Gabapentina previne alterações comportamentais induzidas por anfetamina ou haloperidol em camundongos

Abstract

Schizophrenia is a chronic and highly complex psychiatric illness that manifests with a wide spectrum of changes that include cognitive, negative and positive symptoms. The drugs available for the treatment (antagonists of dopamine D2 receptors) causes numerous metabolic and abnormal movements adverse effects, which leads the patients to abandon of the therapy, and therefore have symptomatic relapses. The manipulation of the dopaminergic system by using psychostimulant drugs such as amphetamine, or by long-term use of haloperidol, has served as experimental model for the screening of drugs with potential for pharmacological treatment of symptoms of schizophrenia and preventing adverse effects, respectively. It has been reported that drugs with a GABAergic agonist action may improve the positive and negative symptoms of schizophrenia or reduce the incidence of tardive dyskinesia (TD), thereby reducing dopaminergic activity. Thus, the aim of this study was to evaluate the possible modulatory and neuroprotective effects of gabapentin (GBP), a gamma-aminobutyric acid analog, on behavioral and biochemical alterations induced by the administration of amphetamine or haloperidol in mice. Firstly, the animals received vehicle (0,9% NaCl) or different doses of GBP (10, 30, 100 mg/kg) and, 30 minutes after, received a single dose of amphetamine (1.25 mg/kg), both by intraperitoneal route. Behavioral analyses in open field, stereotypy, Y maze and social interaction tests were performed 25 minutes after the administration of amphetamine. Amphetamine induced memory impairment, hyperlocomotion, stereotyped behavior and social withdrawal. GBP prevented the working memory and social interaction deficit as well as reduced stereotypies induced by amphetamine. However, GBP had no effect on hyperlocomotion. In addition, the effects of GBP were evaluated on haloperidol-induced orofacial dyskinesia (OD) model, an adverse effect of dopaminergic antagonists, where the animals received daily doses of haloperidol (1.25 mg/kg) and/or GBP (100 mg/kg) for 28 days and vacuous chewing movements (VCM) were recorded on the 1st (before the beginning of administrations) and on the 28th day as well as changes in the open field test on 28th day of treatment. Treatment with haloperidol increased the number of VCM and decreased the locomotor activity. Co-treatment with GBP prevented these effects. Biochemical parameters related to dopaminergic and gabaergic activity were evaluated. There was no statistically significant difference in tyrosine hydroxylase (TH) immunoreactivity, monoamine levels as well as the glutamate decarboxylase (GAD) immunoreactivity in the striatum of animals treated with both drugs. The results suggest that GBP may be a promising therapeutic agent in controlling the clinical symptoms of schizophrenia and to avoid the development of adverse effects by the current treatments resulting in improving the quality of life for patients.