IN RATS
Luis Ricardo PerozaA, Larissa Finger SchafferB, Alcindo BusanelloB, Catiuscia Molz de FreitasA, Ana Paula C. CerettaB, Elizete ReisB, Roselei FachinettoA,B
APrograma de Pós-Graduação em Bioquímica Toxicológica, Universidade Federal de Santa
Maria, RS, Brazil.
BPrograma de Pós-Graduação em Farmacologia, Universidade Federal de Santa Maria, RS,
Brazil.
*Corresponding author:
Drª. Roselei Fachinetto Centro de Ciências da Saúde
Departamento de Fisiologia e Farmacologia Programa de Pós-Graduação em Farmacologia 97105-900, Santa Maria, RS, Brazil
Tel: x21-55-220-8096 Fax: x21-55-220-8241 e-mail: [email protected]
ABSTRACT
Antipsychotics used to treat schizophrenia can induced movement disorders, such as tardive dyskinesia (TD), and little is known about the effect of these drugs on the cerebral cortex. In this study, rats were treated with haloperidol decanoate (1mg/kg) or risperidone (2mg/kg) for 28 days. Twenty four hours after the last administration, rats were submitted to behavioral analysis for quantification of the vacuous chewing movements (VCMs) and then the cerebral cortex was used to evaluate the effect of both antipsychotics on oxidative damage or antioxidant markers (TBARS, catalase activity and levels of proteic- and non-proteic thiols) and also dopaminergic parameters (monoamine oxidase [MAO] activity, tyrosine hydroxylase [TH] and dopamine transporter (DAT) immunoreactivity). As results, the treatment with haloperidol, but not with risperidone, significantly increased the number of VCM. However, no difference was observed on oxidative or antioxidant parameters neither in dopaminergic parameters in the cerebral cortex of rats treated with haloperidol or risperidone. Our results suggest that the oxidative and dopaminergic markers in cerebral cortex evaluated in this study seem not to be involved in the development of haloperidol-induced VCMs.
Keywords: Tardive dyskinesia, Antipsychotic, Monoamine oxidase, Tyrosine hydroxylase,
Dopamine transporter.
INTRODUCTION
Schizophrenia is a severe psychiatric disease that affects 1% of the population worldwide and it is associated with functional dysfunction of cortical and subcortical brain areas, among which the prefrontal cortex (PFC) plays a major role (Kirkbride et al., 2012). The cortical area which is a target of the antipsychotic drugs is involved in cognitive and affective functions and contains a large density of monoaminergic axons and receptors which modulate the cortex function (Artigas, 2010; Fuster, 2001).
Antipsychotic drugs are used to treat schizophrenia (Andreazza et al., 2015). Based on their properties and potential side effects they are referred as typical or atypical, (Meltzer, 2013). Typical antipsychotic are dopamine antagonists, that mainly block dopamine D2 receptors. An example is haloperidol, which is a butyrophenone that has strong activity against delusions and hallucinations symptoms due to its effects on the mesolimbic pathway of the brain. On the other hand, the blockade of mesocortical intensifies the negative symptoms and/or cognitive deficits and the blockade of the nigrostriatal pathway has been associated with the
development of movement disorder, such as tardive dyskinesia (TD) (Brisch et al., 2014; Brody et al., 1998). TD is characterized by late onset of involuntary facial, limb, and trunk movements following chronic exposure to antipsychotic drug treatment (Marsalek, 2000).
Atypical antipsychotics have a different pharmacological profile, and usually have fewer behavior disorders. In addition to the influence on the dopamine system, they also affect serotonin receptor subtypes such as serotonin 2A (5-HT2A) (Meltzer, 2013). In the schizophrenia, the negative symptoms may be due to a primary deficiency of dopamine or a secondary deficiency caused by excess serotonin inhibiting dopamine release. Therefore, the blockage of serotonin receptors in the mesocortical pathway by atypical antipsychotics can improve negative symptoms (Stahl, 2000). Risperidone is a benzisoxazole derivative belonging to atypical antipsychotics group (Megens et al., 1994). However, the use of atypical antipsychotics causes other important metabolic side effects (Leo & Regno, 2000).
Many of the side effects related to the use of these antipsychotics (principally by the typical ones) have been studied and several hypotheses have been proposed to explain the development of them, such as oxidative stress (Burger et al., 2005a; 2005b; Naidu et al., 2003; Singh et al., 2003), neuroinflammation (Bishnoi et al., 2008), dopaminergic supersensitivity (Andreassen & Jorgensen, 2000), among others. Many effects induced by the use of this medication are still unknown, as well the mechanisms that lead to the side effects are not fully elucidated. In general, the focus of studies are in basal ganglia whithout investigate the changes promoted in other brain regions as cortex that is affected by typical and atypical drugs.
There are evidence on the literature that the blockade of dopamine D2 receptors results in a decrease in dopamine neurotransmission, which is followed by a compensation effect of increased dopamine synthesis and release in the brain (Rogoza et al., 2004). Dopamine is normally deaminated by monoamine oxidase (MAO), which results in the production of 3,4- dihydroxyphenylacetic acid (DOPAC). This neurotransmitter is also metabolized by auto- oxidation, which leads to the formation of hydrogen peroxide (H2O2) (Halliwell, 2006).
Therefore, the increased synthesis of dopamine after blockade of dopamine D2 receptors, could lead to an increased metabolism of this neurotransmitter, thus leading to the production of reactive metabolites and it is significantly important because oxidative damage to lipids, proteins and DNA can occur when the amount of reactive species surpasses the capacity of the antioxidant defence system (Andreazza et al., 2015).
The blockade of dopamine receptors could also change the dopaminergic transmission by influencing the activity of the dopamine transporter (DAT), which regulates the re-uptake of free dopamine from the intra-synaptic cleft (Han et al., 2009), and the activity of the tyrosine
hydroxylase (TH), the rate-limiting enzyme in the biosynthetic pathways of catecholamine-type neurotransmitters, such as dopamine, epinephrine and norepinephrine (Asanuma et al., 2003). However, little is known about the changes promoted by antipsychotics in cerebral cortex as well as if these alterations are related with motor disfunctions caused by typical antipsychotics. Therefore, were evaluated the effects of typical and atypical antipsychotic (haloperidol and risperidone, respectively) on behavioral and in the markers oxidative damage and antioxidant defenses and also in dopaminergic markers in cerebral cortex comparing them.