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

A-582941, cholinergic alpha 7 nicotinic receptor agonist, improved cognitive and negative symptoms of the sub-chronic MK-801 model of schizophrenia in rats

OBJECTIVES Nicotinic receptor systems are involved in a wide variety of behavioural functions, including cognitive function, and nicotinic medications, may provide beneficial treatment for cognitive dysfunctions such as schizophrenia. According to the results of postmortem studies of schizophrenic patients, alpha 7 nicotinic acethylcholine receptor (α7 NAChR) binding levels and protein expressions were found to be decreased in cognition-related areas such as hippocampus and prefrontal cortex. In addition to this the fact that the prevalence of tobacco consumption is greater than healthy individuals encouraged research of nicotinic receptors in schizophrenia pathogenesis and treatment. In this study, we examined the effect of A-582941, a partial agonist of α7 NAChR, in the sub-chronic MK-801 model of schizophrenia in rats. METHODS Wistar Hannover rats were divided into five groups as follows and and all drug administrations were done intraperitoneally (i.p.) excluding the last dose of MK-801, which was done subcutaneously (s.c.): control (saline), vehicle (DMSO), MK-801 (0.2 mg/kg), MK-801 + A-582941 (1 mg/kg) and a positive control group (MK-801 + Clozapine) (5 mg/kg) (n = 8–10 in each). MK-801 was injected twice a day for 7 days. Prepulse inhibition of the acustic startle response (PPI) test was conducted after the last dose of MK-801 and animals were allowed to wait for a week for a washout period. A-582941 and Clozapine treatments were given for 10 days. The novel object recognition test (NORT) and social interaction (SI) and Morris water maze (MWM) tests were conducted. RESULTS PPI, discrimination index in NORT, social following behaviour in SI and swimming time in platform area in the MWM test were decreased by MK-801 injection, while latencies to platform finding in MWM and social avoidance in SI tests were increased. Clozapine increased the prepulse inhibition, discrimination index swimming in platform area and decreased platform-finding latencies and social avoidance in comparison with the MK-801 group. Although the A-582941 treatment has no effect on PPI, it increased the discrimination index, swimming time in platform area, following behaviour and decreased avoidance and platform-finding latencies. CONCLUSION Clozapine treatment improved the disruptive effect of MK-801 on PPI, NORT, and SI tests as expected. A-582941 treatment improved social deficits and cognitive dysfunctions on both visual and spatial memory. Therefore, A-582941 had a stronger effect on the negative symptoms and cognitive dysfunctions compared to that of Clozapine. The results of this study clearly suggested that α7 NAChR ligands might be a better treatment option, especially on cognitive and negative symptoms of schizophrenia