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Chronic reductions in serotonin transporter function prevent 5-HT1B-induced behavioral effects in mice.

ABSTRACT: BACKGROUND:Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts, images, or impulses and/or repetitive stereotypical behavior. Obsessive-compulsive disorder patients exhibit reduced prepulse inhibition (PPI) and symptom exacerbation after challenge with 5-HT1B receptor agonists. Recently, gain-of-function alleles of the serotonin transporter (5-HTT) have been associated with OCD. We tested the hypothesis that reducing 5-HTT function chronically, either genetically or via serotonin reuptake inhibitor (SRI) treatment, attenuates PPI deficits and perseverative hyperlocomotion induced by 5-HT1B agonists in mice. METHODS:Mice received subchronic or chronic pretreatment with the SRI fluoxetine and acute treatment with RU24969 (5-HT1A/1B agonist) or 8-OH-DPAT (5-HT1A agonist) and were assessed for PPI, locomotor activity, and spatial patterns of locomotion. The same measures were evaluated in 5-HTT wild-type (WT), heterozygous (HT), and knockout (KO) mice after RU24969 treatment. The effects of WAY100635 (5-HTA antagonist) or GR127935 (5-HT1B/D antagonist) pretreatment on RU24969-induced effects were evaluated. Finally, 5-HT1B binding and functional coupling were assessed in 5-HTT-WT, -HT, and -KO mice, and normal fluoxetine-treated mice. RESULTS:Chronic, but not subchronic, fluoxetine treatment prevented RU24969-induced PPI deficits and perseverative hyperlocomotion. These RU24969-induced effects were mediated via 5-HT1B and not 5-HT1A receptors. 5-HTT-KO mice showed no effects of RU24969, and 5-HTT-HT mice exhibited intermediate phenotypes. 5-HT1B binding and functional coupling were reduced in the globus pallidus and substantia nigra of 5-HTT-KO mice. CONCLUSIONS:Our results demonstrate that chronic, but not subchronic, fluoxetine treatment and 5-HTT knockout robustly attenuate 5-HT1B agonist-induced PPI deficits and perseverative hyperlocomotion. These results may have implications for the etiology and treatment of OCD.

SUBMITTER: Shanahan NA

PROVIDER: S-EPMC2674010 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Chronic reductions in serotonin transporter function prevent 5-HT1B-induced behavioral effects in mice.

Shanahan Nancy A NA Holick Pierz Kerri A KA Masten Virginia L VL Waeber Christian C Ansorge Mark M Gingrich Jay A JA Geyer Mark A MA Hen Rene R Dulawa Stephanie C SC

Biological psychiatry 20081114 5

<h4>Background</h4>Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts, images, or impulses and/or repetitive stereotypical behavior. Obsessive-compulsive disorder patients exhibit reduced prepulse inhibition (PPI) and symptom exacerbation after challenge with 5-HT1B receptor agonists. Recently, gain-of-function alleles of the serotonin transporter (5-HTT) have been associated with OCD. We tested the hypothesis that reducing 5-HTT function chronically, either genetically o ...[more]

PMID: 19013555

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Project description:Reduced function of the serotonin transporter (SERT) is associated with increased susceptibility to anxiety and depression and with type-2 diabetes, which is especially true in older women. Preference for a "Western diet" (WD), enriched with saturated fat, cholesterol, and sugars, may aggravate these conditions. In previous studies, decreased glucose tolerance, central and peripheral inflammation, dyslipidemia, emotional, cognitive, and social abnormalities were reported in WD-fed young female mice. We investigated the metabolic, molecular, and behavioral changes associated with a 3-week-long dietary regime of either the WD or control diet in 12-month-old female mice with three different Sert genotypes: homozygous (Slc6a4) gene knockout (Sert -/-: KO), heterozygous (Sert +/-: HET), or wild-type mice (Sert +/+: WT). In the WT-WD and KO-WD groups, but not in HET-WD-fed mice, most of changes induced by the WD paralleled those found in the younger mice, including brain overexpression of inflammatory marker Toll-like receptor 4 (Tlr4) and impaired hippocampus-dependent performance in the marble test. However, the 12-month-old female mice became obese. Control diet KO mice exhibited impaired hippocampal-dependent behaviors, increased brain expression of the serotonin receptors Htr2c and Htr1b, as well as increased Tlr4 and mitochondrial regulator, peroxisome proliferator-activated receptor gamma-coactivator-1a (Ppargc1a). Paradoxically, these, and other changes, were reversed in KO-WD mutants, suggesting a complex interplay between Sert deficiency and metabolic factors as well as potential compensatory molecular mechanisms that might be disrupted by the WD exposure. Most, but not all, of the changes in gene expression in the brain and liver of KO mice were not exhibited by the HET mice fed with either diet. Some of the WD-induced changes were similar in the KO-WD and HET-WD-fed mice, but the latter displayed a "rescued" phenotype in terms of diet-induced abnormalities in glucose tolerance, neuroinflammation, and hippocampus-dependent performance. Thus, complete versus partial Sert inactivation in aged mice results in distinct metabolic, molecular, and behavioral consequences in response to the WD. Our findings show that Sert +/- mice are resilient to certain environmental challenges and support the concept of heterosis as evolutionary adaptive mechanism.

Project description:BACKGROUND: Women are at great risk for mood and anxiety disorders during their childbearing years and may become pregnant while taking antidepressant drugs. In the treatment of depression and anxiety disorders, selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed drugs, while it is largely unknown whether this medication affects the development of the central nervous system of the fetus. The possible effects are the product of placental transfer efficiency, time of administration and dose of the respective SSRI. METHODOLOGY/PRINCIPAL FINDINGS: In order to attain this information we have setup a study in which these parameters were measured and the consequences in terms of physiology and behavior are mapped. The placental transfer of fluoxetine and fluvoxamine, two commonly used SSRIs, was similar between mouse and human, indicating that the fetal exposure of these SSRIs in mice is comparable with the human situation. Fluvoxamine displayed a relatively low placental transfer, while fluoxetine showed a relatively high placental transfer. Using clinical doses of fluoxetine the mortality of the offspring increased dramatically, whereas the mortality was unaffected after fluvoxamine exposure. The majority of the fluoxetine-exposed offspring died postnatally of severe heart failure caused by dilated cardiomyopathy. Molecular analysis of fluoxetine-exposed offspring showed long-term alterations in serotonin transporter levels in the raphe nucleus. Furthermore, prenatal fluoxetine exposure resulted in depressive- and anxiety-related behavior in adult mice. In contrast, fluvoxamine-exposed mice did not show alterations in behavior and serotonin transporter levels. Decreasing the dose of fluoxetine resulted in higher survival rates and less dramatic effects on the long-term behavior in the offspring. CONCLUSIONS: These results indicate that prenatal fluoxetine exposure affects fetal development, resulting in cardiomyopathy and a higher vulnerability to affective disorders in a dose-dependent manner.

Project description:Preclinical evidence implicates the serotonin receptor 5-hydroxytryptamine 1B (5-HT1B) in the effects of cocaine. This study explores 5-HT1B in humans by examining receptor availability in vivo in subjects whose primary addiction is cocaine dependence (CD) using positron emission tomography.Study participants included 14 medically healthy subjects with CD (mean age = 41 ± 6 years) who were compared with 14 age-matched healthy control subjects (mean age = 41 ± 8 years) with no past or current history of cocaine or other illicit substance abuse. Participants underwent magnetic resonance imaging followed by positron emission tomography with the highly selective 5-HT1B tracer, [(11)C]P943, for purposes of quantifying regional binding potential. Voxel-based morphometry and gray matter masking also were employed to control for potential partial volume effects.The [(11)C]P943 positron emission tomography imaging data in nine candidate regions (amygdala, anterior cingulate cortex, caudate, frontal cortex, hypothalamus, pallidum, putamen, thalamus, and ventral striatum) showed significant or nearly significant reductions of regional binding potential in subjects with CD in three regions: anterior cingulate (-16%, p < .01), hypothalamus (-16%, p = .03), and frontal cortex (-7%, p = .08). Voxel-based morphometry showed significant gray matter reductions in the frontal cortex of subjects with CD. After gray matter masking, statistically significant reductions in the [(11)C]P943 regional binding potential were either retained (anterior cingulate, -14%, p = .01; hypothalamus, -20%, p < .01) or achieved (frontal cortex, -14%, p < .01). Whole-brain voxel-wise parameter estimation confirmed these results. Secondary analyses were also significant in some regions for years of cocaine and daily tobacco use.The reductions found in this study suggest that 5-HT1B receptors may contribute to the etiology or expression of CD and potentially represent a target for medication development.

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Chronic reductions in serotonin transporter function prevent 5-HT1B-induced behavioral effects in mice.

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Chronic reductions in serotonin transporter function prevent 5-HT1B-induced behavioral effects in mice.

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