovered receptors for serotonin [12], has been found to modulate behaviors affected by antidepressant drugs. In both the forced swim test and the tail suspension test, inactivation or blockade of the 5-HT 7 receptor lead to antidepressantlike behavior [7,13,35]. Furthermore, inactivation or pharmacological blockade of the 5-HT 7 receptor lead to changes in rapid eye movement sleep that are opposite to those seen in depression [8,13]. In addition, it has been shown that certain antidepressants might exert some of their effects by acting directly at the 5-HT 7 receptor [26].Obsessive-compulsive disorder (OCD) is a debilitating disease with an overall prevalence of close to 1 % [15]. There is strong evidence in support of a significant role for 5-HT in OCD and antidepressant drugs, mainly selective serotonin reuptake inhibitors (SSRIs), are the pharmacological treatment of choice for OCD [4,15]. However, as many as 40 % of patients do not respond to currently available treatment options [15], so continued research is necessary. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the c...

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supporting

confidence: 86%

The 5-HT7 receptor influences stereotypic behavior in a model of obsessive-compulsive disorder

Hedlund

Sutcliffe

2007

Neuroscience Letters

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“…High doses of Flx have been also used in behavioral studies, although it seems uncertain whether Flx effects in animal models of anxiety or stress are related to its antidepressant activity (Cryan et al, 2002). Others have studied behavioral effects of acute administration of the drug, which again, may have no relationship with antidepressant activity (Hirano et al, 2005). However, one study by Contreras et al (2001) described physiological and behavioral changes in rats after a chronic (21 days), but not acute, dose of 0.5-1 mg/kg, which is equivalent to the one used by us.…”

Section: Discussion Low Levels Of Flx and Rbx Induce Specific Changesmentioning

confidence: 99%

Clinically Relevant Doses of Fluoxetine and Reboxetine Induce Changes in the TrkB Content of Central Excitatory Synapses

Wyneken

Sandoval

et al. 2006

Neuropsychopharmacol

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We have studied the effect of low doses of two widely used antidepressants, fluoxetine (Flx) and reboxetine (Rbx), on excitatory synapses of rat brain cortex and hippocampus. After 15 days of Flx treatment (0.67 mg/kg/day), its plasma level was 20.775.6 ng/ml. Analysis of postsynaptic densities (PSDs) by immunoblotting revealed no changes in the glutamate receptor subunits GluR1, NR1, NR2A/ B, mGluR1a nor in the neurotrophin receptor p75 NTR . However, the brain-derived neurotrophic factor (BDNF) receptor TrkB decreased by 42.876%, and remained decreased after 6 weeks of treatment. The BDNF and TrkB content in homogenates of cortex and hippocampus began to rise at 9 and 15 days, respectively, and remained high for up to 6 weeks. Similar results were obtained following chronic Rbx administration at 0.128 mg/kg/day. We propose that BDNF, whose synthesis is increased by antidepressants, and which is in part released at synaptic sites, binds to TrkB in PSDs, leading to the internalization of the BDNF-TrkB complex and, thus, to a decrease of TrkB in the PSDs. This was paralleled by greater levels of phosphorylated (ie activated) TrkB in the light membrane fraction, that contains signaling endosomes. The retrograde transport of endocyted BDNF/TrkB complexes from spines to cell bodies, where it activates the synthesis of more BDNF, is a protracted process, potentially requiring several cycles of TrkB/BDNF complex endocytosis and transport. This positive feedback mechanism may help explain the time-lag between drug administration and its therapeutic effect, that is, the antidepressant drug paradox.

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“…Locomotor activities of the rat kept in separate cages were measured simultaneously. Counts of locomotor activity were recorded in 5 min intervals over 60 h with a computer-linked analysis system (MDC; Neuroscience Idea) (Hirano et al, 2005). Rats were maintained under a 12 h light/dark cycle with lights on at 8:00 A.M. in a temperature-and humidity-controlled room.…”

Section: Behaviormentioning

confidence: 99%

Rats Harboring S284LChrna4Mutation Show Attenuation of Synaptic and Extrasynaptic GABAergic Transmission and Exhibit the Nocturnal Frontal Lobe Epilepsy Phenotype

et al. 2008

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Mutations of genes encoding ␣4, ␤2, or ␣2 subunits (CHRNA4, CHRNB2, or CHRNA2, respectively) of nAChR [neuronal nicotinic ACh (acetylcholine) receptor] cause nocturnal frontal lobe epilepsy (NFLE) in human. NFLE-related seizures are seen exclusively during sleep and are characterized by three distinct seizure phenotypes: "paroxysmal arousals," "paroxysmal dystonia," and "episodic wandering." We generated transgenic rat strains that harbor a missense mutation S284L, which had been identified in CHRNA4 in NFLE. The transgenic rats were free of biological abnormalities, such as dysmorphology in the CNS, and behavioral abnormalities. The mRNA level of the transgene (mutant Chrna4) was similar to the wild type, and no distorted expression was detected in the brain. However, the transgenic rats showed epileptic seizure phenotypes during slow-wave sleep (SWS) similar to those in NFLE exhibiting three characteristic seizure phenotypes and thus fulfilled the diagnostic criteria of human NFLE. The therapeutic response of these rats to conventional antiepileptic drugs also resembled that of NFLE patients with the S284L mutation. The rats exhibited two major abnormalities in neurotransmission: (1) attenuation of synaptic and extrasynaptic GABAergic transmission and (2) abnormal glutamate release during SWS. The currently available genetically engineered animal models of epilepsy are limited to mice; thus, our transgenic rats offer another dimension to the epilepsy research field.

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Relationship between brain serotonin transporter binding, plasma concentration and behavioural effect of selective serotonin reuptake inhibitors

Cited by 87 publications

References 22 publications

The 5-HT7 receptor influences stereotypic behavior in a model of obsessive-compulsive disorder

The 5-HT7 receptor influences stereotypic behavior in a model of obsessive-compulsive disorder

Clinically Relevant Doses of Fluoxetine and Reboxetine Induce Changes in the TrkB Content of Central Excitatory Synapses

Rats Harboring S284LChrna4Mutation Show Attenuation of Synaptic and Extrasynaptic GABAergic Transmission and Exhibit the Nocturnal Frontal Lobe Epilepsy Phenotype

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