Anti-schizophrenic activities of histamine H3 receptor antagonists in rats treated with MK-801
More details
Hide details
Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard, Hamdard Nagar, New Delhi
Danish Mahmood   

Dept of Pharmacology, Faculty of Pharmacy, Jamia Hamdard, Hamdard Nagar, New Delhi-110062
J Pre Clin Clin Res. 2015;9(1):11–17
Animal models based on N-methyl-d-aspartate (NMDA) receptor blockade have been widely reported. Ketamine and MK- 801, the two noncompetitive antagonists of NMDA receptors, produce behaviors related to schizophrenia and exacerbated symptoms in patients with schizophrenia. The study presented here investigated the effect of subchronic dosing (once-daily, 7 day) of histamine H3 receptor (H3R) antagonists, ciproxifan (CPX) (3 mg/kg, i.p.) and clobenpropit (CBP) (15 mg/kg, i.p) including clozapine (CLZ) (3.0 mg/kg, i.p.) and chlorpromazine (CPZ) (3.0 mg/kg, i.p.), the atypical and typical antipsychotic, respectively, on MK-801(0.2 mg/kg, i.p.)-induced locomotor activity, and dopamine and histamine levels in rats. Atypical and typical antipsychotic was used to serve as clinically relevant reference agents to compare the effects of the H3R antagonists. MK-801 significantly increased horizontal activity which was reduced with CPX and CBP. The attenuation of MK-801-induced locomotor hyperactivity produced CPX and CBP were comparable to CLZ and CPZ. Dopamine and histamine levels were measured in striatum and hypothalamus, respectively, of rat brain. The MK-801 induced increase of the striatal dopamine level was reduced in rats pretreated with CPX and CBP including CLZ. CPZ also significantly lowered striatal dopamine levels, though the decrease was less robust compared to CLZ, CPX and CBP. MK-801 increased histamine content although to a lesser degree. Subchronic treatment with CPX and CBP exhibited further increased histamine levels in the hypothalamus compared to MK-801 treatment alone. Histamine H3 receptor agonist, R-α methylhistamine (10 mg/kg, i.p.) counteracted the effect of CPX and CBP. The findings of the present study support our previous work showing positive effects of CPX and CBP on MK-801-induced schizophrenia like behaviors in rodents. However, clinical studies have reported no antipsychotic effects with histamine H3 receptor antagonists.
Jentsch JD, Roth RH. The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1999; 20(3): 201–225.
Luby ED, Cohen BD, Rosenbaum G, Gottlieb JS, Kelley R. Study of a new schizophrenomimetic drug; sernyl. AMA Arch Neuro. Psychiatry 1959; 81(3): 363–369.
Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 1991;148(10): 1301–1308.
Bubenikova Valesova V, Horácek J, Vrajová M. Höschl C. Models of schizophrenia in humans and animals based on inhibition of NMDA receptors. Neurosci Biobehav Rev. 2008; 32: 1014–1023.
Mohn AR, Gainetdinov RR, Caron MG, Koller BH (1999) Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 1999; 98(4): 427–436.
Tricklebank MD, Singh L, Oles RJ, Preston C, Iversen SD. The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor. Eur J Pharmacol. 1989; 167(1): 127–135.
Manahan-Vaughan D, von Haebler D, Winter C, Juckel G, Heinemann U. A single application of MK801 causes symptoms of acute psychosis, deficits in spatial memory, and impairment of synaptic plasticity in rats. Hippocampus 2008; 18(2): 125–134.
Yu J, Qi D, Xing M, Li R, Jiang K, Peng Y, Cui D. MK-801 induces schizophrenic behaviors through downregulating Wnt signaling pathways in male mice. Brain Res. 2011; 1385: 281–292.
Gilmour G, Dix S, Fellini L, Gastambide F, Plath N, Steckler T, et al. NMDA receptors, cognition and schizophrenia--testing the validity of the NMDA receptor hypofunction hypothesis. Neuropharmacology 2012; 62(3): 1401–1412.
Adell A, Jiménez-Sánchez L, López-Gil X, Romón T. Is the acute NMDA receptor hypofunction a valid model of schizophrenia? Schizophr Bul. 2012; 38(1): 9–14.
Arrang JM, Garbarg M, Schwartz JC. Auto-inhibition of histamine release mediated by a novel class (H3) of histamine receptor. Nature 1983; 302: 832–837.
Schlicker E, Malinowska B, Kathmann M, Gothert M. Modulation of neurotransmitter release via histamine H heteroreceptors. Fundam Clin Pharmacol. 1994; 8: 128–137.
Arrang JM. Histamine and schizophrenia. Int Rev Neurobiol. 2007; 78: 247–287.
Ligneau X, Lin J, Vanni-Mercier G, Jouvet M, Muir JL, Ganellin CR, Stark H, Elz S, et al. Neurochemical and behavioral effects of ciproxifan, a potent histamine H3-receptor antagonist. J Pharmacol Exp Ther. 1998; 287(2): 658–666.
Pillot C, Ortiz J, Héron A, Ridray S, Schwartz JC, and Arrang JM. Ciproxifan, a histamine H3 receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat. J Neurosci. 2002; 22: 7272–7280.
Mahmood D, Khanam R, Pillai KK, Akhtar M. Protective effects of Histamine H3 receptor ligands in schizophrenic behaviors in experimental models. Pharmacol Rep. 2012; 4: 191–204.
Burban A, Sadakhom C, Dumoulin D, Rose C, Le Pen G, Frances H, Arrang JM. Modulation of prepulse inhibition and stereotypies in rodents: no evidence for antipsychotic-like properties of histamine H3-receptor inverse agonists. Psychopharmacology (Berl). 2010; 210: 591–604.
Bardgett ME, Points M, Kleier J, Blankenship M, Griffith MS. The H3 antagonist, ciproxifan, alleviates the memory impairment but enhances the motor effects of MK-801 (dizocilpine) in rats. Neuropharmacology 2010; 59(6): 492–502.
Bardgett ME, Davis NN, Schultheis PJ, Griffith MS. Ciproxifan, an H3 receptor antagonist, alleviates hyperactivity and cognitive deficits in the APP Tg2576 mouse model of Alzheimer’s disease. Neurobiol Learn Mem. 2011; 95(1): 64–72.
Liljequist S, Ossowska K, Grabowska-Andén M, Andén NE. Effect of the NMDA receptor antagonist, MK-801, on locomotor activity and on the metabolism of dopamine in various brain areas of mice. Eur J Pharmacol. 1991; 195: 55–61.
Su F, Wang F, Zhu R, Li H. Determination of 5-Hydroxytryptamine, norepinephrine, dopamine and their metabolites in rat brain tissue by LC–ESI–MS–MS. Chromatographia 2009; 69: 207–213.
Leurs R, Blandina P, Tedford C, Timmerman H. Therapeutic potential of histamine H3 receptor agonists and antagonists. Trends Pharmacol Sci. 1998; 19: 177–83.
Akhtar M, Uma DP, Ali A, Pillai KK, Vohora D. Antipsychotic like profile of thioperamide, a selective H3-receptor antagonist in mice. Fundam Clin Pharmacol. 2006; 20: 373–378.
Ligneau X, Landais L, Perrin D, Piriou J, Uguen M, Denis E, et al. Brain histamine and schizophrenia: Potential therapeutic application of H3-receptor inverse agonists studied with BF2.649. Biochem Pharmacol. 2007; 47: 1215–1224.
Sander K, Kottke T, Stark H. Histamine H3 receptor antagonists go to clinics. Biol Pharm Bull. 2008; 31: 2163–2181.
Gemkow MJ, Devenport AJ, Harich S, Ellenbroek BA, Cesura, A, Hallett D. The histamine H3 receptor as a therapeutic drug target for CNS disorders. Drug Discov Today. 2009; 14: 509–515.
Raddatz R, Hudkins RL, Mathiasen JR, Gruner JA, Flood DG, Aimone LD. CEP-26401 (irdabisant), a potent and selective histamine H3 receptor antagonist/inverse agonist with cognition-enhancing and wake-promoting activities. J Pharmacol Exp Ther. 2012; 340: 124–133.
Egan M, Zhao X, Gottwald R, Harper-Mozley L, Zhang Y, Snavely D, et al. Randomized crossover study of the histamine H3 inverse agonist MK-0249 for the treatment of cognitive impairment in patients with schizophrenia. Schizophr Res. 2013; 146(1–3): 224–230.
Haig GM, Bain E, Robieson W, Othman AA, Baker J, Lenz RA. A randomized trial of the efficacy and safety of the H3 antagonist ABT-288 in cognitive impairment associated with schizophrenia. Schizophr Bull. 2014; 40(6): 1433–1442.
Bardgett ME, Points M, Roflow J, Blankenship M, Griffith MS. Effects of the H(3) antagonist, thioperamide, on behavioral alterations induced by systemic MK-801administration in rats. Psychopharmacology (Berl). 2009; 205(4): 589–597.
Schwartz JC. The histamine H3 receptor: from discovery to clinical trials with pitolisant. Br J Pharmacol. 2011; 163: 713–721.
Brown JW, Whitehead CA, Basso AM, Rueter LE, Zhang M. Preclinical evaluation of non-imidazole histamine H3 receptor antagonists in comparison to atypical antipsychotics for the treatment of cognitive deficits associated with schizophrenia. Int J Neuropsychopharmacol. 2013; 16(4): 889–904.