title: The P-glycoprotein inhibitor cyclosporin A differentially influences behavioural and neurochemical responses to the antidepressant escitalopram.
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.
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Pharmacodelivery Group, School of Pharmacy, University College Cork, Cork, Ireland; Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland.
authors.forename: Fionn E
authors.initials: FE
authors.lastname: O'Brien
authors.affiliation: Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland.
authors.forename: Richard M
authors.initials: RM
authors.lastname: O'Connor
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Psychiatry, University College Cork, Cork, Ireland.
authors.forename: Gerard
authors.initials: G
authors.lastname: Clarke
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork, Cork, Ireland; Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Donovan
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Psychiatry, University College Cork, Cork, Ireland.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Dinan
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork, Cork, Ireland.
authors.forename: Brendan T
authors.initials: BT
authors.lastname: Griffin
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland. Electronic address: j.cryan@ucc.ie.
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
mesh_terms: D006916:5-Hydroxytryptophan / Q000633:toxicity; D000818:Animals; D000928:Antidepressive Agents / Q000633:toxicity*; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D015283:Citalopram / Q000633:toxicity*; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004338:Drug Combinations; D004563:Electrochemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D019417:Hindlimb Suspension / Q000379:methods; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020230:Serotonin Syndrome / Q000139:chemically induced* / Q000188:drug therapy*
chemical_list: D000928:Antidepressive Agents; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D015283:Citalopram; D006897:Hydroxyindoleacetic Acid; D016572:Cyclosporine; D006916:5-Hydroxytryptophan
keywords: 5-HIAA; 5-HT; 5-HTP; 5-hydroxyindoleacetic acid; 5-hydroxytryptophan; BBB; CsA; Cyclosporin A; Escitalopram; HPLC; HPLC with electrochemical detection; HPLC-ECD; MAOI; Microdialysis; P-glycoprotein; P-gp; PFC; SNRI; SSRI; Serotonin syndrome; TST; Tail suspension test; blood-brain barrier; cyclosporin A; high performance liquid chromatography; monoamine oxidase inhibitor; prefrontal cortex; selective serotonin reuptake inhibitor; serotonin; serotonin-noradrenaline reuptake inhibitor; tail suspension test