Memory deterioration based on the tobacco smoke exposure and methylazoxymethanol acetate administration vs. aripiprazole, olanzapine and enrichment environment conditions

Highlights

• Tobacco smoke exposure and methylazoxymethanol acetate deteriorate memory.

• Aripiprazole and olanzapine reduce deterioration of spatial memory functions.

• Enriched environment conditions have a major procognitive effect.

Abstract

Enrichment environment conditions, as well as tobacco smoke exposure, may affect cognitive function (e.g. spatial memory) in an animal model of schizophrenia and schizophrenic patients.

The aim of this study was to find whether spatial memory function impairment is found in methylazoxymethanol acetate treated rats (an animal model of schizophrenia) and whether aripiprazole (1.5 mg/kg) and olanzapine (0.5 mg/kg) modify these functions. We also were able to determine whether tobacco smoke exposure and enrichment environment conditions have an impact on drug efficacy.

The effect of methylazoxymethanol acetate, tobacco smoke exposure, enrichment environment and the use of drugs were studied in the Morris Water Maze test (spatial memory).

The results of our study clearly show that enriched environment may have a procognitive effect while tobacco smoke and methylazoxymethanol acetate have a contradictory effect. This paper also confirmed that the use of neuroleptics, namely ARI and OLA, reduced the process of spatial memory deterioration tested in the Morris water maze both in terms of the number of escape latencies and crossed quadrants.

Introduction

Schizophrenia is one of the most common mental diseases (according to WHO, 24 million people worldwide are affected by schizophrenia (Funaki, 2009)). Tobacco smoking causes major health consequences both in healthy individuals and those suffering from schizophrenia (Kelly and McCreadie, 2000). It is estimated that long-term tobacco smoking may reduce life expectancy by as much as 10 years and depend on the duration of the addiction (Doll et al., 2004). Smokers much more frequently experience: cardiovascular diseases, chronic obstructive pulmonary disease, or lung cancer (Doll et al., 2004). Diseases concomitant to schizophrenia may reduce the patient's life expectancy by 20% compared to the general population (Kelly and McCreadie, 2000). Half of the cigarettes in the world are smoked by persons with various mental disorders (Lasser et al., 2000). What is important is that this addiction is observed much more frequently in schizophrenia than in the case of other mental disorders. Unfortunately, this addiction is rarely taken into consideration when determining the psychotropic drug dosage regimen, even though it is a common knowledge that tobacco smoke ingredients are strong inducers of liver enzymes participating in biotransformation of various xenobiotics. Recent studies show a major importance of central nicotinic receptors in the pathogenesis mechanism of some mental diseases, such as depression and schizophrenia. They also indicate a correlation between the incidence of these diseases in the general population and nicotine's ability to release numerous neurotransmitters in the CNS (such as DA, 5-HT, NA) (Suemaru et al., 2002). Smoking may be a way of “self-treatment” of adverse effects of the pharmacotherapy used and probably a way to “compensate” for the reduced number of nicotinic receptors in patients with depression or schizophrenia (Spring et al., 2003).

Experimental and clinical studies indicate an increased risk of schizophrenia and the accompanying cognitive function disorders in the offspring of mothers treated by methylazoxymethanol acetate (MAM) during pregnancy (Moore et al., 2006). In accordance with the methodology used, MAM (mitotoxin) is administered to pregnant females on day 17 of gestation, i.e. in the 3rd trimester of fetal growth during which the subcortical and cerebellar regions proliferate, leading to a number of disturbances in the developing brain structures. Frontal and temporal cortex and paralimbic regions are particularly vulnerable to mitotoxin (Hradetzky et al., 2012). Neuroplastic deterioration of these regions consequently leads to neurotransmitter release disorders (specifically of DA, NA, and 5-HT) which induces disorders of various types of memory, and hampers attention and concentration (Featherstone et al., 2007; Flagstad et al., 2005; Gourevitch et al., 2004; Moore et al., 2006). The extent of irregularities observed in the animals depends on the dose and the fetal growth stage at the time of MAM administration. Numerous studies have shown that MAM administered to females on day 17 of gestation caused neuroanatomical changes, behavioral disorders, and cognitive deficits of attention, declarative memory, and operating memory similar to those observed in schizophrenic human patients (Brown et al., 2012; Featherstone et al., 2007; Lodge and Grace, 2009; Moore et al., 2006). In addition to that, MAM-induced rats present with lower resistance to stress which may also exacerbate memory deficits and reduce learning capabilities (Snyder et al., 2013). In comparison to other animal models of schizophrenia, MAM injection belongs to a developmental group of models as well as e.g. prenatal stress procedure (Kinnunen et al., 2003) or maternal deprivation (Llorente et al., 2010) method. Literature describe also models created by pharmacological interventions (e.g. ketamine (Geyer et al., 2001), PCP (Kapur and Seeman, 2002)), lesion models (e.g. neonatal ventral hippocampal lesion (Lipska and Weinberger, 2000)) and genetic models (e.g. DISC-A, DTNBP1 (Jones et al., 2011)). High scientific value of developmental models is associated with the neurodevelopmental theory which stipulates that at an early stage of body development, a number of interactions between genetic and environmental factors may present themselves, and consequently adversely affect the development of neurons (their stratification and spatial arrangement) which may, in turn, cause disorders of brain cytoarchitecture development (Gabryel, 2008; Ratajczak et al., 2013).

In the case of experimental studies, enriched environment (EE) means that the animals are housed in larger cages with extra equipment (Alvarez et al., 2014). EE is a type of a certain level of social and developmental stimulation of cognitive and behavioral functions using inanimate materials. Enriched environment stimulates the brains of laboratory animals as a result of combining social interactions, physical activities, and continuous learning opportunities. Abundance of stimuli and an opportunity for physical activity have a positive effect on shaping and development of many brain structures, in particular the hippocampus and the neocortex. Enriched environment also contributes to enhanced neurogenesis and synaptogenesis, improving memory and learning abilities, also by increasing the brain level of brain-derived neurotrophic factor (BDNF) (Cao et al., 2014). It is also suggested that such an environment regulates the level of MMP-9 enzyme facilitating proBDNF conversion into BDNF inside the hippocampus (Cao et al., 2014). Increased level of this protein play a vital role in synaptic plasticity, positively affect many brain functions, primarily the memorizing ability, and has an anti-depressant effect (Cao et al., 2014).

Learning ability and spatial memory in animal schizophrenia models are assessed using The Morris water maze test (Larsson et al., 2002; Morris, 1984). During the test, the rodents initially acquire and process, and then memorize information on spatial arrangement. In the next attempts, they use the previously acquired information to quickly find and climb on the platform (Buccafusco, 2009). Correct completion of the task requires involvement and joint action of neurons from various brain regions, such as prefrontal cortex and the hippocampus (Morris, 1984). Reduced number of crossed quadrants and reduced time necessary to find the platform are the measure of spatial memory improvement during subsequent training sessions (Larsson et al., 2002).

Treatment of schizophrenia consists in simultaneous combination of pharmacotherapy and non-pharmacological treatment in the form of psychotherapy and social therapy. Aripiprazole (ARI) and olanzapine (OLA) belong to the group of atypical antipsychotics which – compared to classic drugs – have a positive effect on deficit symptoms and cause fewer adverse effects (Khanna et al., 2013).

The aim of this paper was to assess whether tobacco smoke ingredients impair cognitive functions of newborn animals from mothers exposed to methylazoxymethanol acetate (MAM) treatment, and whether such drugs as ARI (1.5 mg/kg) and OLA (0.5 mg/kg) in single and repeated administration modify these functions. The paper also analyses the effect of enrichment environment (EE) on animals upon ARI and OLA administration in or without tobacco smoke exposure conditions.