The Natural Protoalkaloid Methyl-2-Amino-3-Methoxybenzoate (MAM) Alleviates Positive as well as Cognitive Symptoms in Rat and Mouse Schizophrenia Models

  • Authors: Bright Y.1, Maas D.2, Verheij M.3, Paladini M.4, Amatdjais-Groenen H.5, Molteni R.6, Riva M.7, Martens G.8, Homberg J.1
  • Affiliations:
    1. Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour,, Radboud University Medical Centre
    2. epartment of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre
    3. Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre
    4. Department of Pharmacological and Biomolecular Sciences, Universita’ degli Studi di Milano,
    5. System Chemistry, Institute for Molecules and Materials,, Radboud University
    6. Department of Medical Biotechnology and Translational Medicine,, Universita’ degli Studi di Milano
    7. Department of Pharmacological and Biomolecular Sciences, Universita’ degli Studi di Milano
    8. Department of Molecular Animal Physiology,, Donders Institute for Brain, Cognition and Behaviour, Faculty of Science
  • Issue: Vol 22, No 2 (2024)
  • Pages: 323-338
  • Section: Neurology
  • URL: https://rjpbr.com/1570-159X/article/view/644646
  • DOI: https://doi.org/10.2174/1570159X21666230720122354
  • ID: 644646

Cite item

Full Text

Abstract

The development of new antipsychotics with pro-cognitive properties and less side effects represents a priority in schizophrenia drug research. In this study, we present for the first time a preclinical exploration of the effects of the promising natural atypical antipsychotic Methyl-2-Amino-3- Methoxybenzoate (MAM), a brain-penetrable protoalkaloid from the seed of the plant Nigella damascena. Using animal models related to hyperdopaminergic activity, namely the pharmacogenetic apomorphine (D2/D1 receptor agonist)-susceptible (APO-SUS) rat model and pharmacologically induced mouse and rat models of schizophrenia, we found that MAM reduced gnawing stereotypy and climbing behaviours induced by dopaminergic agents. This predicts antipsychotic activity. In line, MAM antagonized apomorphine-induced c-Fos and NPAS4 mRNA levels in post-mortem brain nucleus accumbens and dorsolateral striatum of APO-SUS rats. Furthermore, phencyclidine (PCP, an NMDA receptor antagonist) and 2,5-Dimethoxy-4-iodoamphetamine (DOI, a 5HT2A/2C receptor agonist) induced prepulse inhibition deficits, reflecting the positive symptoms of schizophrenia, which were rescued by treatment with MAM and atypical antipsychotics alike. Post-mortem brain immunostaining revealed that MAM blocked the strong activation of both PCP- and DOI-induced c-Fos immunoreactivity in a number of cortical areas. Finally, during a 28-day subchronic treatment regime, MAM did not induce weight gain, hyperglycemia, hyperlipidemia or hepato- and nephrotoxic effects, side effects known to be induced by atypical antipsychotics. MAM also did not show any cataleptic effects. In conclusion, its brain penetrability, the apparent absence of preclinical side effects, and its ability to antagonize positive and cognitive symptoms associated with schizophrenia make MAM an exciting new antipsychotic drug that deserves clinical testing.

About the authors

Yami Bright

Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour,, Radboud University Medical Centre

Email: info@benthamscience.net

Dorien Maas

epartment of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre

Email: info@benthamscience.net

Michel Verheij

Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre

Email: info@benthamscience.net

Maria Paladini

Department of Pharmacological and Biomolecular Sciences, Universita’ degli Studi di Milano,

Email: info@benthamscience.net

Helene Amatdjais-Groenen

System Chemistry, Institute for Molecules and Materials,, Radboud University

Email: info@benthamscience.net

Raffaella Molteni

Department of Medical Biotechnology and Translational Medicine,, Universita’ degli Studi di Milano

Email: info@benthamscience.net

Marco Riva

Department of Pharmacological and Biomolecular Sciences, Universita’ degli Studi di Milano

Email: info@benthamscience.net

Gerard Martens

Department of Molecular Animal Physiology,, Donders Institute for Brain, Cognition and Behaviour, Faculty of Science

Email: info@benthamscience.net

Judith Homberg

Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour,, Radboud University Medical Centre

Author for correspondence.
Email: info@benthamscience.net

References

  1. WHO 2019. Available from: https://www.who.int/news-room/fact-sheets/detail/schizophrenia
  2. Kapur, S.; Zipursky, R.; Jones, C.; Remington, G.; Houle, S. Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am. J. Psychiatry, 2000, 157(4), 514-520. doi: 10.1176/appi.ajp.157.4.514 PMID: 10739409
  3. Meltzer, H.Y.; Matsubara, S.; Lee, J.C. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J. Pharmacol. Exp. Ther., 1989, 251(1), 238-246. PMID: 2571717
  4. Remington, G.; Kapur, S. Atypical antipsychotics: are some more atypical than others? Psychopharmacology, 2000, 148(1), 3-15. doi: 10.1007/s002130050017 PMID: 10663410
  5. Gründer, G.; Hippius, H.; Carlsson, A. The ‘atypicality’ of antipsychotics: a concept re-examined and re-defined. Nat. Rev. Drug Discov., 2009, 8(3), 197-202. doi: 10.1038/nrd2806 PMID: 19214197
  6. Üçok, A.; Gaebel, W. Side effects of atypical antipsychotics: A brief overview. World Psychiatry, 2008, 7(1), 58-62. doi: 10.1002/j.2051-5545.2008.tb00154.x PMID: 18458771
  7. Meltzer, H.Y.; Alphs, L.; Green, A.I.; Altamura, A.C.; Anand, R.; Bertoldi, A.; Bourgeois, M.; Chouinard, G.; Islam, M.Z.; Kane, J.; Krishnan, R.; Lindenmayer, J.P.; Potkin, S. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch. Gen. Psychiatry, 2003, 60(1), 82-91. doi: 10.1001/archpsyc.60.1.82 PMID: 12511175
  8. Idänpään-Heikkilä, J.; Alhava, E.; Olkinuora, M.; Palva, I.P. Agranulocytosis during treatment with chlozapine. Eur. J. Clin. Pharmacol., 1977, 11(3), 193-198. doi: 10.1007/BF00606409 PMID: 856603
  9. Kapur, S.; Remington, G. Dopamine D2 receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol. Psychiatry, 2001, 50(11), 873-883. doi: 10.1016/S0006-3223(01)01251-3 PMID: 11743942
  10. Seeman, P. Dopamine D2 receptors as treatment targets in schizophrenia. Clin. Schizophr. Relat. Psychoses, 2010, 4(1), 56-73. doi: 10.3371/CSRP.4.1.5 PMID: 20643630
  11. Im, D.; Inoue, A.; Fujiwara, T.; Nakane, T.; Yamanaka, Y.; Uemura, T.; Mori, C.; Shiimura, Y.; Kimura, K.T.; Asada, H.; Nomura, N.; Tanaka, T.; Yamashita, A.; Nango, E.; Tono, K.; Kadji, F.M.N.; Aoki, J.; Iwata, S.; Shimamura, T. Structure of the dopamine D2 receptor in complex with the antipsychotic drug spiperone. Nat. Commun., 2020, 11(1), 6442. doi: 10.1038/s41467-020-20221-0 PMID: 33353947
  12. de Bartolomeis, A.; Barone, A.; Begni, V.; Riva, M.A. Present and future antipsychotic drugs: A systematic review of the putative mechanisms of action for efficacy and a critical appraisal under a translational perspective. Pharmacol. Res., 2022, 176, 106078. doi: 10.1016/j.phrs.2022.106078 PMID: 35026403
  13. Tamminga, C.A. Partial dopamine agonists in the treatment of psychosis. J. Neural Transm., 2002, 109(3), 411-420. doi: 10.1007/s007020200033 PMID: 11956961
  14. Lieberman, J.A. Dopamine partial agonists: a new class of antipsychotic. CNS Drugs, 2004, 18(4), 251-267. doi: 10.2165/00023210-200418040-00005 PMID: 15015905
  15. de Bartolomeis, A.; Tomasetti, C.; Iasevoli, F. Update on the mechanism of action of aripiprazole: translational insights into antipsychotic strategies beyond dopamine receptor antagonism. CNS Drugs, 2015, 29(9), 773-799. doi: 10.1007/s40263-015-0278-3 PMID: 26346901
  16. Guilera, G.; Pino, O.; Gómez-Benito, J.; Rojo, J.E. Antipsychotic effects on cognition in schizophrenia: A meta-analysis of randomised controlled trials. Eur. J. Psychiatry, 2009, 23(2), 77-89. doi: 10.4321/S0213-61632009000200002
  17. Geyer, M.A.; Olivier, B.; Joëls, M.; Kahn, R.S. From antipsychotic to anti-schizophrenia drugs: role of animal models. Trends Pharmacol. Sci., 2012, 33(10), 515-521. doi: 10.1016/j.tips.2012.06.006 PMID: 22810174
  18. Ellenbroek, B.A.; Liégeois, J.F. JL 13, an atypical antipsychotic: A preclinical review. CNS Drug Rev., 2003, 9(1), 41-56. doi: 10.1111/j.1527-3458.2003.tb00243.x PMID: 12595911
  19. Geyer, M.A.; Swerdlow, N.R.; Mansbach, R.S.; Braff, D.L. Startle response models of sensorimotor gating and habituation deficits in schizophrenia. Brain Res. Bull., 1990, 25(3), 485-498. doi: 10.1016/0361-9230(90)90241-Q PMID: 2292046
  20. Swerdlow, N.R.; Geyer, M.A. Using an animal model of deficient sensorimotor gating to study the pathophysiology and new treatments of schizophrenia. Schizophr. Bull., 1998, 24(2), 285-301. doi: 10.1093/oxfordjournals.schbul.a033326 PMID: 9613626
  21. Geyer, M.A.; Krebs-Thomson, K.; Braff, D.L.; Swerdlow, N.R. Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology, 2001, 156(2-3), 117-154. doi: 10.1007/s002130100811 PMID: 11549216
  22. Rots, N.Y.; Cools, A.R.; Bérod, A.; Voorn, P.; Rostène, W.; de Kloet, E.R. Rats bred for enhanced apomorphine susceptibility have elevated tyrosine hydroxylase mRNA and dopamine D2-receptor binding sites in nigrostriatal and tuberoinfundibular dopamine systems. Brain Res., 1996, 710(1-2), 189-196. doi: 10.1016/0006-8993(95)01379-2 PMID: 8963658
  23. Cools, A.R.; Brachten, R.; Heeren, D.; Willemen, A.; Ellenbroek, B. Search after neurobiological profile of individual-specific features of wistar rats. Brain Res. Bull., 1990, 24(1), 49-69. doi: 10.1016/0361-9230(90)90288-B PMID: 2310946
  24. Cools, A.R.; Ellenbroek, B.A.; Gingras, M.A.; Engbersen, A.; Heeren, D. Differences in vulnerability and susceptibility to dexamphetamine in Nijmegen high and low responders to novelty: a dose-effect analysis of spatio-temporal programming of behaviour. Psychopharmacology, 1997, 132(2), 181-187. doi: 10.1007/s002130050334 PMID: 9266615
  25. van der Elst, M.C.J.; Wunderink, Y.S.; Ellenbroek, B.A.; Cools, A.R. Differences in the cellular mechanism underlying the effects of amphetamine on prepulse inhibition in apomorphine-susceptible and apomorphine-unsusceptible rats. Psychopharmacology, 2007, 190(1), 93-102. doi: 10.1007/s00213-006-0587-9 PMID: 17031706
  26. Ellenbroek, B.A.; Geyer, M.A.; Cools, A.R. The behavior of APO-SUS rats in animal models with construct validity for schizophrenia. J. Neurosci., 1995, 15(11), 7604-7611. doi: 10.1523/JNEUROSCI.15-11-07604.1995 PMID: 7472511
  27. van der Elst, M.C.J.; Ellenbroek, B.A.; Cools, A.R. Cocaine strongly reduces prepulse inhibition in apomorphine-susceptible rats, but not in apomorphine-unsusceptible rats: Regulation by dopamine D2 receptors. Behav. Brain Res., 2006, 175(2), 392-398. doi: 10.1016/j.bbr.2006.09.014 PMID: 17079027
  28. van der Elst, M.C.J.; Verheij, M.M.M.; Roubos, E.W.; Ellenbroek, B.A.; Veening, J.G.; Cools, A.R. A single exposure to novelty differentially affects the accumbal dopaminergic system of apomorphine-susceptible and apomorphine-unsusceptible rats. Life Sci., 2005, 76(12), 1391-1406. doi: 10.1016/j.lfs.2004.10.023 PMID: 15670618
  29. Maas, D.A.; Eijsink, V.D.; Spoelder, M.; van Hulten, J.A.; De Weerd, P.; Homberg, J.R.; Vallès, A.; Nait-Oumesmar, B.; Martens, G.J.M. Interneuron hypomyelination is associated with cognitive inflexibility in a rat model of schizophrenia. Nat. Commun., 2020, 11(1), 2329. doi: 10.1038/s41467-020-16218-4 PMID: 32393757
  30. Tuinstra, T.; Verheij, M.; Willemen, A.; Iking, J.; Heeren, D.J.; Cools, A.R. Retrieval of spatial information in Nijmegen high and low responders: Involvement of β-adrenergic mechanisms in the nucleus accumbens. Behav. Neurosci., 2000, 114(6), 1088-1095. doi: 10.1037/0735-7044.114.6.1088 PMID: 11142641
  31. Fico, G.; Bader, A.; Flamini, G.; Cioni, P.L.; Morelli, I. Essential Oil of Nigella damascena L. (Ranunculaceae). Seeds. J. Essent. Oil Res., 2003, 15(1), 57-58. doi: 10.1080/10412905.2003.9712267
  32. Ogawa, K.; Nakamura, S.; Hosokawa, K.; Ishimaru, H.; Saito, N.; Ryu, K.; Fujimuro, M.; Nakashima, S.; Matsuda, H. New diterpenes from Nigella damascena seeds and their antiviral activities against herpes simplex virus type-1. J. Nat. Med., 2018, 72(2), 439-447. doi: 10.1007/s11418-017-1166-6 PMID: 29288328
  33. Atanasov, A.G.; Waltenberger, B.; Pferschy-Wenzig, E.M.; Linder, T.; Wawrosch, C.; Uhrin, P.; Temml, V.; Wang, L.; Schwaiger, S.; Heiss, E.H.; Rollinger, J.M.; Schuster, D.; Breuss, J.M.; Bochkov, V.; Mihovilovic, M.D.; Kopp, B.; Bauer, R.; Dirsch, V.M.; Stuppner, H. Discovery and resupply of pharmacologically active plant-derived natural products: A review. Biotechnol. Adv., 2015, 33(8), 1582-1614. doi: 10.1016/j.biotechadv.2015.08.001 PMID: 26281720
  34. WHO Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems., 2004. Available from:https://apps.who.int/iris/bitstream/handle/10665/43034/9241592214_eng.pdf
  35. Phua, D.H.; Zosel, A.; Heard, K. Dietary supplements and herbal medicine toxicities—when to anticipate them and how to manage them. Int. J. Emerg. Med., 2009, 2(2), 69-76. doi: 10.1007/s12245-009-0105-z PMID: 20157447
  36. Pardridge, W.M. Drug transport across the blood-brain barrier. J. Cereb. Blood Flow Metab., 2012, 32(11), 1959-1972. doi: 10.1038/jcbfm.2012.126 PMID: 22929442
  37. Dong, X. Current strategies for brain drug delivery. Theranostics, 2018, 8(6), 1481-1493. doi: 10.7150/thno.21254 PMID: 29556336
  38. Ljungberg, T.; Ungerstedt, U. A method for simultaneous recording of eight behavioral parameters related to monoamine neurotransmission. Pharmacol. Biochem. Behav., 1978, 8(4), 483-489. doi: 10.1016/0091-3057(78)90088-6 PMID: 209479
  39. Wischhof, L.; Aho, H.E.A.; Koch, M. DOI-induced deficits in prepulse inhibition in Wistar rats are reversed by mGlu2/3 receptor stimulation. Pharmacol. Biochem. Behav., 2012, 102(1), 6-12. doi: 10.1016/j.pbb.2012.03.011 PMID: 22469865
  40. Yamada, S.; Harano, M.; Annoh, N.; Nakamura, K.; Tanaka, M. Involvement of serotonin 2A receptors in phencyclidine-induced disruption of prepulse inhibition of the acoustic startle in rats. Biol. Psychiatry, 1999, 46(6), 832-838. doi: 10.1016/S0006-3223(98)00356-4 PMID: 10494453
  41. Dudchenko, P.A. An overview of the tasks used to test working memory in rodents. Neurosci. Biobehav. Rev., 2004, 28(7), 699-709. doi: 10.1016/j.neubiorev.2004.09.002 PMID: 15555679
  42. Olivier, J.D.A.; Van Der Hart, M.G.C.; Van Swelm, R.P.L.; Dederen, P.J.; Homberg, J.R.; Cremers, T.; Deen, P.M.T.; Cuppen, E.; Cools, A.R.; Ellenbroek, B.A. A study in male and female 5-HT transporter knockout rats: An animal model for anxiety and depression disorders. Neuroscience, 2008, 152(3), 573-584. doi: 10.1016/j.neuroscience.2007.12.032 PMID: 18295409
  43. Nonkes, L.J.P.; Tomson, K.; Mærtin, A.; Dederen, J.; Roald Maes, J.H.; Homberg, J. Orbitofrontal cortex and amygdalar over-activity is associated with an inability to use the value of expected outcomes to guide behaviour in serotonin transporter knockout rats. Neurobiol. Learn. Mem., 2010, 94(1), 65-72. doi: 10.1016/j.nlm.2010.04.002 PMID: 20388545
  44. Paxinos, G.; Watson, C. Paxinos and Watson’s The rat brain in stereotaxic coordinates, 7th ed; Elsevier Academic Press: Cambridge, Massachusetts, 2014. doi: 10.1007/s40473-014-0013-2 PMID: 25215267
  45. Yui, K.; Goto, K.; Ikemoto, S.; Ishiguro, T.; Angrist, B.; Duncan, G.E.; Sheitman, B.B.; Lieberman, J.A.; Bracha, S.H.; Ali, S.F. Neurobiological basis of relapse prediction in stimulant-induced psychosis and schizophrenia: The role of sensitization. Mol. Psychiatry, 1999, 4(6), 512-523. doi: 10.1038/sj.mp.4000575 PMID: 10578232
  46. Scruggs, J.L.; Patel, S.; Bubser, M.; Deutch, A.Y. DOI-Induced activation of the cortex: dependence on 5-HT2A heteroceptors on thalamocortical glutamatergic neurons. J. Neurosci., 2000, 20(23), 8846-8852. doi: 10.1523/JNEUROSCI.20-23-08846.2000 PMID: 11102493
  47. Hervig, M.E.; Thomsen, M.S.; Kalló, I.; Mikkelsen, J.D. Acute phencyclidine administration induces c-Fos-immunoreactivity in interneurons in cortical and subcortical regions. Neuroscience, 2016, 334, 13-25. doi: 10.1016/j.neuroscience.2016.07.028 PMID: 27476436
  48. Burcham, P. Target-Organ Toxicity: Liver and Kidney. In: An Introduction to Toxicology; Springer-Verlag: London, 2014; pp. 151-187.
  49. Białoń, M.; Wąsik, A. Advantages and limitations of animal Schizophrenia models. Int. J. Mol. Sci., 2022, 23(11), 5968. doi: 10.3390/ijms23115968 PMID: 35682647
  50. Deutsch, S.I. Animal Models of Psychosis. In: Transgenic and Knockout Models of Neuropsychiatric Disorders; Flint, J., Ed.; Humana Press Inc: Totowa, NJ, 2006; pp. 193-220. doi: 10.1007/978-1-59745-058-4_10
  51. Forrest, A.D.; Coto, C.A.; Siegel, S.J. Animal models of psychosis: Current state and future directions. Curr. Behav. Neurosci. Rep., 2014, 1(2), 100-116. doi: 10.1007/s40473-014-0013-2 PMID: 25215267
  52. Howes, O.D.; Kapur, S. The dopamine hypothesis of schizophrenia: version III-the final common pathway. Schizophr. Bull., 2009, 35(3), 549-562. doi: 10.1093/schbul/sbp006 PMID: 19325164
  53. Sipes, T.E.; Geyer, M.A. DOI disruption of prepulse inhibition of startle in the rat is mediated by 5-HT2A and not by 5-HT2C receptors. Behav. Pharmacol., 1995, 6(8), 839-842. doi: 10.1097/00008877-199512000-00010 PMID: 11224388
  54. Sanberg, P.R.; Bunsey, M.D.; Giordano, M.; Norman, A.B. The catalepsy test: Its ups and downs. Behav. Neurosci., 1988, 102(5), 748-759. doi: 10.1037/0735-7044.102.5.748 PMID: 2904271
  55. Floresco, S.B.; Zhang, Y.; Enomoto, T. Neural circuits subserving behavioral flexibility and their relevance to schizophrenia. Behav. Brain Res., 2009, 204(2), 396-409. doi: 10.1016/j.bbr.2008.12.001 PMID: 19110006
  56. Stahl, S.M. Psychosis and schizophrenia. In: Stahl’s Essential Psychopharmacology, 4th ed; Cambridge University Press: New York, 2013; pp. 129-236.
  57. Aringhieri, S.; Carli, M.; Kolachalam, S. Molecular targets of atypical antipsychotics: From mechanism of action to clinical differences. Pharmacol. Ther., 2018, 192, 20-41. doi: 10.1016/j.pharmthera.2018.06.012
  58. Kaar, S.J.; Natesan, S.; McCutcheon, R.; Howes, O.D. Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology. Neuropharmacology, 2020, 172, 107704. doi: 10.1016/j.neuropharm.2019.107704 PMID: 31299229
  59. Costall, B.; Naylor, R.J.; Nohria, V. Climbing behaviour induced by apomorphine in mice: A potential model for the detection of neuroleptic activity. Eur. J. Pharmacol., 1978, 50(1), 39-50. doi: 10.1016/0014-2999(78)90251-0 PMID: 28233
  60. Costall, B.; Fortune, D.H.; Naylor, R.J.; Nohria, V. The mesolimbic system, denervation and the climbing response in the mouse. Eur. J. Pharmacol., 1980, 66(2-3), 207-215. doi: 10.1016/0014-2999(80)90144-2 PMID: 6108225
  61. Vasse, M.; Protais, P. Potentiation of apomorphine-induced stereotyped behaviour by acute treatment with dopamine depleting agents: A potential role for an increased stimulation of D1 dopamine receptors. Neuropharmacology, 1989, 28(9), 931-939. doi: 10.1016/0028-3908(89)90192-5 PMID: 2554186
  62. Quock, R.M.; Bloom, A.S.; Sadowski, J.A. Possible noradrenergic involvement in naloxone potentiation of apomorphine-induced stereotypic climbing in mice. Pharmacol. Biochem. Behav., 1984, 21(5), 733-736. doi: 10.1016/S0091-3057(84)80011-8 PMID: 6096896
  63. Jang, C.G.; Park, Y.; Tanaka, S.; Ma, T.; Loh, H.H.; Ho, I.K. Involvement of µ-opioid receptors in potentiation of apomorphineinduced climbing behavior by morphine: studies using µ-opioid receptor gene knockout mice. Brain Res. Mol. Brain Res., 2000, 78(1-2), 204-206. doi: 10.1016/S0169-328X(00)00094-2 PMID: 10891603
  64. Ito, S.; Mori, T.; Sawaguchi, T. Differential effects of µ-opioid, δ-opioid and κ-opioid receptor agonists on dopamine receptor agonist-induced climbing behavior in mice. Behav. Pharmacol., 2006, 17(8), 691-701. doi: 10.1097/FBP.0b013e32801155a1 PMID: 17110795
  65. Sovilla, J.Y.; Magistretti, P.; Schorderet, M. Potentiation of apomorphine-induced climbing behaviour in mice by d-LSD. Prog. Neuropsychopharmacol., 1979, 3(5-6), 503-511. doi: 10.1016/0364-7722(79)90004-3
  66. Young, K.A.; Zavodny, R.; Hicks, P.B. Effects of serotonergic agents on apomorphine-induced locomotor activity. Psychopharmacology, 1993, 110(1-2), 97-102. doi: 10.1007/BF02246956 PMID: 7870905
  67. Ellenbroek, B.A.; Cools, A.R. Animal models for the negative symptoms of schizophrenia. Behav. Pharmacol., 2000, 11(3 & 4), 223-233. doi: 10.1097/00008877-200006000-00006 PMID: 11103877

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Bentham Science Publishers