Citalopram-mediated anxiolysis and differing neurobiological responses in both sexes of a genetic model of depression (original) (raw)
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Strain-dependent antidepressant-like effects of citalopram in the mouse tail suspension test
Psychopharmacology, 2005
Rationale: Variations in the effects of antidepressant drugs between different mouse strains are important for drug discovery and could lead to the identification of genes that predict differences in drug efficacy. Objectives: This study compared behavioral baselines and dose-dependent responses to the selective serotonin reuptake inhibitor (SSRI) citalopram in eight inbred mouse strains (C57BL/6J, DBA/2J, C3H/HeJ, BALB/cJ, A/J, 129/ SvEmsJ, 129/SvImJ, and BTBR) using the tail suspension test (TST). Results: The DBA/2J, BALB/cJ, and BTBR strains were the most responsive to the effects of citalopram. Citalopram was least effective in the C57BL/6J and A/J strains. The antidepressant-like effects of citalopram in the TST were not correlated with changes in locomotor activity or deprivation-induced feeding behavior across the individual mouse strains, suggesting that patterns of sensitivity to citalopram are behaviorally specific and unlikely to result from pharmacokinetic variables. As an initial search for genetic polymorphisms causing differences in citalopram sensitivity, polymorphic forms of the tryptophan hydroxylase 2 (tph2) gene were genotyped and found to be not correlated with citalopram responsive (DBA/2J and BALB/cJ) and nonresponsive (A/J and C57BL/6J) strains. Conclusions: The TST strain survey described here: (1) suggested the most appropriate strains for screening potential antidepressants, (2) identified parental strains appropriate for quantitative trait loci mapping of genomic loci regulating SSRI sensitivity, and (3) indicated appropriate background strains for measuring an antidepressantlike response to the SSRI citalopram. The pattern of response agrees with a previous mouse strain survey that examined sensitivity to fluoxetine in the forced swim test (Lucki et al. Psychopharmacology 155:315-322, 2001).
Journal of neural transmission (Vienna, Austria : 1996), 2016
Pharmacogenetic approach to antidepressant (AD) response is a promising avenue toward individualizing AD treatment. This is particularly relevant in pediatric populations because of concerns about the suicide risk of serotonin selective reuptake inhibitors (SSRIs), resulting in a black-box warning. However, to date, no specific gene or polymorphism has been consistently implicated as a marker of AD side effect (SE) in the pediatric population. The aim of this study was to examine the association between polymorphisms in genes related to the serotonergic system and citalopram SE's in children and adolescents with major depressive disorder (MDD)/dysthymia and/or anxiety disorders. Outpatients (N = 87, 44 % males), aged 7-18 years with a DSM-IV-TR diagnosis of MDD/dysthymia and/or an anxiety disorder were treated in an 8-week open trial with 20-40 mg/day of citalopram. SE's were rated using a questionnaire devised specifically for this study. Association analysis between known/...
Neuropsychobiology, 2013
Background: Serotonergic genes have been widely investigated regarding antidepressant response in major depressive disorder (MDD) but results are still not univocal. Methods: 159 MDD patients treated with citalopram were genotyped and evaluated by the 21-item Hamilton Depression Rating Scale at the beginning and every 4 weeks during the 12-week follow-up. Four serotonin-related genetic variants were tested for association with treatment outcome: tryptophane hydroxylase 1 (TPH1) rs1800532, monoamine oxidase A µVNTR, serotonin 2A receptor rs6311 and serotonin 2C receptor rs6318. The effect of these polymorphisms was tested both in the whole sample and in depressive subtypes with usually higher clinical severity: psychotic and melancholic MDD. Results: No effect on response, remission and symptom improvement was found for the four polymorphisms. However, rs1800532 was found to affect the outcome depending on the MDD subtype: the A allele predicted worse response both in MDD with psycho...
Physiology & Behavior, 2018
Depression is associated with significant functional disabilities. Application of new drugs which could enhance the effectiveness of antidepressants drug and reduce side effects of their long-term use seems necessary. Citicoline is used as an effective chemical agent for improving the symptoms of some neurodegenerative diseases. Therefore, in this survey, the application of citicoline as an adjuvant drug was evaluated in mice model of depression. A total of 180 adult NMRI male albino mice were used in this study. All groups were exposed to chronic unexpected mild stress (CUMS) followed by treatment with various doses of citalopram or/and citicoline or saline for 21 days. Sucrose preference (SP), open field (OF), and forced swimming test (FST) were applied to evaluate depression symptoms in the groups. The results indicated that only citicoline at the 5 mg/kg dose had shifted its status from being noneffective to become significantly effective in the co-administered group. The means of SP, OFT, and FST of the treatment groups were significantly different in favor of coadministered group compared with the other groups as well as the control group. Based on the results, it can be concluded that administration of citicoline, as an adjuvant drug, in combination with citalopram, enhanced the effectiveness of selective serotonin reuptake inhibitors (SSRI) drugs for depression treatment.
CITALOPRAM -ANXTIDEPRESSANT AND ANXIOLYTIC PROFILE OF SELECTIVE SEROTONIN UPTAKE INHIBITOR IN RATS
Serotonin is the well-known neurotransmitter extensively distributed in the CNS. Mainly 5-HT and its related drugs are used in psychiatry and neurology. Selective serotonin re-uptake inhibitors (SSRIs) were initially introduced as antidepressants, and their potential as anxiolytic has been observed in the treatment of social phobia, post-traumatic stress disorder, and generalized anxiety disorder. SSRIs are the latest generated antidepressants having the selective mechanism of action towards 5-Hydroxytryptamine (Serotonin; 5-HT) without affecting any other unwanted effects on other neurotransmitters. The present study was designed to investigate the behavioral effects of oral citalopram (CTP) administration at the dose of 100 mg/kg/day in the rats produced on acute as well as on repeated administration by using different behavioral models, in familiar as well as in novel environment. Male rats were divided into two groups. Animals of CTP group were administrated with CTP orally while water was administrated in controls. Food intake, growth rate and activity in an open field and light/dark transition box were monitored on next day of 1 st and 7 th administration. Locomotive effects of the treatment were analyzed in activity box on next day of each and every administration. Results from the present study revealed the hypophagic and decreased in body weight effects of the citalopram administration while locomotors activity in open field as well as in activity box were increased significantly after the repeated administrations. Anxiolytic like behavior were monitored on repeated administration but not on single administration. These information support clinical discoveries that citalopram is a powerful, very much endured SSRI with antidepressant-like activity.
Pharmacological Reports, 2012
Background: Selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed antidepressant class today and exert their effects by increasing synaptic concentrations of serotonin (5-HT).The forced swim test (FST) is the most widely used animal test predictive of antidepressant action. Rationale of the present study was to investigate the acute effects of citalopram on hepatic tryptophan metabolism and disposition in rats exposed to FST. Methods: We investigated the effects of acute citalopram (20 mg/kg, ip) administration on rat's behavioral responses in FST paradigm, hepatic tryptophan 2,3-dioxygenase (TDO) activity, serum corticosterone levels and brain regional 5-HT metabolism. Results: Citalopram administered to swim-stressed rats showed a decrease in FST-induced increases in plasma corticosterone concentration and 5-HT turnover in hypothalamus, amygdala and hippocampus. The drug also decreases immobility and increases swimming during the FST. Citalopram administration to unstressed rats increases plasma corticosterone concentration but decreases 5-HT turnover in all three brain areas examined. Conclusions: Our findings support the hypothesis that acute citalopram administration increases tryptophan (by inhibiting TDO activity) availability for 5-HT synthesis and activates serotonergic neurotransmission in limbic brain areas in rats exposed to FST paradigm. The mechanism of action of citalopram in ameliorating social stress related depressive disorder in humans is discussed.
Pharmacogenomic Evaluation of the Antidepressant Citalopram in the Mouse Tail Suspension Test
Neuropsychopharmacology, 2006
The identification of genetic variants regulating antidepressant response in human patients would allow for more individualized, rational, and successful drug treatments. We have previously identified the BALB/cJ inbred mouse strain as highly responsive to the selective serotonin reuptake inhibitor (SSRI) citalopram in the tail suspension test (TST), a widely used and well-established screening paradigm for detecting compounds with antidepressant activity. In contrast, A/J mice did not show a significant response to citalopram in this test despite exposure to equivalent plasma levels of the drug. To identify genetic determinants of this differential response, 506 F 2 mice from an intercross between BALB/cJ and A/J mice were phenotyped. Composite interval mapping of 92 mice from the phenotypic extremes revealed three loci on chromosomes 7, 12, and 19 affecting citalopram response in the TST. The quantitative trait locus (QTL) at the telomeric end of chromosome 19 showed the greatest level of significance. Three candidate genes residing in this locus include those for vesicular monoamine transporter 2 (VMAT2, slc18a2), alpha 2A adrenergic receptor (adra2a), and beta 1 adrenergic receptor (adrb1). The protein coding regions of these three genes in BALB/cJ and A/J mice were sequenced and two polymorphisms were found in VMAT2 (Leu117Pro and Ser505Pro), while the transcribed regions of adra2a and adrb1 were of identical sequence between strains. Follow-up studies are needed to determine if the VMAT2 polymorphisms are functional and if they could explain the chromosome 19 QTL. The present quantitative trait study suggests possible candidate genes for human pharmacogenetic studies of therapeutic responses to SSRIs such as citalopram.
Experimental and Clinical Psychopharmacology, 2011
Individual vulnerability to psychopathologies is linked to a number of genetic polymorphisms including the serotonin transporter (5HTT) promoter polymorphic region (5HTTLPR). A single copy of the short variant (s-variant) allele of 5HTTLPR confers increased susceptibility to anxiety disorders and depression and decreased efficacy of serotonin-releasing agents in pharmacotherapy compared to the homozygous long 5HTTLPR variant (l/l). The data suggesting that the 5HTTLPR polymorphism modulates the efficacy of serotonin-releasing agents in pharmacotherapy is inconsistent. Other factors such as age, gender, and hormonal status could interact with 5HTTLPR genotype to affect individual physiological and behavioral responses to serotonin reuptake inhibitors such as citalopram. Indeed, estradiol and progesterone, the primary female steroid hormones, exert an array of effects on the serotonergic system, including 5HTT expression. The present study used ovariectomized female rhesus monkeys to determine the interaction between the 5HTTLPR polymorphism and the effects of mid-follicular levels of estradiol and luteal levels of progesterone on serotonergic responsivity to acute citalopram administration. The increase in serum prolactin, a surrogate measure of serotonin activity, following citalopram administration was significantly larger in l/l females than in s-variant females over the course of two hours during concurrent estradiol and progesterone hormone replacement only. These data suggest that ovarian function and the 5HTTLPR polymorphism interact to gate serotonergic reactivity in females, suggesting that clinicians should be aware of the ovarian status and 5HTTLPR genotype of women when considering serotonergic pharmacotherapy in women.