Preclinical Pharmacology of Citalopram

Popik, Piotr

doi:10.1097/00004714-199910001-00002

Cited by 24 publications

(17 citation statements)

References 158 publications

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“…Citalopram is unique among the clinically available SSRIs in having the greatest selectivity for SERT over NET in vitro (27,41) and does not, after systemic application, increase NE concentrations in vivo (4) [it has been reported to increase NE after reverse dialysis in the hippocampus (42)]. In accordance with this finding, the present data show that citalopram is the only antidepressant tested that is equally effective in manifesting its behavioral effects in mice with and without NE.…”

Section: Discussionsupporting

confidence: 85%

“…The greatly diminished behavioral effects in the TST of fluoxetine, sertraline, and paroxetine as compared with citalopram correlate with the selectivity of these compounds for inhibition of 5-HT versus NE reuptake in vitro, with citalopram being the most selective (27). One explanation for the differential effects of these SSRIs could be related to a unique aspect of the Dbh Ϫ/Ϫ mice.…”

Section: Resultsmentioning

confidence: 99%

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Norepinephrine-deficient mice lack responses to antidepressant drugs, including selective serotonin reuptake inhibitors

Cryan

O’Leary

Jin

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

241

127

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Mice unable to synthesize norepinephrine (NE) and epinephrine due to targeted disruption of the dopamine ␤-hydroxylase gene, Dbh, were used to critically test roles for NE in mediating acute behavioral changes elicited by different classes of antidepressants. To this end, we used the tail suspension test, one of the most widely used paradigms for assessing antidepressant activity and depression-related behaviors in normal and genetically modified mice. Dbh ؊/؊ mice failed to respond to the behavioral effects of various antidepressants, including the NE reuptake inhibitors desipramine and reboxetine, the monoamine oxidase inhibitor pargyline, and the atypical antidepressant bupropion, even though they did not differ in baseline immobility from Dbh ؉/؊ mice, which have normal levels of NE. Surprisingly, the effects of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, sertraline, and paroxetine were also absent or severely attenuated in the Dbh ؊/؊ mice. In contrast, citalopram (the most selective SSRI) was equally effective at reducing immobility in mice with and without NE. Restoration of NE by using L-threo-3,4-dihydroxyphenylserine reinstated the behavioral effects of both desipramine and paroxetine in Dbh ؊/؊ mice, thus demonstrating that the reduced sensitivity to antidepressants is related to NE function, as opposed to developmental abnormalities resulting from chronic NE deficiency. Microdialysis studies demonstrated that the ability of fluoxetine to increase hippocampal serotonin was blocked in Dbh ؊/؊ mice, whereas citalopram's effect was only partially attenuated. These data show that NE plays an important role in mediating acute behavioral and neurochemical actions of many antidepressants, including most SSRIs.A ntidepressant medications are thought to elicit their therapeutic effects by increasing synaptic concentrations of the monoamines serotonin (5-HT) and͞or norepinephrine (NE) (1). Most tricyclic antidepressants enhance NE and 5-HT transmission because they inhibit presynaptic reuptake, although most of these drugs have affinity for other neurotransmitter receptors that contribute to their side effect profile. More recently, selective 5-HT reuptake inhibitors (SSRIs) have become widely prescribed because of their improved safety profile from limited interaction with other neurotransmitter receptors (1). However, some investigators have recently challenged whether SSRIs produce effects selectively on the serotonergic system over the noradrenergic and dopaminergic systems (2, 3). Indeed, a number of in vivo microdialysis studies have shown that acute (4-6) and chronic (7-9) treatment with certain SSRIs can increase extracellular concentrations of NE in addition to that of 5-HT.Attempts to delineate the role of NE in the behavioral effects of antidepressants have used inhibition of synthetic enzymes to deplete the neurotransmitter or chemical lesion techniques to destroy NE terminals. However, many depletion agents, such as the tyrosine hydroxylase inhibitor ␣-methyl-p-tyrosine or the v...

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Section: Discussionsupporting

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Norepinephrine-deficient mice lack responses to antidepressant drugs, including selective serotonin reuptake inhibitors

Cryan

O’Leary

Jin

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

241

127

View full text Add to dashboard Cite

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“….05; significance of differences to vehicle values in unpaired t-test (Popik 1999), which has not, to date, been examined in this experimental procedure. This reduction reflected a variable influence on response rates but a consistent reduction in reinforcement rates.…”

Section: Actions Of Ssris: Decrease In Efficiencymentioning

confidence: 98%

Differential modulation of efficiency in a food-rewarded "differential reinforcement of low-rate" 72-s schedule in rats by norepinephrine and serotonin reuptake inhibitors

et al. 2002

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The present experimental procedure demonstrates, in analogy to imipramine and mianserin, robust and consistent increases in efficiency with NARIs. Their effects may be distinguished from a decrease in efficiency elicited by SSRIs, and a lack of activity of SNRIs and DARIs. While the reasons underlying the ineffectiveness of SSRIs (in contrast to previous studies) remain to be clarified, these data underline the importance of adrenergic mechanisms in the control of behaviour under conditions of delayed responding. Further, they support the interest of DRL 72-s procedures for the characterisation of diverse classes of antidepressant agent.

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“…Long-term administration of citalopram, the most selective serotonin reuptake inhibitor, has been associated with a downregulation of 5-HT1A (serotonin) autoreceptors (30). Long-term administration may increase the availability of serotonin at serotonergic receptors in the central nervous system (31). Citalopram may reduce baroreflex sensitivity via stimulation of the 5-HT2 or 5-HT3 receptors.…”

Section: Fig 3 Low Frequency Rr Intervals (Lf Rr) Gain Of the Tranmentioning

confidence: 99%

Specific Serotonin Reuptake Inhibition in Major Depressive Disorder Adversely Affects Novel Markers of Cardiac Risk

et al. 2007

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There exists a growing body of evidence linking depression with cardiovascular events, although the mechanisms responsible remain unknown. We investigated the role of the autonomic nervous system and inflammation in the link between coronary heart disease and major depressive disorder (MDD), and examined the cardiac risk modification following pharmacological treatment of depression. We measured cardiac baroreflex function, heart rate variability, pulse pressure and high sensitivity C-reactive protein (hsCRP), all of which have an impact on cardiac risk, pre-and post-treatment in 25 patients with MDD, with no history of coronary heart disease, and in 15 healthy subjects. Treatment consisted of selective serotonin reuptake inhibitors for approximately 12 weeks. No significant differences were observed between untreated MDD patients and healthy subjects in blood pressure, heart rate, baroreflex sensitivity or heart rate variability.Pulse pressure and hsCRP, however, were significantly elevated in patients with MDD prior to treatment (p =0.023 and p =0.025, respectively). Moreover, while pharmacotherapy was effective in alleviating depression, surprisingly, each of cardiac baroreflex function, heart rate variability, pulse pressure and hsCRP was modified (p <0.05) in a manner likely to increase cardiac risk. In conclusion, this study demonstrated higher pulse pressure and hsCRP plasma levels in patients with MDD, which might contribute to increased cardiac risk. Following treatment vagal activity was reduced, as indicated by reductions in baroreflex sensitivity and heart rate variability, accompanied by increases in pulse pressure and plasma hsCRP levels. Mechanisms potentially responsible for generating cardiac risk in patients treated with selective serotonin reuptake inhibitors may need to be therapeutically targeted to reduce the incidence of coronary heart disease in this pop-

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Preclinical Pharmacology of Citalopram

Cited by 24 publications

References 158 publications

Norepinephrine-deficient mice lack responses to antidepressant drugs, including selective serotonin reuptake inhibitors

Norepinephrine-deficient mice lack responses to antidepressant drugs, including selective serotonin reuptake inhibitors

Differential modulation of efficiency in a food-rewarded "differential reinforcement of low-rate" 72-s schedule in rats by norepinephrine and serotonin reuptake inhibitors

Specific Serotonin Reuptake Inhibition in Major Depressive Disorder Adversely Affects Novel Markers of Cardiac Risk

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