H3 histamine receptor antagonist pitolisant reverses some subchronic disturbances induced by olanzapine in mice

Abstract

The use of atypical antipsychotic drugs like olanzapine is associated with side effects such as sedation and depression-like symptoms, especially during the initial period of the use. It is believed that the occurrence of these undesirable effectsis mainly the result of the histamine H1receptors blockade by olanzapine. In addition, use of olanzapine increases the level of triglycerides in the blood, which correlates with growing obesity. The aim of this study was to investigate the influence of pitolisant – H3 histamine antagonist - on subchronic olanzapine-induced depresion-like symptoms, sedation and hypertriglicerydemia. Forced swim test was conducted to determinate depressive-like effect of olanzapine and antidepressive-like activity during the co-administered pitolisant. The test was performed after the first and fifteenth day of the treatment of the mice. The spontaneous activity of the mice was measured on the fourteenth day of the treatment with a special, innovative RFID-system (Radio-frequency identification system) – TraffiCage (TSE-Systems, Germany). Triglyceride levels were determined on the sixteenth day of the experiment after 15 cycles of drug administration. Daily olanzapine treatment (4 mg/kg b.w., i.p., d.p.d) for 15 days significantly induces sedation (p < 0.05) and prolongs immobility time in forced swim tests (FST) in mice (p < 0.05); and also elevates the level of triglycerides (p < 0.05). Administration of pitolisant (10 mg/kg b.w., i.p.) subsequentto olanzapine normalizes these adverse effects. This study presents a promising alternative for counteracting some behavioral changes and metabolic disturbances which occur in the early period of treatment with antipsychotic drugs.

The histamine H3 receptor inverse agonist pitolisant reduces body weight in obese mice

“…We suggest that improvement of these metabolic parameters may also be related to the weight loss that occurred after pitolisant treatment, but might be as well linked to another mechanism. As has been shown by Dudek et al (2016), pitolisant reduced triglyceride levels in mice with olanzapine-induced disorders. However, obesity was not present in these studies, therefore improvement of metabolic parameters in triglyceride levels might not be associated with weight reduction.…”

“…Control mice were fed on a standard diet (Labofeed B, Morawski Feed Manufacturer, Poland) and drank water only. After 12 weeks, mice with obesity induced via their diet were randomly divided into three equal groups that had the same mean body weight and were treated intraperitoneally with test compounds at the following doses: pitolisant 10 mg/kg bw/day (Dudek et al 2016; Uguen et al 2013; Zhang et al 2012) or metformin 100 mg/kg bw/day (Al-Barazanji et al 2015; Tahara et al 2011); control group: vehicle =1% Tween 80, 0.35 ml/kg (high-fat/sugar diet + vehicle = obesity control group) once daily in the morning, between 9:00 and 10:00 AM for 14 days. Control mice (control without obesity) were maintained on a standard diet, with intraperitoneal administration of vehicle = 1% Tween 80, 0.35 ml/kg (standard diet + vehicle = control group).…”

Single Administration of HBK-15—a Triple 5-HT1A, 5-HT7, and 5-HT3 Receptor Antagonist—Reverses Depressive-Like Behaviors in Mouse Model of Depression Induced by Corticosterone

“…Forced swim test was performed according to the method described by Porsolt and colleagues [ 32 ] and previously described [ 33 , 34 ]. Mice were placed individually for 6 min in glass cylinders (height 25 cm, diameter 10 cm) containing 10 cm 3 of water (23–25 °C).…”

KD-64 – a new selective A2Aadenosine receptor antagonist has anti-inflammatory activity but contrary to the non-selective antagonist – caffeine does not reduce diet-induced obesity in mice

“…The locomotor activity was recorded with an Opto M3 multichannel activity monitor (MultiDevice Software v1.3, Columbus Instruments, USA). It was evaluated as the distance travelled by the animals while attempting to climb upward [48]. After ip administration of KD-64 compound at the doses of 1, 5 or 10 mg/kg, each mouse was placed in a cage for a 30 minutes habituation period.…”

“…The animals were subcutaneously implanted with a radio-frequency identificator (RFID), which enabled to count the presence and time spent in different areas of the cage. The obtained data was grouped using an appropriate computer program [48].…”