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Adaptive Mechanisms Following Antidepressant Drugs: Focus On Pharmacological Reports 71 (2019) 994–1000 Contents lists available at ScienceDirect Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep Original article Adaptive mechanisms following antidepressant drugs: Focus on serotonin 5-HT2A receptors a, a a,1 a Dawid Gawlinski *, Irena Smaga , Magdalena Zaniewska , Kinga Gawlinska , b a Agata Faron-Górecka , Małgorzata Filip a Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Drug Addiction Pharmacology, Kraków, Poland b Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Pharmacology, Laboratory of Biochemical Pharmacology, Kraków, Poland A R T I C L E I N F O A B S T R A C T Article history: Background: There is a strong support for the role of serotonin (5-HT) neurotransmission in depression Received 29 January 2019 and in the mechanism of action of antidepressants. Among 5-HT receptors, 5-HT2A receptor subtype Received in revised form 16 April 2019 seems to be an important target implicated in the above disorder. Accepted 20 May 2019 Methods: The aim of the study was to investigate the effects of antidepressants, such as imipramine Available online 21 May 2019 (15 mg/kg), escitalopram (10 mg/kg) and tianeptine (10 mg/kg) as well as drugs with antidepressant activity, including N-acetylcysteine (100 mg/kg) and URB597 (a fatty acid amide hydrolase inhibitor, Keywords: 0.3 mg/kg) on the 5-HT receptor labeling pattern in selected rat brain regions. Following acute or Autoradiography 2A chronic (14 days) drug administration, rat brains were analyzed by using autoradiography with the 5- Antidepressant 3 Depression HT2A receptor antagonist [ H]ketanserin. 5-HT2A receptor Results: Single dose or chronic administration of imipramine decreased the radioligand binding in the 3 claustrum and cortical subregions. The [ H]ketanserin binding either increased or decreased in cortical areas after acute N-acetylcysteine and URB597 administration, respectively. A similar shift towards 3 reduction of the [ H]ketanserin binding was detected in the nucleus accumbens shell following either acute treatment with imipramine, escitalopram, N-acetylcysteine and URB597 or repeated administra- tion of imipramine, tianeptine and URB597. Conclusions: In conclusion, the present result indicate different sensitivity of brain 5-HT2A receptors to antidepressant drugs depending on schedule of drug administration and rat brain regions. The decrease of accumbal shell 5-HT2A receptor labeling by antidepressant drugs exhibiting different primary mechanism of action seems to be a common targeting mechanism associated with the outcome of depression treatment. © 2019 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved. Introduction Moreover, approximately 40% of patients with drug resistant depression are not responsive to therapy and basic of pathophysi- Depression disorder is one of the most common neuropsychi- ology still remains unclear [2]. Hence, researchers search for new atric diseases worldwide leading to disability in the social and drugs and targets for pharmacotherapy with elevated efficacy and personal life. Although there is a wide pool of antidepressant fewer side effects. drugs, responding to the available pharmacological treatment The serotonin (5-HT) neurotransmission plays a significant role often is not sufficiently effective [1]. In addition, it often takes even in physiological processes, such as the awake and sleep regulation, more than 8 weeks to positive clinical conditions and until the emotions and mood, sexual behavior, learning and memory, as well treatment effects are visible, beyond present side effects. as pathological states, including eating disorders, anxiety or aggression. The irregularity in 5-HT system function had been implicated in pathogenesis of depression and target of its treatment since the discovery of the first antidepressant drugs * Corresponding author. in the 1950s. Research indicated that neuronal activation in the E-mail address: [email protected] (D. Gawlinski). 1 dorsal raphe nucleus, located in the midbrain is one of the primary Present address: Maj Institute of Pharmacology, Polish Academy of Sciences, sources of 5-HT neurons in the central nervous system, is Department of Pharmacology, Laboratory of Pharmacology and Brain Biostructure, Kraków, Poland. implicated in characteristic antidepressant drug action [3,4]. The http://dx.doi.org/10.1016/j.pharep.2019.05.012 1734-1140/© 2019 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved. D. Gawlinski et al. / Pharmacological Reports 71 (2019) 994–1000 995 central 5-HT system originating from the dorsal raphe nucleus has association between specific HTR2A single nucleotide polymor- widespread projections to emotion-related brain structures phisms (SNPs) and susceptibility to majordepression and/or severity important for the development of symptoms of depression of its episodes has been found. This association was also reported in including the amygdala, hippocampus, basal ganglia and cortex severe forms of suicidal ideation, especially those with suicidal [4]. The strongest evidence for the role of the 5-HT neurotrans- attempts or melancholic features [7]. Interestingly, variations in the mission in the treatment of depression is related to the efficacy of gene encoding the 5-HT2A receptor have been linked to the outcome antidepressants which modulate 5-HT levels in the brain. A of the depression treatment with SSRIs [8]. Additionally, reports of majority of antidepressants block the 5-HT transporter (SERT) postmortem brain samples from adult and teenage suicide victims (such as tricyclic antidepressants and selective 5-HT reuptake have shown higher levels of 5-HT2A receptors [8]. Furthermore, a inhibitors (SSRIs)) or inhibit degradation of 5-HT (monoamine greater number of 5-HT2A receptors in the platelets of suicidal oxidase inhibitors). SSRIs and the dual 5-HT and noradrenalin victims were suggested as a biological marker of suicidal behavior reuptake inhibitors (SNRIs) provide more than 90% of the global [9]. Unfortunately, knowledge and evidence about the consequences antidepressant drugs [5]. of administration of antidepressant drugs on 5-HT2A receptor Among 5-HTreceptors,5-HT2A receptorsarewidelydistributedat expression in the brain are limited. varying densities throughout the brain, with the highest density in The aim of the present work was to investigate the potential the neocortex, where they are localized on g-aminobutyric acid changes in 5-HT2A receptor labeling in different rat brain structures (GABA)-ergic interneurons or glutamatergic projection neurons [6]. after acute and repeated administration of antidepressants. We Numerousclinical studies highlightcontributionof 5-HT2A receptors focused on three antidepressants with different mechanisms of tothe pathogenesisofdepressionand antidepressant drug action.An action, including imipramine (IMI; a SNRI), escitalopram (ESC; a Table 1 3 Examples of 5-HT2A receptor labeling in the control rat brain. Representative autoradiograms of [ H]ketanserin binding in the brain of rats treated repeatedly with vehicle. The color outlines A–J show the brain areas in which optical densities were quantified. A - motor cortex (II–III layers) B - motor cortex (V layer) C - prelimbic cortex D - infralimbic cortex E - cingulate cortex F - dorsal striatum (caudate putamen) G - nucleus accumbens core H - nucleus accumbens shell I - claustrum J - ventral dentate gyrus 996 D. Gawlinski et al. / Pharmacological Reports 71 (2019) 994–1000 SSRI) and tianeptine (TIA; a selective 5-HT reuptake enhancer), incubation period, tissue sections were washed twice in an ice-cold along with drugs in which antidepressant activity has been (4 C) TrisÀHCl buffer for 10 min and once in cold (4 C) distilled demonstrated in preclinical and clinical studies, including N- water for 10 min, and then dried with cool air. acetylcysteine (NAC) (mucolytic drug) and cyclohexylcarbamic Radiolabeled, dried brain sections were exposed to tritium- 3 acid 3-carbamoylbiphenyl-3-yl ester (URB597, a fatty acid amide sensitive screens ([ H]-Fujifilm imaging plates; BAS-IP TR 2025E, hydrolase (FAAH) inhibitor) [10–12]. Fuji Photo Film, Japan) in photosensitive cassettes (The Bass IP Cassettes, 20 cm  25 cm, Fujifilm, Japan) for one week at 4 C. The Material and methods obtained autoradiograms were read out with a BAS-5000 IP Image Reader version 1.1. (Fujifilm, Japan), and quantitative analysis was Animals performed using the MULTI GAUGE version 3.0. software (Fujifilm, Japan). Optical densities of gray values on the film were converted Adult male Wistar rats weighing 280–300 g were used for into bound radioactivity with a polynomial standard regression 3 experiments. The animals were kept under standard laboratory curve derived from autoradiographic [ H]microscale (RPA 510, UK). conditions (12 h light/dark cycle at 22 Æ 2 C and 55 Æ 10% The binding signal was measured in selected brain regions: motor humidity with free access to food and water). All procedures cortex (II–III layers and V layer), prelimbic, infralimbic and were carried out in accordance with directive 2010/63/EU and with cingulate cortices, dorsal striatum, nucleus accumbens core, approval of the Local Ethical Committee in Krakow, Poland (the nucleus accumbens shell, claustrum and ventral dentate gyrus. approval number 59/2012). There were 7–8 rats/group. The brain regions were identified
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