Comparison of behavioural and molecular effects of two different schizophrenia models induced by subchronic MK-801 administration in rats

Schizophrenia is a severe psychiatric disorder with about 1% prevalance. NMDA receptor antagonists such as Phencyclidine (PCP) and MK-801 are commonly used for modeling schizophrenia in rodents. In literature, despite of the concensus about subchronic PCP administration (commonly 7 days, bi-daily administration followed by a 1 week washout period), there are different subchronic administration regimens for MK-801 beside 7 days, bidaily (MK-801-7), such as 14 days (MK-801-14) daily or 28 days daily injections. In this study, we aimed to compare two prevalant MK-801 models (MK-801-7 and MK-801-14, 0.2 mg/kg) in both behavioural and molecular changes. Wistar Hannover rats grouped as control (n=10), MK-801-14 (n=8) and MK-801-7 (n=8). Prepulse inhibition of acustic startle response (PPI), novel object recognition test (NORT), social interaction (SI) and Morris's water maze (MWM) tests were used for behavioural analyzes while real time polimerase chain reaction (Rt-PCR) was conducted for molecular analyzes of glutamic acid decarboxilase 67 (GAD67) and parvalbumin. Our results showed decreased PPI in MK-801-14 and MK- 801-7 groups. Moreover, in both models platform finding latencies were increased and swimming time in platform area was decreased in MWM. MK-801-14 and MK-801-7 reduced following and raised avoiding behaviours in SI. In Rt-PCR, GAD67 mRNA levels were decreased by MK-801-14 and MK-801-7 administrations. However, only MK-801-7 decreased discrimination index in NORT and parvalbumin mRNA levels. In this study, it has been showed that although MK-801-14 and MK-801-7 administrations revealed smiliar schizophrenia like symptoms in rats, MK-801-7 has partial superiories in certain aspects.

PDF

___

[1] Tandon R, Keshavan MS, Nasrallah HA. Schizophrenia, "just the facts" what we know in 2008. 2. Epidemiology and etiology. Schizophr Res. 2008; 102(1-3): 1-18.

[2] Schwartz TL, Sachdeva S, Stahl SM. Glutamate neurocircuitry: theoretical underpinnings in schizophrenia. Front Pharmacol. 2012; 3: 195.

[3] Snigdha S, Neill JC. Efficacy of antipsychotics to reverse phencyclidine-induced social interaction deficits in female rats--a preliminary investigation. Behav Brain Res. 2008; 187(2): 489-494.

[4] Lahti AC, Weiler MA, Tamara M, Parwani A, Tamminga CA. Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology. 2001; 25(4): 455-467.

[5] Akbarian S, Sucher N, Bradley D, Tafazzoli A, Trinh D, Hetrick WP, Potkin SG, Sandman CA, Bunney WE Jr, Jones EG. Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics. J Neurosci. 1996; 16(1): 19-30.

[6] Kristiansen L, Beneyto M, Haroutunian V, Meador-Woodruff J. Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia. Mol Psychiatry. 2006; 11(8): 737-747.

[7] Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci. 2005; 6(4): 312- 324.

[8] Lewis DA, Curley AA, Glausier JR, Volk DW. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci. 2012; 35(1): 57-67.

[9] Heckers S, Konradi C. GABAergic mechanisms of hippocampal hyperactivity in schizophrenia. Schizophr Res. 2015; 167(1): 4-11.

[10] Jones CA, Watson DJ, Fone KC. Animal models of schizophrenia. Br J Pharmacol. 2011; 164(4): 1162-1194.

[11] Neill JC, Harte MK, Haddad PM, Lydall ES, Dwyer DM. Acute and chronic effects of NMDA receptor antagonists in rodents, relevance to negative symptoms of schizophrenia: a translational link to humans. Eur Neuropsychopharmacol. 2014; 24(5): 822-835.

[12] Li JT, Su YA, Guo CM, Feng Y, Yang Y, Huang RH, Si TM. Persisting cognitive deficits induced by low-dose, subchronic treatment with MK-801 in adolescent rats. Eur J Pharmacol. 2011; 652(1): 65-72.

[13] Beninger RJ, Forsyth JK, Van Adel M, Reynolds JN, Boegman RJ, Jhamandas K. Subchronic MK-801 behavioural deficits in rats: partial reversal by the novel nitrate GT 1061. Pharmacol Biochem Behav. 2009; 91(4): 495-502.

[14] Callahan PM, Terry Jr AV, Tehim A. Effects of the nicotinic α7 receptor partial agonist GTS-21 on NMDAglutamatergic receptor related deficits in sensorimotor gating and recognition memory in rats. Psychopharmacology (Berl). 2014; 231(18): 3695-3706.

[15] Mansbach RS, Geyer MA. Effects of phencyclidine and phencyclidine biologs on sensorimotor gating in the rat. Neuropsychopharmacology. 1989; 2(4): 299-308.

[16] Mansbach RS, Geyer MA, Braff DL. Dopaminergic stimulation disrupts sensorimotor gating in the rat. Psychopharmacology (Berl). 1988; 94(4): 507-514.

[17] Unal G, Aricioglu F. A-582941, cholinergic alpha 7 nicotinic receptor agonist, improved cognitive and negative symptoms of the sub-chronic MK-801 model of schizophrenia in rats. Psychiatry and Clinical Psychopharmacology. 2018; 28(1): 4-13.

[18] Unal G, Ates A, Aricioglu F. Agmatine attenuated cognitive and social deficits in subchronic MK-801 model of schizophrenia in rats. Psychiatry and Clinical Psychopharmacology. 25 Jan 2018. http://dx.doi.org/10.1080/24750573.2018.1426696.

[19] Neill JC, Barnes S, Cook S, Grayson B, Idris NF, McLean SL, Snigdha S, Rajagopal L, Harte MK. Animal models of cognitive dysfunction and negative symptoms of schizophrenia: focus on NMDA receptor antagonism. Pharmacol Ther. 2010; 128(3): 419-432.

[20] Li JT, Feng Y, Su YA, Wang XD, Si TM. Enhanced interaction among ErbB4, PSD-95 and NMDAR by chronic MK-801 treatment is associated with behavioral abnormalities. Pharmacol Biochem Behav. 2013; 108: 44-53.

[21] D’Hooge R, De Deyn PP. Applications of the Morris water maze in the study of learning and memory. Brain Res Rev. 2001; 36(1): 60-90.

[22] Janhunen S, Svärd H, Talpos J, Kumar G, Steckler T, Plath N, Lerdrup L, Ruby T, Haman M, Wyler R, Ballard TM. The subchronic phencyclidine rat model: relevance for the assessment of novel therapeutics for cognitive impairment associated with schizophrenia. Psychopharmacology (Berl). 2015; (21-22): 4059-4083.

[23] Didriksen M, Skarsfeldt T, Arnt J. Reversal of PCP-induced learning and memory deficits in the Morris’ water maze by sertindole and other antipsychotics. Psychopharmacology (Berl). 2007; 193(2): 225-233.

[24] Wass C, Archer T, Pålsson E, Fejgin K, Klamer D, Engel JA, Svensson L. Effects of phencyclidine on spatial learning and memory: nitric oxide-dependent mechanisms. Behav Brain Res. 2006; 171(1): 147-153.

[25] Semkovska M, Bedard M, Stip E. Hypofrontality and negative symptoms in schizophrenia: synthesis of anatomic and neuropsychological knowledge and ecological perspectives. L'encephale. 2001; 27(5): 405-415.

[26] Kamińska K, Rogóż Z. The effect of combined treatment with risperidone and antidepressants on the MK-801- induced deficits in the social interaction test in rats. Pharmacol Rep. 2015; 67(6): 1183-1187.

[27] Seillier A, Giuffrida A. Evaluation of NMDA receptor models of schizophrenia: divergences in the behavioral effects of sub-chronic PCP and MK-801. Behav Brain Res. 2009; 204(2): 410-415.

[28] Matsuoka T, Sumiyoshi T, Tanaka K, Tsunoda M, Uehara T, Itoh H, Kurachi M. NC-1900, an arginine–vasopressin analogue, ameliorates social behavior deficits and hyperlocomotion in MK-801-treated rats: Therapeutic implications for schizophrenia. Brain Res. 2005; 1053(1): 131-136.

[29] Bevins RA, Besheer J. Object recognition in rats and mice: a one-trial non-matching-to-sample learning task to study 'recognition memory'. Nat Protoc. 2006; 1(3): 1306-1311.

[30] Morris R. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods. 1984; 11(1): 47-60.