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Genetic Regulation of Behavioral and Neuronal Responses to Fluoxetine

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Genetic Regulation of Behavioral and Neuronal Responses to Fluoxetine Neuropsychopharmacology (2008) 33, 1312–1322 & 2008 Nature Publishing Group All rights reserved 0893-133X/08 $30.00 www.neuropsychopharmacology.org Genetic Regulation of Behavioral and Neuronal Responses to Fluoxetine 1 1 1 1 ,1 Brooke H Miller , Laura E Schultz , Anisha Gulati , Michael D Cameron and Mathew T Pletcher* 1Department of Molecular Therapeutics, The Scripps Research InstituteFScripps Florida, Jupiter, FL, USA Despite widespread use of antidepressants, the factors underlying the behavioral response to antidepressants are unknown. It has been shown that antidepressant treatment promotes the proliferation and survival of neurons in the adult hippocampus via enhanced serotonergic signaling, but it is unclear whether hippocampal neurogenesis is responsible for the behavioral response to antidepressants. Furthermore, a large subpopulation of patients fails to respond to antidepressant treatment due to presumed underlying genetic factors. In the present study, we have used the phenotypic and genotypic variability of inbred mouse strains to show that there is a genetic component to both the behavioral and neuronal effects of chronic fluoxetine treatment, and that this antidepressant induces an increase in hippocampal cell proliferation only in the strains that also show a positive behavioral response to treatment. Furthermore, the behavioral and neuronal responses are associated with an upregulation of genes known to promote neuronal proliferation and survival. These results suggest that inherent genetic predisposition to increased serotonin-induced neurogenesis may be a determinant of antidepressant efficacy. Neuropsychopharmacology (2008) 33, 1312–1322; doi:10.1038/sj.npp.1301497; published online 4 July 2007 Keywords: inbred mouse strains; fluoxetine; tail suspension test; neurogenesis; BrdU; depression INTRODUCTION has, therefore, been hypothesized that increased mono- aminergic transmission is a precursor to molecular and Major depressive disorder (MDD) affects up to 5% of the neural changes that underlie the remission of depression. general population, with a further 15% suffering less severe These changes are likely to include chronic alterations in forms of the disorder (Kessler et al, 2003). While 80% of gene expression and neuronal plasticity that change the patients will experience partial relief of depressive symp- activity of the neural circuitry that regulates mood (Nestler toms, complete remission occurs in only 50–60% of all cases et al, 2002). One of the most intriguing hypotheses despite treatment with multiple antidepressants (Nestler associates antidepressant treatment with elevated neuronal et al, 2002; Rush et al, 2006). Even in patients who respond proliferation and survival rates (Duman et al, 1997; Altar, to drug therapy, chronic treatmentFon the order of weeks 1999; Duman et al, 2001). or monthsFis required before antidepressants provide Neurogenesis is primarily defined as the production of clinical benefit. The result is that many MDD patients suffer new nervous tissue, and is characterized by labeling cells for months or years before finding effective treatment. It is undergoing S phase with the nucleotide precursors bromo- likely that individual genetic differences regulate the 3 deoxyuridine (BrdU) or [ H]thymidine (Duman et al, 2001). response to antidepressants, but few polymorphisms have However, the definition of neurogenesis may be generalized been identified (Binder and Holsboer, 2006; McMahon to encompass subsequent related processes, such as et al, 2006). neuronal differentiation, survival, and incorporation into One barrier to developing more effective treatments for functional networks. In the adult mammalian brain, depression is that the mechanism by which antidepres- neurogenesis is largely restricted to the olfactory bulbs sants act is poorly understood: although antidepressants and the subgranular zone (SGZ) of the hippocampus, a produce elevation of synaptic serotonin levels within region lined with serotonergic fibers (Kaplan and Hinds, minutes of administration (Ross and Renyi, 1975; Bel 1977). Approximately 250 000 new neurons are born and Artigas, 1992; Malagie et al, 1995), measurable clinical monthly in the SGZ of the adult rat, 50–70% of which response may not occur for weeks (Katz et al, 2004). It differentiate into neurons that migrate into the granule cell layer (Hastings and Gould, 1999; Cameron and McKay, *Correspondence: Dr MT Pletcher, The Scripps Research InstituteF 2001). Antidepressants have been shown to increase both Scripps Florida, Jupiter, FL 33458, USA, Tel: + 1 561 799 8832, proliferation and survival of hippocampal neurons under Fax: + 1 561 799 8805, E-mail: [email protected] basal conditions: in the hippocampus of unstressed mice, Received 5 January 2007; revised 21 May 2007; accepted 29 May 2007 chronic antidepressant treatment results in a 60% increase Genetic regulation of fluoxetine response BH Miller et al 1313 in BrdU labeling (Santarelli et al, 2003). Antidepressants can MATERIALS AND METHODS also ameliorate the negative impact of stressors or glucocorticoids on neuronal proliferation: in rats, adminis- Behavioral Testing tration of fluoxetine for 1 week following an acute stressor Male 129S1/SvImJ, A/J, DBA/2J, and SWR/J mice, age prevents the stress-induced reduction in neuronal prolif- 3–5 weeks, were obtained from The Jackson Laboratory eration (Malberg and Duman, 2003), and in tree shrews, (Bar Harbor, ME) and maintained on a 12 : 12 light/dark antidepressant administration prevents the effects of cycle with lights on at 0700 h. Following at least 1 week chronic stress on neuronal atrophy (Czeh et al, 2001). The of acclimation, mice were provided with either untreated time course of antidepressant-induced changes in neuro- or fluoxetine-treated drinking water available ad libitum. genesis closely mimics the time required for mood-elevating Fluoxetine-HCl was obtained from Spectrum Chemicals effects in humans: 1–5 days of selective serotonin reuptake (Gardena, CA). Differences in daily water consumption were inhibitor (SSRI) treatment has no effect on BrdU labeling, previously determined for each strain by measuring water 7–14 days of treatment increases the rate of neuronal intake for 3 weeks from at least 12 mice per strain (129S1/ proliferation, but a minimum of 3–4 weeks of treatment is SvImJ and A/J mice ¼ 5.2 ml (70.36 and 0.22 ml, respec- required to produce an increase in survival (Malberg et al, tively) per day, SWR/J ¼ 5.9 ml (70.29 ml) per day, and 2000; De Foubert et al, 2004). It has recently been shown DBA/2J ¼ 6.4 ml (70.58 ml) per day). We also determined that antidepressant-induced neurogenesis may be necessary the average weight at 10 weeks of age (129S1/SvImJ ¼ for the behavioral response to antidepressants: mice that 23.972.8 g, A/J ¼ 24.872.3 g, DBA/2J ¼ 25.571.4 g, SWR/ received chronic fluoxetine treatment in combination with J ¼ 20.871.3 g), and used this information to dilute irradiation of the hippocampus to prevent neurogenesis fluoxetine in the water to provide a daily dosage of 0, 5, failed to show a response to treatment in two separate 10, 14, or 18 mg/kg/mouse, depending on the experimental behavioral tasks (Santarelli et al, 2003). To date, no human context. To determine whether the addition of fluoxetine to studies have conclusively associated a change in neurogen- the water-affected drinking behavior, and, therefore, esis with depression or the response to antidepressants. fluoxetine intake, water intake for fluoxetine-treated mice However, a number of imaging studies have shown that was monitored. No difference in water intake between the depressed patients have reduced hippocampal volume control and drug-treated mice was observed. compared to normal subjects (Sheline et al, 1996; Videbech Mice were 8–12 weeks of age at the time of behavioral and Avnkilde, 2004), while depressed patients treated testing, which was performed during the light phase of successfully with antidepressants have a normal hippocam- the light/dark cycle between 1300 and 1600 h. Behavioral pal volume (Sheline et al, 2003). despair was measured using a mouse tail suspension The effect of antidepressants on neurogenesis is primarily apparatus from Med Associates (Georgia, VT). Scotch tape mediated by serotonergic regulation of intracellular signal- was used to suspend mice by the tail inside the cubicle, and ing mechanisms that upregulate transcription and growth activity, as measured by load, was recorded for 7 min in 60-s factors involved in neuronal proliferation (Duman et al, blocks, with threshold ¼ 3, gain ¼ 8, and resolution ¼ 2001). In general, conditions that are associated with 200 ms. As all strains were uniformly active for the first reduced serotonergic transmission, such as aging, malnu- minute, only minutes 2–7 were used for determining the trition, or chronically elevated corticosterone reduce SGZ percent of time spent immobile, which was calculated by proliferation, while stimuli that increase neurogenesis, dividing the number of seconds of immobility from blocks 2 such as electroconvulsive therapy and adrenalectomy to 7 by 360. All results are expressed in terms of the percent also increase serotonin levels (Gould, 1999). Under basal of time spent immobile. Approximately 20% of DBA/2J conditions, serotonin appears to play a vital role in mice climbed their tails during behavioral testing; these neurogenesis: injection of either a serotonin neuron-specific mice were excluded from data analysis. All animal
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