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The Effects of Neurotensin Agonist PD149163 on Scopolamine-Induced Learning and Memory Impairment in Mice

Year 2021, Volume: 9 Issue: 2, 720 - 731, 25.06.2021
https://doi.org/10.33715/inonusaglik.829609

Abstract

Neurotensin (NT) is a tridecapeptide that acts as a neuromodulator, neurotransmitter and neurohormone in the central nervous system. NT plays a role in physiological processes such as regulation of body temperature, pain, motor activity, learning and memory formation. In this study, it has been planned to investigate the effects of acute and chronic usage of NT agonist PD149163 on scopolamine induced learning and memory impairment This study has been approved by Trakya University Animal Experiments Local Ethics Committee with the decision number 2019.02.01. In the study, a total of 32 male Balb/c mice were divided into 4 groups. Learning and memory functions were evaluated in the Morris water maze test. After 7 days of scopolamine (1 mg / kg i.p.) administration, it was examined whether acute and chronic (4mg/kg, i.p, 7 day) PD149163 improved learning and memory impairment. In the study, the data from swimming trainings were analyzed with repeated measures two-way variance analysis (ANOVA). Probe data were evaluated by using one-way variance analysis. Chronic PD149163 had no effect in either the learning phase or the retention phase in the Morris water maze test. Acute PD149163 had no effect on scopolamine-induced memory impairment. In our study, no curative effect of NT agonist in scopolamine-induced memory impairment has been observed. Although NT receptors are considered as new drug targets, we think that a large number of studies are needed in this field.

References

  • Akbaş, S. (2019). Nörotensinin farelerde ipuçlu ve bağlamsal korku koşullanma üzerine etkisi. (Yayınlanmamış yüksek lisans tezi). Trakya Üniversitesi Sağlık Bilimleri Enstitüsü, Edirne.
  • Azmi, N., Norman, C., Spicer, C. H., Bennett, G. W. (2006). Effects of a neurotensin analogue (PD149163) and antagonist (SR142948A) on the scopolamine-induced deficits in a novel object discrimination task. Behavioural Pharmacology, 17(4), 357-362.
  • Boules, M., Fredrickson, P., Richelson, E. (2006). Bioactive analogs of neurotensin: focus on CNS effects. Peptides, 27(10), 2523-2533.
  • Carraway, R., Leeman, S. E. (1973). The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami. J Biol Chem, 248(19), 6854-6861.
  • Feng, Y. P., Wang, J., Dong, Y. L., Wang, Y. Y., Li, Y. Q. (2015). The roles of neurotensin and its analogues in pain. Curr Pharm Des, 21(7), 840-848.
  • Ferraro, L., Tomasini, M. C., Mazza, R., Fuxe, K., Fournier, J., Tanganelli, S., Antonelli, T. (2008). Neurotensin receptors as modulators of glutamatergic transmission. Brain Res Rev, 58(2), 365-373.
  • Gahete, M. D., Rubio, A., Cordoba-Chacon, J., Gracia-Navarro, F., Kineman, R. D., Avila, J., . . . Castano, J. P. (2010). Expression of the ghrelin and neurotensin systems is altered in the temporal lobe of Alzheimer's disease patients. J Alzheimers Dis, 22(3), 819-828.
  • Gully, D., Canton, M., Boigegrain, R., Jeanjean, F., Molimard, J. C., Poncelet, M., . . . Brouard A. (1993). Biochemical and pharmacological profile of a potent and selective nonpeptide antagonist of the neurotensin receptor. Proc Natl Acad Sci U S A, 90(1), 65-69.
  • Harrison, F. E., Hosseini, A. H., Dawes, S. M., Weaver, S., May, J. M. (2009). Ascorbic acid attenuates scopolamine-induced spatial learning deficits in the water maze. Behav Brain Res, 205(2), 550-558.
  • Hillhouse, T. M., Prus, A. J. (2013). Effects of the neurotensin NTS1 receptor agonist PD149163 on visual signal detection in rats. Eur J Pharmacol, 721(1-3), 201-207.
  • Jansen, K. L., Faull, R. L., Dragunow, M., Synek, B. L. (1990). Alzheimer's disease: changes in hippocampal N-methyl-D-aspartate, quisqualate, neurotensin, adenosine, benzodiazepine, serotonin and opioid receptors--an autoradiographic study. Neuroscience, 39(3), 613-627.
  • Karaman, I., Kizilay-Ozfidan, G., Karadag. C. H., Ulugol, A. (2013). Lack of effect of ceftriaxone, a GLT-1 transporter activator, on spatial memory in mice. Pharmacol Biochem Behav, 108, 61-65.
  • Keiser, A. A., Matazel, K. S., Esser, M. K., Feifel, D., Prus, A. J. (2014). Systemic administration of the neurotensin NTS(1)-receptor agonist PD149163 improves performance on a memory task in naturally deficient male brown Norway rats. Exp Clin Psychopharmacol, 22(6), 541-547.
  • Kinkead, B., Nemeroff, C. B. (2006). Novel treatments of schizophrenia: targeting the neurotensin system. CNS Neurol Disord Drug Targets, 5(2), 205-218.
  • Kleczkowska, P., Lipkowski, A. W. (2013). Neurotensin and neurotensin receptors: characteristic, structure-activity relationship and pain modulation--a review. Eur J Pharmacol, 716(1-3), 54-60.
  • Kosaki, Y., Lin, T. C., Horne, M. R., Pearce, J. M., Gilroy, K. E. (2014). The role of the hippocampus in passive and active spatial learning. Hippocampus, 24(12), 1633-1652.
  • László, K., Tóth, K., Kertes, E., Péczely, L., Ollmann, T., Lénárd, L. (2010). Effects of neurotensin in amygdaloid spatial learning mechanisms. Behav Brain Res, 210(2), 280-283.
  • László, K., Tóth, K., Kertes, E., Péczely, L., Ollmann, T., Madarassy-Szücs, A., Lénárd, L. (2012). The role of neurotensin in passive avoidance learning in the rat central nucleus of amygdala. Behavioural brain research, 226(2), 597–600.
  • László, K., Péczely, L., Kovács, A., Zagoracz, O., Ollmann, T., Kertes, E., Kállai, V., . . . Lénárd, L. (2018). The role of intraamygdaloid neurotensin and dopamine interaction in conditioned place preference. Behavioural brain research, 344, 85–90.
  • Lénárd, L., László, K., Kertes, E., Ollmann, T., Peczely, L., Kovacs, A., . . . Karadi, Z. (2018). Substance P and neurotensin in the limbic system: Their roles in reinforcement and memory consolidation. Neurosci Biobehav Rev, 85, 1-20.
  • Lim, D. W., Son, H. J., Um, M. Y., Kim, I. H., Han, D., Cho, S., Lee, C. H. (2016). Enhanced cognitive effects of demethoxycurcumin, a natural derivative of curcumin on scopolamine-ınduced memory ımpairment in mice. Molecules, 21(8), 1022.
  • Mazella, J., Botto, J. M., Guillemare, E., Coppola, T., Sarret, P., Vincent, J. P. (1996). Structure, functional expression, and cerebral localization of the levocabastine-sensitive neurotensin/neuromedin N receptor from mouse brain. J Neurosci, Sep 15, 16(18), 5613-5620.
  • Mazella, J., Zsurger, N., Navarro, V., Chabry, J., Kaghad, M., Caput, D., . . . Vincent, J. P. (1998). The 100-kDa neurotensin receptor is gp95/sortilin, a non-G-protein-coupled receptor. J Biol Chem, 273(41), 26273-26276.
  • Ouyang, Q., Zhou, J., Yang, W., Cui, H., Xu, M., Yi, L. (2017). Oncogenic role of neurotensin and neurotensin receptors in various cancers. Clinical and experimental pharmacology & physiology, 44(8), 841–846.
  • Petrie, K. A., Bubser, M., Casey, C. D., Davis, M. D., Roth, B. L., Deutch, A. Y. (2004). The neurotensin agonist PD149163 increases Fos expression in the prefrontal cortex of the rat. Neuropsychopharmacology, 29(10), 1878-1888.
  • Saiyasit, N., Sripetchwandee, J., Chattipakorn, N., Chattipakorn, S. C. (2018). Potential roles of neurotensin on cognition in conditions of obese-insulin resistance. Neuropeptides, 72, 12–22.
  • Saygın M., Öztürk Ö. (2015). Investigation of the effects of sleep disorders on the hippocampal mediated learning and memory in rats. Süleyman Demirel Üniversitesi Sağlık Bilimleri Dergisi, 6(1), 47-48.
  • St-Gelais, F., Jomphe, C., Trudeau, L. E. (2006). The role of neurotensin in central nervous system pathophysiology: what is the evidence? J Psychiatry Neurosci, 31(4), 229-245.
  • Tirado-Santiago, G., Lazaro-Munoz, G., Rodriguez-Gonzalez, V., Maldonado-Vlaar, C. S. (2006). Microinfusions of neurotensin antagonist SR 48692 within the nucleus accumbens core impair spatial learning in rats. Behav Neurosci, 120(5), 1093-1102.
  • Tyler-McMahon, B. M., Boules, M., Richelson, E. (2000). Neurotensin: peptide for the next millennium. Regul Pept, 93(1-3), 125-136.
  • Vorhees, C. V., Williams, M. T. (2006). Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc, 1(2), 848-858.
  • Xiao, Z., Cilz, N. I., Kurada, L., Hu, B., Yang, C., Wada, E., . . . Lei, S. (2014). Activation of neurotensin receptor 1 facilitates neuronal excitability and spatial learning and memory in the entorhinal cortex: beneficial actions in an Alzheimer's disease model. J Neurosci, 34(20), 7027-7042.
  • Yamada, D., Wada, E., Amano, T., Wada, K., Sekiguchi, M. (2010). Lack of neurotensin type 1 receptor facilitates contextual fear memory depending on the memory strength. Pharmacol Biochem Behav, 96(3), 363-369.
  • Yiannopoulou, K. G., Papageorgiou, S. G. (2013). Current and future treatments for Alzheimer's disease. Ther Adv Neurol Disord, 6(1), 19-33.

FARELERDE SKOPOLAMİNLE BOZULMUŞ ÖĞRENME VE BELLEK ÜZERİNE NÖROTENSİN AGONİSTİ PD149163’ÜN ETKİSİ

Year 2021, Volume: 9 Issue: 2, 720 - 731, 25.06.2021
https://doi.org/10.33715/inonusaglik.829609

Abstract

Nörotensin (NT), santral sinir sisteminde nöromodülatör, nörotransmitter ve nörohormon olarak görev yapan bir tridekapeptittir. NT; vücut sıcaklığının düzenlenmesi, ağrı, motor aktivite, öğrenme ve bellek yapılanması gibi fizyolojik süreçlerde rol oynar. Bu çalışmada NT agonisti PD149163’ün akut ve kronik kullanımının skopolaminle oluşturulmuş bellek bozukluğu üzerine etkilerinin incelenmesi amaçlandı. Bu çalışma Trakya Üniversitesi Hayvan Deneyleri Yerel Etik kurulundan 2019.02.01 karar no ile onaylanmıştır. Çalışmada toplam 32 adet Balb/c türü erişkin erkek fare 4 gruba ayrıldı. Öğrenme ve bellek fonksiyonları Morris su labirenti testinde değerlendirildi. 7 gün boyunca skopolamin (1 mg/kg i.p.) uygulandıktan sonra akut ve kronik (7 gün, 4 mg/kg, i.p) PD149163 tedavisinin öğrenme ve bellek bozukluğunu geri döndürüp döndürmediği incelendi. Çalışmada yüzme eğitimlerinden elde edilen veriler, tekrarlayan ölçümler iki yönlü varyans analizi (ANOVA ) ile analiz edildi. Probe verileri tek yönlü varyans analizi ile değerlendirildi. Kronik PD149163 uygulamasının Morris su labirenti testinde ne öğrenme fazında ne de bellek fazında iyileştirici bir etkisi olmadı. Akut PD149163 uygulamasının skopolaminle oluşturulmuş bellek bozukluğu üzerine herhangi bir etkisi olmadı. Çalışmamızda NT agonistinin skopolaminle oluşturulan öğrenme ve bellek bozukluğunda düzeltici etkisi görülmemiştir. NT reseptörleri yeni ilaç hedefleri olarak değerlendirilmelerine karşın bu alanda yapılacak çok fazla sayıda çalışmaya ihtiyaç olduğu düşüncesindeyiz.

Thanks

Araştırmamızda davranış deneylerinin gerçekleşmesinde büyük emeği olan Öğr.Gör. Kübra Duvan AYDEMİR ve Araş. Gör Dilşat ERÜMİT; deneyimlerinden faydalandığımız Prof. Dr. Ahmet ULUGÖL ve Prof. Dr. Ç. Hakan KARADAĞ’a teşekkür ederiz.

References

  • Akbaş, S. (2019). Nörotensinin farelerde ipuçlu ve bağlamsal korku koşullanma üzerine etkisi. (Yayınlanmamış yüksek lisans tezi). Trakya Üniversitesi Sağlık Bilimleri Enstitüsü, Edirne.
  • Azmi, N., Norman, C., Spicer, C. H., Bennett, G. W. (2006). Effects of a neurotensin analogue (PD149163) and antagonist (SR142948A) on the scopolamine-induced deficits in a novel object discrimination task. Behavioural Pharmacology, 17(4), 357-362.
  • Boules, M., Fredrickson, P., Richelson, E. (2006). Bioactive analogs of neurotensin: focus on CNS effects. Peptides, 27(10), 2523-2533.
  • Carraway, R., Leeman, S. E. (1973). The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami. J Biol Chem, 248(19), 6854-6861.
  • Feng, Y. P., Wang, J., Dong, Y. L., Wang, Y. Y., Li, Y. Q. (2015). The roles of neurotensin and its analogues in pain. Curr Pharm Des, 21(7), 840-848.
  • Ferraro, L., Tomasini, M. C., Mazza, R., Fuxe, K., Fournier, J., Tanganelli, S., Antonelli, T. (2008). Neurotensin receptors as modulators of glutamatergic transmission. Brain Res Rev, 58(2), 365-373.
  • Gahete, M. D., Rubio, A., Cordoba-Chacon, J., Gracia-Navarro, F., Kineman, R. D., Avila, J., . . . Castano, J. P. (2010). Expression of the ghrelin and neurotensin systems is altered in the temporal lobe of Alzheimer's disease patients. J Alzheimers Dis, 22(3), 819-828.
  • Gully, D., Canton, M., Boigegrain, R., Jeanjean, F., Molimard, J. C., Poncelet, M., . . . Brouard A. (1993). Biochemical and pharmacological profile of a potent and selective nonpeptide antagonist of the neurotensin receptor. Proc Natl Acad Sci U S A, 90(1), 65-69.
  • Harrison, F. E., Hosseini, A. H., Dawes, S. M., Weaver, S., May, J. M. (2009). Ascorbic acid attenuates scopolamine-induced spatial learning deficits in the water maze. Behav Brain Res, 205(2), 550-558.
  • Hillhouse, T. M., Prus, A. J. (2013). Effects of the neurotensin NTS1 receptor agonist PD149163 on visual signal detection in rats. Eur J Pharmacol, 721(1-3), 201-207.
  • Jansen, K. L., Faull, R. L., Dragunow, M., Synek, B. L. (1990). Alzheimer's disease: changes in hippocampal N-methyl-D-aspartate, quisqualate, neurotensin, adenosine, benzodiazepine, serotonin and opioid receptors--an autoradiographic study. Neuroscience, 39(3), 613-627.
  • Karaman, I., Kizilay-Ozfidan, G., Karadag. C. H., Ulugol, A. (2013). Lack of effect of ceftriaxone, a GLT-1 transporter activator, on spatial memory in mice. Pharmacol Biochem Behav, 108, 61-65.
  • Keiser, A. A., Matazel, K. S., Esser, M. K., Feifel, D., Prus, A. J. (2014). Systemic administration of the neurotensin NTS(1)-receptor agonist PD149163 improves performance on a memory task in naturally deficient male brown Norway rats. Exp Clin Psychopharmacol, 22(6), 541-547.
  • Kinkead, B., Nemeroff, C. B. (2006). Novel treatments of schizophrenia: targeting the neurotensin system. CNS Neurol Disord Drug Targets, 5(2), 205-218.
  • Kleczkowska, P., Lipkowski, A. W. (2013). Neurotensin and neurotensin receptors: characteristic, structure-activity relationship and pain modulation--a review. Eur J Pharmacol, 716(1-3), 54-60.
  • Kosaki, Y., Lin, T. C., Horne, M. R., Pearce, J. M., Gilroy, K. E. (2014). The role of the hippocampus in passive and active spatial learning. Hippocampus, 24(12), 1633-1652.
  • László, K., Tóth, K., Kertes, E., Péczely, L., Ollmann, T., Lénárd, L. (2010). Effects of neurotensin in amygdaloid spatial learning mechanisms. Behav Brain Res, 210(2), 280-283.
  • László, K., Tóth, K., Kertes, E., Péczely, L., Ollmann, T., Madarassy-Szücs, A., Lénárd, L. (2012). The role of neurotensin in passive avoidance learning in the rat central nucleus of amygdala. Behavioural brain research, 226(2), 597–600.
  • László, K., Péczely, L., Kovács, A., Zagoracz, O., Ollmann, T., Kertes, E., Kállai, V., . . . Lénárd, L. (2018). The role of intraamygdaloid neurotensin and dopamine interaction in conditioned place preference. Behavioural brain research, 344, 85–90.
  • Lénárd, L., László, K., Kertes, E., Ollmann, T., Peczely, L., Kovacs, A., . . . Karadi, Z. (2018). Substance P and neurotensin in the limbic system: Their roles in reinforcement and memory consolidation. Neurosci Biobehav Rev, 85, 1-20.
  • Lim, D. W., Son, H. J., Um, M. Y., Kim, I. H., Han, D., Cho, S., Lee, C. H. (2016). Enhanced cognitive effects of demethoxycurcumin, a natural derivative of curcumin on scopolamine-ınduced memory ımpairment in mice. Molecules, 21(8), 1022.
  • Mazella, J., Botto, J. M., Guillemare, E., Coppola, T., Sarret, P., Vincent, J. P. (1996). Structure, functional expression, and cerebral localization of the levocabastine-sensitive neurotensin/neuromedin N receptor from mouse brain. J Neurosci, Sep 15, 16(18), 5613-5620.
  • Mazella, J., Zsurger, N., Navarro, V., Chabry, J., Kaghad, M., Caput, D., . . . Vincent, J. P. (1998). The 100-kDa neurotensin receptor is gp95/sortilin, a non-G-protein-coupled receptor. J Biol Chem, 273(41), 26273-26276.
  • Ouyang, Q., Zhou, J., Yang, W., Cui, H., Xu, M., Yi, L. (2017). Oncogenic role of neurotensin and neurotensin receptors in various cancers. Clinical and experimental pharmacology & physiology, 44(8), 841–846.
  • Petrie, K. A., Bubser, M., Casey, C. D., Davis, M. D., Roth, B. L., Deutch, A. Y. (2004). The neurotensin agonist PD149163 increases Fos expression in the prefrontal cortex of the rat. Neuropsychopharmacology, 29(10), 1878-1888.
  • Saiyasit, N., Sripetchwandee, J., Chattipakorn, N., Chattipakorn, S. C. (2018). Potential roles of neurotensin on cognition in conditions of obese-insulin resistance. Neuropeptides, 72, 12–22.
  • Saygın M., Öztürk Ö. (2015). Investigation of the effects of sleep disorders on the hippocampal mediated learning and memory in rats. Süleyman Demirel Üniversitesi Sağlık Bilimleri Dergisi, 6(1), 47-48.
  • St-Gelais, F., Jomphe, C., Trudeau, L. E. (2006). The role of neurotensin in central nervous system pathophysiology: what is the evidence? J Psychiatry Neurosci, 31(4), 229-245.
  • Tirado-Santiago, G., Lazaro-Munoz, G., Rodriguez-Gonzalez, V., Maldonado-Vlaar, C. S. (2006). Microinfusions of neurotensin antagonist SR 48692 within the nucleus accumbens core impair spatial learning in rats. Behav Neurosci, 120(5), 1093-1102.
  • Tyler-McMahon, B. M., Boules, M., Richelson, E. (2000). Neurotensin: peptide for the next millennium. Regul Pept, 93(1-3), 125-136.
  • Vorhees, C. V., Williams, M. T. (2006). Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc, 1(2), 848-858.
  • Xiao, Z., Cilz, N. I., Kurada, L., Hu, B., Yang, C., Wada, E., . . . Lei, S. (2014). Activation of neurotensin receptor 1 facilitates neuronal excitability and spatial learning and memory in the entorhinal cortex: beneficial actions in an Alzheimer's disease model. J Neurosci, 34(20), 7027-7042.
  • Yamada, D., Wada, E., Amano, T., Wada, K., Sekiguchi, M. (2010). Lack of neurotensin type 1 receptor facilitates contextual fear memory depending on the memory strength. Pharmacol Biochem Behav, 96(3), 363-369.
  • Yiannopoulou, K. G., Papageorgiou, S. G. (2013). Current and future treatments for Alzheimer's disease. Ther Adv Neurol Disord, 6(1), 19-33.
There are 34 citations in total.

Details

Primary Language Turkish
Subjects Clinical Sciences
Journal Section Araştırma Makalesi
Authors

Ruhan Deniz Topuz 0000-0002-1520-3754

Oktay Kaya This is me 0000-0001-9639-8022

Publication Date June 25, 2021
Submission Date November 23, 2020
Acceptance Date April 7, 2021
Published in Issue Year 2021 Volume: 9 Issue: 2

Cite

APA Topuz, R. D., & Kaya, O. (2021). FARELERDE SKOPOLAMİNLE BOZULMUŞ ÖĞRENME VE BELLEK ÜZERİNE NÖROTENSİN AGONİSTİ PD149163’ÜN ETKİSİ. İnönü Üniversitesi Sağlık Hizmetleri Meslek Yüksek Okulu Dergisi, 9(2), 720-731. https://doi.org/10.33715/inonusaglik.829609