Elsevier

Behavioural Brain Research

Volume 261, 15 March 2014, Pages 17-25
Behavioural Brain Research

Research report
The P-glycoprotein inhibitor cyclosporin A differentially influences behavioural and neurochemical responses to the antidepressant escitalopram

https://doi.org/10.1016/j.bbr.2013.11.027Get rights and content

Highlights

  • Cyclosporin A (CsA) exacerbates escitalopram-induced serotonin syndrome in mice.

  • CsA pre-treatment enhances brain distribution of escitalopram in mice.

  • A combination of CsA and escitalopram reduces prefrontal cortex 5-HT turnover in mice.

  • CsA pre-treatment does not augment the activity of escitalopram in the TST in mice.

  • CsA attenuates increases in extracellular 5-HT in response to escitalopram in rats.

Abstract

Recent studies have raised the possibility that P-glycoprotein (P-gp) inhibition may represent a putative augmentation strategy for treatment with certain antidepressants. Indeed, we have previously shown that administration of the P-gp inhibitor verapamil increased the brain distribution and behavioural effects of the antidepressant escitalopram. The aim of the current study was to investigate if similar effects occur with another P-gp inhibitor, cyclosporin A (CsA). CsA pre-treatment exacerbated the severity of behaviours in an escitalopram-induced mouse model of serotonin syndrome, a potentially life-threatening adverse drug reaction associated with serotonergic drugs. P-gp inhibition by CsA enhanced the brain distribution of escitalopram by 70–80%. Serotonin (5-HT) turnover in the prefrontal cortex was reduced by escitalopram, and this effect was augmented by CsA. However, CsA pre-treatment did not augment the effect of escitalopram in the tail suspension test (TST) of antidepressant-like activity. Microdialysis experiments revealed that pre-treatment with CsA failed to augment, but blunted, the increase in extracellular 5-HT in response to escitalopram administration. This blunting effect may contribute to the lack of augmentation in the TST. Taken together, the present studies demonstrate that co-administration of CsA and escitalopram produces differential effects depending on the behavioural and neurochemical assays employed. Thus, the results highlight the need for further studies involving more selective pharmacological tools to specifically evaluate the impact of P-gp inhibition on behavioural responses to antidepressants which are subject to efflux by P-gp.

Introduction

Currently available drug treatments for depression have unsatisfactory efficacy, with an estimated 50–60% of patients failing to adequately respond to antidepressant treatment [1]. Hence, there is a major impetus to elucidate, and overcome, the mechanisms underlying resistance to antidepressant drug treatment. Increasing evidence from preclinical and clinical studies has highlighted a key role for the multidrug resistance efflux transporter P-glycoprotein (P-gp), expressed at the blood–brain barrier (BBB), in limiting the brain distribution, and therefore efficacy, of several antidepressant drugs [2], [3], [4], [5], [6].

We have recently demonstrated that the selective serotonin reuptake inhibitor (SSRI) escitalopram, one of the most commonly prescribed antidepressants, is a transported substrate of human P-gp in vitro [7]. Moreover, pre-treatment with the P-gp inhibitor verapamil enhanced the brain distribution of escitalopram and augmented its antidepressant-like activity in mice [7], as measured in the tail suspension test (TST), one of the most widely used models for assessing antidepressant activity in rodents [8]. In addition, microdialysis studies revealed that administration of another P-gp inhibitor, cyclosporin A (CsA), also resulted in enhanced brain levels of escitalopram in rats, thereby confirming the involvement of P-gp in its BBB transport [7]. These results raise the possibility that treatment with escitalopram, and potentially other antidepressants which are transported P-gp substrates, could be augmented by adjunctive therapy with a P-gp inhibitor.

Notwithstanding the potential of P-gp inhibition to enhance antidepressant brain distribution and therapeutic efficacy, the possibility that adjunctive P-gp inhibitor therapy may elicit unwanted side effects merits further consideration. Indeed, there is evidence to suggest that concurrent administration of serotonin (5-HT) enhancing antidepressants and CsA, which is a clinically used immunosuppressant as well as an inhibitor of P-gp, can result in serious adverse drug reactions. Three case studies describing incidences of serotonin syndrome, a potentially life-threatening adverse drug reaction associated with excessive serotonergic neurotransmission [9], in patients treated with CsA and 5-HT enhancing antidepressants, including escitalopram, have been published [10], [11], [12]. In addition, there have been over 30 reports of CsA-related serotonin syndrome since 2001, according to the FDA Adverse Event Reporting System (http://www.ehealthme.com/ds/cyclosporine/serotonin+syndrome; accessed 29.09.13).

In the present studies, the effect of CsA administration in an escitalopram-induced mouse model of serotonin syndrome was investigated to determine if CsA impacts on the severity of behaviours associated with this model. In addition, further behavioural studies were undertaken to determine if CsA pre-treatment would augment the antidepressant-like activity of escitalopram in the TST, as previously reported for another P-gp inhibitor (verapamil) [7]. Finally, the neurochemical effects of this drug combination were assessed by measuring brain tissue levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid, and by conducting intracerebral microdialysis studies to investigate the effect of pre-treatment with CsA on the increase in extracellular 5-HT in response to escitalopram administration.

Section snippets

Drugs and chemicals

Cyclosporin A (CsA; Sandimmun Concentrate for Solution for Infusion) was purchased from Uniphar Group (Ireland). Escitalopram oxalate was purchased from Discovery Fine Chemicals (Dorset, UK). 5-hydroxytryptophan (5-HTP) was obtained from Sigma–Aldrich (Ireland), as were all other chemicals, reagents and materials unless otherwise stated.

Animals

Male C57BL/6JOlaHsd mice (6–8 weeks old) and male Sprague Dawley rats (weighing 265–315 g), purchased from Harlan Laboratories, UK, were used in these studies.

Pre-treatment with CsA exacerbated the severity of behaviours associated with a mouse model of serotonin syndrome

A statistically significant difference in overall serotonin syndrome score was observed between the groups (F(3, 24) = 24.351, p < 0.001; Fig. 1B). In addition, statistically significant differences between the groups for each of the three most prominent behaviours were observed (Fig. 1C–E): tics (F(3, 24) = 14.762, p < 0.001), tremor (F(3, 24) = 7.838, p = 0.001) and hind limb abduction (F(3, 24) = 14.257, p < 0.001).

For the overall score, as well as for each of these individual behaviours, pre-treatment with

Discussion

Increasing preclinical evidence indicates that inhibition of the drug efflux transporter P-gp at the BBB may represent a putative strategy to augment therapy with certain antidepressants by increasing their brain delivery [2], [5], [7], [17], [24]. However, the potential clinical consequences of this strategy in terms of increased side effects merit careful consideration. The prospect of increasing the risk of serious side effects is a particular concern in light of case studies reporting

Conclusion

In conclusion, the present data reveal novel, but complex, pharmacokinetic and pharmacodynamic interactions between CsA and the SSRI escitalopram. Firstly, we demonstrate that CsA pre-treatment exacerbates the severity of symptoms associated with an escitalopram-induced mouse model of serotonin syndrome. This finding, in conjunction with previously published case studies [10], [11], [12], indicates that caution should be exercised if CsA is to be administered concurrently with a serotonergic

Conflict of interest

The authors report no potential conflicts of interest.

Acknowledgments

The authors wish to thank Patrick Fitzgerald, Rachel Moloney and staff in the University College Cork Biological Services Unit for technical assistance with this study. The Alimentary Pharmabiotic Centre is a research centre funded by Science Foundation Ireland (SFI), through the Irish Government's National Development Plan. T. G. D. and J. F. C. are supported by SFI (grant nos. 07/CE/B1368 and 12/RC/2273). The SFI-funded Strategic Research Cluster grant no. 07/SRC/B1154 and the Irish Drug

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