Chronic Reductions in Serotonin Transporter Function Prevent 5-HT1B-Induced Behavioral Effects in Mice

Committee on Neurobiology, University of Chicago, Chicago, Illinois 60637, USA.
Biological psychiatry (Impact Factor: 10.26). 12/2008; 65(5):401-8. DOI: 10.1016/j.biopsych.2008.09.026
Source: PubMed


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.
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.
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.
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.

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Available from: Stephanie C Dulawa, Dec 14, 2013
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    • "This behavioural response was not attenuated by depletion of brain 5-HT, suggesting a post synaptic mechanism (Cheetham and Heal, 1993). Studies in mice have generally attributed RU 24969-induced hyperlocomotion to 5- HT 1B mechanisms because it was selectively attenuated by pretreatment with 5-HT 1B , but not 5-HT 1A , antagonists (Cheetham and Heal, 1993; Shanahan et al., 2009). In the rat, however, there is a lack of consensus as to whether this effect is due to 5-HT 1A or 5-HT 1B activation because , in different circumstances, RU 24969-induced hyperlocomotion has been blocked by both 5-HT 1A and 5-HT 1B antagonists (Chaouloff et al., 1999; Kalkman, 1995; O'Neill and Parameswaran, 1997). "
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    ABSTRACT: RU 24969 is a widely used, but non-selective, 5-HT1B/1A agonist that decreases fluid consumption and increases forward locomotion. The mechanism underlying these behavioural responses is not, however, well understood. Accordingly, effects of the selective 5-HT1A and 5-HT1B antagonists, WAY 100635, and GR 127935, respectively, on these two responses to RU 24969 were determined. RU 24969 (0.03-3.0 mg/kg, s.c.) dose-dependently decreased water consumption in water deprived rats. This effect was attenuated by GR 127935 (3.0 mg/kg), but not by WAY 100635 (1.0 mg/kg). RU 24969 (0.3-3.0 mg/kg) dose-dependently increased forward locomotion but a higher dose was required to produce this response than the adipsic response. The increased locomotor response was attenuated by WAY 100635 (1.0 mg/kg), but not GR 127935 (3.0 mg/kg). These results suggest that RU 24969-induced adipsia is mediated by 5-HT1B mechanisms, while RU 24969-induced hyperlocomotion is mediated by 5-HT1A mechanisms.
    Pharmacology Biochemistry and Behavior 05/2014; 124. DOI:10.1016/j.pbb.2014.05.008 · 2.78 Impact Factor
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    • "This down-regulation is a delayed effect of chronic exposure to SRI and also has a cumulative effect. Consistently with this delay, in a study by Shanahan et al. (2009) study, four weeks of fluoxetine pretreatment was required to reduce 5-HT1BR-induced perseverative behavior in mice. Therefore, we could hypothesize that 4 weeks is the minimum time required to observe improvement in obsessive-compulsive behavior, as a consequence of SRI down-regulation of 5HT1DR (the human correspondent to 5- HT1BR in mice). "
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    ABSTRACT: Unlabelled: In major depression, early response to treatment has been strongly associated with final outcome. We aimed to investigate the ability of early improvement (4 weeks) to predict treatment response at 12 weeks in DSM-IV-defined obsessive-compulsive disorder (OCD) patients treated with serotonin reuptake inhibitors (SRI). We conducted an SRI practical trial with 128 subjects. Inclusion criteria: age range 18-65 years-old, baseline Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score ≥ 16, and absence of previous adequate pharmacological treatment. Systematic assessments were performed at baseline, 4 and 12 weeks of treatment. Treatment response at 12 weeks was defined as a 35% or greater reduction in baseline Y-BOCS score. Stepwise logistic regression was used to test the relationship between early improvement and treatment response at 12 weeks, taking into account additional potential predictive factors. Different thresholds of early improvement were tested and their predictive power was calculated. Early improvement, defined as a 20% or greater reduction from baseline Y-BOCS score at 4 weeks, predicted response at 12 weeks with 75.6% sensitivity and 61.9% specificity. According to a logistic regression including demographic and clinical features as explaining variables, early improvement was the best predictor of treatment response (OR = 1.05, p < 0.0001). Only 19.8% of patients who did not improve at 4 weeks were responders after 12 weeks. In contrast, 55.3% of the individuals who showed early improvement were responders at 12 weeks (Pearson Chi-Square = 17.06, p < 0.001). Early improvement predicted OCD treatment response with relatively good sensitivity and specificity, such that its role in early decision-making warrants further investigation in wider samples. Trial registration: Identifier NCT00680602.
    Journal of Psychiatric Research 08/2013; 47(11). DOI:10.1016/j.jpsychires.2013.07.006 · 3.96 Impact Factor
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    • "The impact of maternal depression on newborns has effects that last beyond infancy, as onethird of school-aged children of depressed mothers suffer from depression and anxiety disorders (Pilowsky et al., 2006). Beyond childhood, animal studies have shown that neonatal SSRI exposure suppresses adult serotonergic signaling and elicits depressiveand anxiety-like behaviors in adulthood (Ansorge et al., 2008; Shanahan et al., 2009). Maternal depressive states and prenatal exposure to SSRIs both alter fetal health. "
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    ABSTRACT: In addition to its role in the pathophysiology of numerous psychiatric disorders, increasing evidence points to serotonin (5-HT) as a crucial molecule for the modulation of neurodevelopmental processes. Recent evidence indicates that the placenta is involved in the synthesis of 5-HT from maternally derived tryptophan (TRP). This gives rise to the possibility that genetic and environmental perturbations directly affecting placental TRP metabolism may lead to abnormal brain circuit wiring in the developing embryo, and therefore contribute to the developmental origin of psychiatric disorders. In this review, we discuss how perturbations of the placental TRP metabolic pathway may lead to abnormal brain development and function throughout life. Of particular interest is prenatal exposure to maternal depression and antidepressants, both known to alter fetal development. We review existing evidence on how antidepressants can alter placental physiology in its key function of maintaining fetal homeostasis and have long-term effects on fetal forebrain development.
    Frontiers in Cellular Neuroscience 04/2013; 7:47. DOI:10.3389/fncel.2013.00047 · 4.29 Impact Factor
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