Effects of imipramine on cytokines panel in the rats serum during the drug treatment and discontinuation M. Ku  smider a, * , A. Faron-G  orecka a , P. Pabian a , J. Solich a , M. Szlachta a , M. Kolasa a , D. _ Zurawek a , J. W  ojcikowski b , W. Daniel b , M. Dziedzicka-Wasylewska a a Institute of Pharmacology Polish Academy of Sciences, Department of Pharmacology, Sme ˛ tna 12, 31-343 Krakow, Poland b Institute of Pharmacology Polish Academy of Sciences, Department of Pharmacokinetics and Drug Metabolism, Sme ˛ tna 12, 31-343 Krakow, Poland article info Article history: Received 18 July 2017 Received in revised form 18 October 2017 Accepted 27 November 2017 Available online 28 November 2017 Keywords: Time dependent sensitization Antidepressant discontinuation syndrome Antidepressants Imipramine Cytokines Rat serum abstract Time dependent sensitization (TDS) - phenomenon described originally by Chiodo and Antelman (1980) in context of dopamine receptors, refers to cascade of events that continue to develop in the organism, after the initiating stimulus is no longer available. Treatment could be recognized as such a initiating stimulus (in case of depression, example of electroconvulsive therapy would be obvious, but some as- pects of pharmacotherapy too). The process leads to improvement, but, on the other hand, phenomena of kindling in recurrent depression is well known (more relapses and therapies make heavier and longer lasting subsequent episodes). Hence our interest in delayed effects of treatment. Here we report alter- ations in rat immune system after Imipramine (IMI) treatment cessation. Wistar male rats were treated with IMI (10 mg/kg i.p. in 2 ml/kg of saline) repeatedly for 21 days or once - on the last day of drug administration period. Then the 3 weeks discontinuation phase begun, during which, at certain time points (3 h, 72 h, 7days, 21days) the trunk blood was collected. Tissue concentrations of IMI and its metabolite desipramine (DMI), as well as ACTH and various cytokines were measured. The IMI and DMI was detectable only 3 h after the last i.p. injection of the drug. Ever since the second time point (72 h of discontinuation) the levels of either compound were below detection threshold.There was no significant changes in ACTH levels between rat groups, although IMI seemed to attenuate al- terations of the hormone level comparing to control groups. We observed differences between groups regarding certain cytokines at certain time points. Namely: at 72 h of discontinuation IL-2 and IL-4 were elevated in sera of rats treated with IMI acutely; at 7d of discontinuation levels of IL-1a, IL-5, IL-10 and IL- 12 were affected in both acutely and chronically treated animals. Presented data support, regarding some cytokines in serum, the TDS theory. Furthermore they refer to important aspect of antidepressants (ADs) action e antidepressant discontinuation syndrome (ADS). The most frequently, ADS has been described in context of ADs-disrupted monoamine homeostasis. Here, the other principle (i.e. immunomodulation) of the syndrome is proposed. © 2017 Elsevier Ltd. All rights reserved. 1. Introduction The antidepressant discontinuation syndrome (ADS) associated with interruptions in taking antidepressants (ADs), is one of the serious side effects of treatment with ADs. Numerous factors cause patients to discontinue ADs and may include: insufficient educa- tion regarding the required extended duration of use, impatience with the delayed onset of action, side effects, that emerge on ADs initiation, such as anxiety and insomnia, or after extended use, such as sexual dysfunction and weight gain, or overall perception of clinical improvement (Ferguson, 2001). Several studies suggest that up to 30% of patients with depression discontinue their drugs within the first month of initiating treatment and 45e60% of pa- tients discontinue ADs by the end of the third month (Hotopf et al., Abbreviations: ADS, antidepressant discontinuation syndrome; ADs, antide- pressants; DMI, desipramine; ECS, electroconvulsive shock; FST, forced swim test; IMI, imipramine; SNRIs, selective norepinephrine reuptake inhibitors; SSRIs, se- lective serotonin reuptake inhibitors; TCA, tricyclic antidepressants; TDS, time dependent sensitization. * Corresponding author. E-mail address: kusmider@if-pan.krakow.pl (M. Ku smider). Contents lists available at ScienceDirect Neurochemistry International journal homepage: www.elsevier.com/locate/nci https://doi.org/10.1016/j.neuint.2017.11.016 0197-0186/© 2017 Elsevier Ltd. All rights reserved. Neurochemistry International 113 (2018) 85e91