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Current Neuropharmacology

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ISSN (Print): 1570-159X
ISSN (Online): 1875-6190

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Research Article

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

Author(s): Yami Bright, Dorien A. Maas, Michel M.M. Verheij, Maria S. Paladini, Helene I.V. Amatdjais-Groenen, Raffaella Molteni, Marco A. Riva, Gerard J.M. Martens and Judith R. Homberg*

Volume 22, Issue 2, 2024

Published on: 24 July, 2023

Page: [323 - 338] Pages: 16

DOI: 10.2174/1570159X21666230720122354

Price: $65

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.

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[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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/10.1007/s007020200033] [PMID: 11956961]
[14]
Lieberman, J.A. Dopamine partial agonists: a new class of antipsychotic. CNS Drugs, 2004, 18(4), 251-267.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/10.1038/jcbfm.2012.126] [PMID: 22929442]
[37]
Dong, X. Current strategies for brain drug delivery. Theranostics, 2018, 8(6), 1481-1493.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/10.1097/00008877-200006000-00006] [PMID: 11103877]

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