Lovastatin potentiates the antidepressant efficacy of fluoxetine in rats

Renshaw, Perry F.; Parsegian, Aram; Yang, Chongzhe; Novero, Aileen; Yoon, Sujung; Lyoo, In Kyoon; Cohen, Bruce M.; Carlezon, William A.

doi:10.1016/j.pbb.2008.10.017

Cited by 34 publications

(31 citation statements)

References 49 publications

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“…Similarly, the affinity of RTI-55 appears to be unaffected by cholesterol depletion similar to what has been shown for CFT affinity for DAT (12). However, the inhibitor, cocaine, has been shown to induce a more outward-facing conformation than imipramine (28) (40), augmented fluoxetine efficacy (41). Also, roles for both cholesterol and sphingolipid homeostasis in psychiatric disorders have been noted (42,43).…”

Section: Discussionmentioning

confidence: 59%

Cholesterol binding to a conserved site modulates the conformation, pharmacology, and transport kinetics of the human serotonin transporter

Laursen

Severinsen

Kristensen

et al. 2018

Journal of Biological Chemistry

107

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The serotonin transporter (SERT) is important for reuptake of the neurotransmitter serotonin from the synaptic cleft and is also the target of most antidepressants. It has previously been shown that cholesterol in the membrane bilayer affects the conformation of the serotonin transporter. Although recent crystal structures have identified several potential cholesterol binding sites it is unclear whether any of these potential cholesterol sites are occupieed by cholesterol and functionally relevant. In the present study we focus on the conserved Cholesterol Site 1 (CHOL1) located in a hydrophobic groove between TM1a, TM5 and TM7. By molecular dynamics simulations we demonstrate a strong binding of cholesterol to CHOL1 in a membrane bilayer environment. In biochemical experiments we find that cholesterol depletion induces a more inward-facing conformation favoring substrate analog binding. Consistent with this, we find that mutations in CHOL1 with a negative impact on cholesterol binding induce a more inward-facing conformation and vice versa mutations with a positive impact on cholesterol binding induce a more outward-facing conformation. This shift in transporter conformation dictated by the ability to bind cholesterol in CHOL1 affects the apparent substrate affinity, maximum transport velocity and turn-over rates. Taken together we show that occupation of CHOL1 by cholesterol is of major importance in the transporter conformational equilibrium which in turn dictates ligand potency and serotonin transport activity. Based on our findings, we propose a mechanistic model that incorporates the role of cholesterol binding to CHOL1 in the function of SERT.

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Section: Discussionmentioning

confidence: 59%

Cholesterol binding to a conserved site modulates the conformation, pharmacology, and transport kinetics of the human serotonin transporter

Laursen

Severinsen

Kristensen

et al. 2018

Journal of Biological Chemistry

107

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show abstract

“…However, one of the findings, combination of lovastatin with low dose of fluoxetine augments antidepressant-like effect. As indicated by decreased immobility and accelerated swimming among rats, lovastatin increases the antidepressant efficacy of fluoxetine in laboratory animals, [22] and the action of lovastatin may involve the serotonergic instead of noradrenergic pathways, confirming augmentation of serotonergic function by statins. The reduction in immobility time by atorvastatin in our experiment may be due to increased activity in blocking the noradrenaline uptake.…”

Section: Discussionmentioning

confidence: 85%

A study on the effect of atorvastatin on the pharmacokinetic and antidepressant activity of fluoxetine

Bhattarai¹,

Swamy²,

Baral³

et al. 2017

Natl J Physiol Pharm Pharmacol

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Background: Polypharmacy is of wide concern in drug interaction. It is the leading cause of adverse drug reaction, and consequently, increasing the possibility of hospitalization and escalating the cost of care. The incidence of coexisting depression and hyperlipidemia in patients is generally managed by providing numerous drugs for a longer period of time. Aims and Objectives: This study was conducted to observe the effect of atorvastatin on pharmacokinetic parameters of fluoxetine in healthy albino rabbits and to find possible interactions of atorvastatin on the antidepressant activity of fluoxetine using animal screening test. Materials and Methods: Two drugs: Fluoxetine and atorvastatin used concurrently were selected. Healthy male albino rabbits were used to determine the effect of atorvastatin on fluoxetine addressing its pharmacokinetic parameters, whereas rats and mice were used to assess the antidepressant activity of fluoxetine. Two animal models were used to determine its antidepressant activity. Forced swim test (FST) and tail suspension test (TST) were employed in exploring antidepressant activity. High-performance liquid chromatography was used to estimate fluoxetine concentration. Results: The concentration of serum fluoxetine showed slight increment after the atorvastatin treatment for 7 days at 2

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“…These results are consistent with one previous study wherein lovastatin potentiated antidepressant effects of fluoxetine only in chronic FST. 16 Open field test is usually performed to discriminate between the general behavioral stimulation (false positives) and antidepressant effect of study drugs. The OFT study showed no significant difference in the frequency of line crossings, rearings and defecation among all the groups.…”

Section: Discussionmentioning

confidence: 99%

“…8 There is evidence from animal studies that Lovastatin can augment the antidepressant effects of a low dose of fluoxetine in rats, raising the possibility that statins could be used to facilitate the effects of antidepressants in humans. 9 However, the literature search revealed lack of sufficient data either from animal studies or clinical trials related to the antidepressant activity of statins. Hence present experimental study has been designed to evaluate antidepressant activity of simvastatin from the group of available statins.…”

Section: Introductionmentioning

confidence: 99%

Antidepressant activity of Simvastatin in behavioral models of depression in rats

Patke¹,

Tripathi²,

Patke³

et al. 2015

Int J Res Med Sci

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Lovastatin potentiates the antidepressant efficacy of fluoxetine in rats

Cited by 34 publications

References 49 publications

Cholesterol binding to a conserved site modulates the conformation, pharmacology, and transport kinetics of the human serotonin transporter

Cholesterol binding to a conserved site modulates the conformation, pharmacology, and transport kinetics of the human serotonin transporter

A study on the effect of atorvastatin on the pharmacokinetic and antidepressant activity of fluoxetine

Antidepressant activity of Simvastatin in behavioral models of depression in rats

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