Effects of Haloperidol, Olanzapine, Risperidone And Clozapine on Mice Detrusor Muscle Using Organ Bath System

Abstract

Objective: The bladder normally shows no contractility or activity during the filling phase. In the overactive urinary bladder, spontaneous contractions and detrusor instability are seen in the filling phase and urinary incontinence occurs. This study aims to demonstrate the effects of first-generation antipsychotic haloperidol and second-generation antipsychotics olanzapine, risperidone, and clozapine on mice isolated bladder using the organ bath system.
Materials and Methods: 63 male inbred mice were divided as saline, haloperidol 0.125 mg/kg, haloperidol 0.25 mg/kg, olanzapine 1 mg/kg, olanzapine 2 mg/kg, risperidone 0.25 mg/kg, risperidone 0.5 mg/kg, clozapine 1.25 mg/kg and clozapine 2.5 mg/kg groups. Mice were treated with drugs for 21 days. Then, the effects of drugs were investigated on isoproterenol-induced relaxation responses of carbachol-induced contractions in isolated detrusor strips.
Results: We showed that carbachol-induced contractions relaxed by isoproterenol and papaverine in mice detrusor strips obtained from olanzapine, risperidone, and clozapine treated groups. There were no significant differences in KCl-induced contractile responses among the groups.
Conclusion: Olanzapine, risperidone, and clozapine increased the isoproterenol-induced relaxations of the detrusor muscle that increased the bladder capacity. These drugs might be clinically useful for the treatment of overactive urinary bladder in patients that should use antipsychotic drugs. 

Keywords

• Clozapine
• haloperidol
• olanzapine
• overactive urinary bladder
• risperidone

Haloperidol, Olanzapin, Risperidon ve Klozapinin Organ Banyosu Sistemi Kullanılarak Fare Detrusor Kası Üzerine Etkileri

Öz

Amaç: Mesane normalde dolum fazı sırasında herhangi bir kasılma veya aktivite göstermez. Aşırı aktif mesanede, dolum aşamasında spontan kasılmalar ve detrüsör instabilitesi görülür ve idrar kaçırma meydana gelir. Bu çalışma, birinci kuşak antipsikotik olan haloperidol ve ikinci kuşak antipsikotikler olan olanzapin, risperidon ve klozapinin, organ banyosu sistemi kullanılarak izole edilmiş fare mesanesi üzerindeki etkilerini göstermeyi amaçlamaktadır.
Materyal ve Metot: 63 tane kendi içinde yetiştirilmiş erkek fareye salin, haloperidol 0,125 mg/kg, haloperidol 0,25 mg/kg, olanzapin 1 mg/kg, olanzapin 2 mg/kg, risperidon 0,25 mg/kg, risperidon 0,5 mg/kg, klozapin 1,25 mg/kg ve klozapin 2,5 mg/kg uygulandı ve gruplara ayrıldı. Fareler 21 gün boyunca ilaçlarla tedavi edildi. Daha sonra, izole edilmiş fare detrüsör şeritlerinde karbakol ile indüklenen kasılmaların, izoproterenol ile indüklenen gevşeme tepkileri üzerinde ilaçların etkileri araştırıldı.
Bulgular: Olanzapin, risperidon ve klozapin ile tedavi edilen gruplardan elde edilen fare detrüsör şeritlerinde karbakol kaynaklı kasılmaların, izoproterenol ve papaverin tarafından gevşediğini gösterdik. Gruplar arasında KCl'nin neden olduğu kasılma tepkilerinde önemli bir fark yoktu.
Sonuç: Olanzapin, risperidon ve klozapin, mesane kapasitesini artıran detrusor kasının izoproterenol kaynaklı gevşemelerini arttırdı. Bu ilaçlar, antipsikotik ilaç kullanması gereken hastalarda aşırı aktif mesane tedavisinde klinik olarak faydalı olabilir. 

Anahtar Kelimeler

• Aşırı aktif mesane
• haloperidol
• klozapin
• olanzapin
• risperidon

References

1. Truzzi JC, Gomes CM, Bezerra CA, et al. Overactive bladder – 18 years – part I. Int Braz J Urol. 2016;42(2):188-198. doi:10.1590/S1677-5538.IBJU.2015.0365
2. Chuang YC, Liu SP, Lee KS, et al. Prevalence of overactive bladder in China, Taiwanand South Korea: results from a cross‐sectional, population-based study. Low Urin Tract Symptoms. 2019;11(1):48-55. doi:10.1111/luts.12193
3. Xu H, Yang HJ, Rose GM. Chronic haloperidol-induced spatial memory deficits accompany the upregulation of D(1) and D(2) receptors in the caudate putamen of C57BL/6 mouse. Life Sci. 2012;91(9-10):322-328. doi:10.1016/j.lfs.2012.07.025
4. Lee PE, Gill SS, Rochon P. Atypical antipsychotics to treat the neuropsychiatric symptoms of dementia. Neuropsychiatr Dis Treat. 2006;2(4):521-529. doi:10.2147/nedt.2006.2.4.521
5. Kondej M, Stępnicki P, Kaczor AA. Multi-target approach for drug discovery against schizophrenia. Int J Mol Sci. 2018;19(10):3105. doi:10.3390/ijms19103105
6. Colli E, Digesu GA, Olivieri L. Overactive bladder treatments in early phase clinical trials. Expert Opin Investig Drugs. 2007;16(7):999-1007. doi:10.1517/13543784.16.7.999
7. Ulak G, Gumuslu E, Mutlu O, Ertan M, Komsuoglu Celikyurt I, Akar F, Erden F. Effects of olanzapine, clozapine, risperidone and sertindole on FGF2, synapsin and NGF expression in the hippocampus of naive mice. Int J Neuropsychopharmacol. 2016; 19(Suppl 1): 63–64. doi: 10.1093/ijnp/pyw041.45
8. Tanyeri MH, Buyukokuroglu ME, Tanyeri P, Mutlu O, Ulak G, Yildiz Akar F, Erden BF. The effects of chronic treatment with haloperidol, clozapine and aripiprazole on mice isolated vas deferens. Int J Neuropsychopharmacol. 2016; 19(Suppl 1): 37. doi: 10.1093/ijnp/pyw044.648

9. de Groat WC, Griffiths D, Yoshimura N. Neural control of the lower urinary tract. Compr Physiol. 2015;5(1):327–396. doi:10.1002/cphy.c130056
10. Wu WY, Lee SP, Chiang BJ, Lin WY, Chien CT. Urothelial calcium-sensing receptor modulates micturition function via mediating detrusor activity and ameliorates bladder hyperactivity in rats. Pharmaceuticals. 2021;14(10):960. doi:10.3390/ph14100960
11. Choudhary M, van Asselt E, van Mastrigt R, Clavica F. Neurophysiological modeling of bladder afferent activity in the rat overactive bladder model. J Physiol Sci. 2015;65(4):329-338. doi:10.1007/s12576-015-0370-y
12. Corcos J, Przydacz M, Campeau L, et al. CUA guideline on adult overactive bladder. Can Urol Assoc J. 2017;11(5):E142-E173. doi:10.5489/cuaj.4586
13. Girard BM, Tooke K, Vizzard MA. PACAP/receptor system in urinary bladder dysfunction and pelvic pain following urinary bladder ınflammation or stress. Front Syst Neurosci. 2017;11:90. doi:10.3389/fnsys.2017.00090
14. Vouri SM, Kebodeaux CD, Stranges PM, Teshome BF. Adverse events and treatment discontinuations of antimuscarinics for the treatment of overactive bladder in older adults: A systematic review and meta-analysis. Arch Gerontol Geriatr. 2017;69:77-96. doi:10.1016/j.archger.2016.11.006
15. Keller J, Chen J, Simpson S, et al. Voluntary urination control by brainstem neurons that relax the urethral sphincter. Nat Neurosci. 2018;21(9):1229-1238. doi:10.1038/s41593-018-0204-3