At first glance, the intensified response is likely attributed to chronic CLG-induced augmentation in serotonergic neuronal activity, consistent with the working hypothesis proposed in literature (Stanford em et al /em , 2010)

At first glance, the intensified response is likely attributed to chronic CLG-induced augmentation in serotonergic neuronal activity, consistent with the working hypothesis proposed in literature (Stanford em et al /em , 2010). MAOI clorgyline for 3, 6, or 13 days. Syndrome intensity was estimated by measuring 5-HT Chlormezanone (Trancopal) efflux, neuromuscular activity, and body-core temperature in response to challenge injection of clorgyline combined with the SSRI paroxetine. Results showed that this onset of serotonin syndrome is caused by 5-HT efflux exceeding 10-fold above baseline, confirming the presynaptic hypothesis. The neuromuscular and body-core temperature abnormalities, which were otherwise moderate in drug-naive rats, were significantly intensified to a severe level in rats pretreated with daily clorgyline for 3 and 6 days but not in rats pretreated for 13 days. The intensified effect was blocked by M100907 and MK-801, suggesting that variation in syndrome intensity was mediated through a 5-HT2A and NMDA receptor-engaged circuit. Therefore, we concluded that pretreatments of MAOI pharmacologically alter the activity of postsynaptic circuits, which is responsible for changes in syndrome intensity. INTRODUCTION Neural mechanisms for serotonin syndrome induction are different from the intensification. The syndrome induction is dependent on 5HT levels accumulated extracellularly. The syndrome intensification depends on the responsivity of postsynaptic 5-HT2A receptors. The first incident of adverse conversation of serotonin (5-hydroxytryptamine, 5-HT) drugs was reported nearly 60 years ago in a patient taking the monoamine oxidase inhibitor (MAOI) iproniazid in addition to the narcotic pain reliever meperidine for pulmonary tuberculosis treatment (Mitchell, 1955). Comparable reports about 5-HT drug incidents have been increasing for the last two decades because of widespread use of selective serotonin reuptake inhibitors (SSRIs). Affected patients exhibit a wide array of symptoms, collectively called serotonin syndrome (Mason Animal use procedures were in strict accordance with the NIH Guide for the Care and Use of Laboratory Animals and were approved by the Florida Atlantic University-Institutional Animal Care and Use Committees (FAU-IACUC). All efforts were made to reduce the number of animals used and their suffering. Chemicals and Drug Administration CLG (N-methyl-N-propargyl-3-(2,4-dichlorophenoxy) propylamine hydrochloride; Sigma-Aldrich, St Louis, MO, USA) and (+)-MK-801 maleate (Tocris, Ellisville, MO, USA) were dissolved in isotonic saline. PRX (US Pharmacopeia, Rockville, MD, USA) and M100907 (kindly provided by NIH Drug Supply Program) were suspended in water. Drug solutions were prepared immediately before experiments and injected in a constant volume of 1?ml/kg body weight. Note that CLG Rabbit Polyclonal to ADCK2 dose of 2?mg/kg used in this study was based on its effectiveness in induction of serotonin syndrome described in previous investigations (Shioda microdialysis was used to reveal the relationship between excessive 5-HT in the Chlormezanone (Trancopal) brain and intensity of serotonin syndrome in response to drug adverse conversation. Rats were anesthetized by a combination of xylazine (4?mg/kg i.p.) and ketamine (80?mg/kg i.p.) and then mounted in a Kopf stereotaxic frame in a flat skull position. Guide cannulae were implanted, targeting towards the prefrontal cortex (PFC; stereotaxic coordinates at AP +3.3?mm relative to the bregma, ML 0.8?mm to the midline, DV 4.5?mm to the skull surface), and preoptic/anterior hypothalamus (POA; AP 1.1 relative to the bregma, ML 0.9?mm, DV ?9.2?mm). After Chlormezanone (Trancopal) surgery, rats were allowed to recover for 1 week before experiments. One day before microdialysis, the rats were briefly anesthetized with isoflurane for probe insertion. I-shaped microdialysis probes (molecular weight cutoff: 18?kD) were inserted through the guide cannulae targeting to the PFC (2.0?mm in length for the exchange surface) and POA (1.0?mm) and then secured in place with dental cement. The probe inlets were attached to a perfusion line from Raturn system (Bioanalytical System, W. Lafayett, IN), and infused with the artificial cerebrospinal fluid (aCSF; made up of 140?mM NaCl, 3?mM KCl, 1.5?mM CaCl2, 1?mM MgCl2, 0.25?mM NaH2PO4, and 1.0?mM Na2HPO4; pH: 7.4) at a flow rate of 1 1?Scheffe test were used to determine statistical difference between groups of microdialysis, EEG recordings, and changes in Dunn’s test was employed to examine nonparametric data. In some cases, the paired control groups, examined by repeat measures ANOVA followed by Scheffe test. We next examined whether CLG pretreatment could alter 5-HT response to drug adverse interaction. In this study, animals were pretreated once daily with CLG for 3, 6, or 13 days in experimental groups, or saline in control groups on the same schedule. Chronic CLG pretreatments (2?mg/kg, s.c.) elevated the baseline in the PFC (chronic CLG for 4 days, 2.50.3?pg/sample; 7 days, 4.00.7?pg/sample; 14 days, 4.20.4?pg/sample) and POA (4 days,.