Discinesia orofacial induzida por haloperidol em roedores: efeito do tempo de tratamento em marcadores e moduladores dopaminérgicos

Abstract

Chronic treatment with antipsychotics is related to the development of extrapyramidal side effects such as tardive dyskinesia (TD). Characterized by manifesting the vacuous chewing movements (VCMs), orofacial dyskinesia (OD) is an experimental model for researching DT. As in humans, whose prevalence of DT is 25.3%, some animals develop DO. Understanding the mechanisms by which animals “resist” the development of OD will contribute to a better understanding of the pathophysiology of TD, as well as to the development of drugs. Thus, this study aimed to investigate whether the alterations of the dopaminergic modulators and makers in the dopamine nigrostriatal pathway are involved in the “resistance” to the development of the DO. In this study, it was administered haloperidol (intramuscular, 38 mg/Kg) in rats each 28 days. Experimental protocols consist of three times of treatments: 4, 12, and 24 weeks. After 28 days of each administration, it was quantified the number of VCMs and, following, we classified the haloperidol-tread rats into the Low VCM (non-dyskinetic) and High VCM (dyskinetic). Then, we analyzed dopaminergic makers (dopamine levels (DA); monoamine oxidase (MAO) activity; immunoreactivities of tyrosine hydroxylase (TH), dopamine 2 receptor (D2), and dopamine transporter (DAT)) and modulators (immunoreactivities of the glutamate decarboxylase 67 kDa (GAD67) and adenosine 2A receptor (A2A)). Haloperidol increases the number of VCMs at 37.50% of the rats and it decreases the VCMs in rats with spontaneous dyskinesia (SD) that received haloperidol (SD-Hal VCM) after four weeks of treatment. It found negative correlations in the High VCM group between either DA levels in the striatum or MAO-B activity with the immunoreactivity of the GAD67 in the Sn, while it found positive correlations in the SD-Hal VCM group. 12-weeks treatment of haloperidol decreases the MAO-A activity in the Sn and the immunoreactivity of the GAD67 in the same region. However, this effect seems to be only related to the treatment and not to the development of the VCMs. The number of VCMs after 24 weeks inversely correlated with the MAO-A activity and, also, with the immunoreactivity of GAD67 in the striatum from the rats that develop DO, which was found an increase in the prevalence of 50%. Low VCM group showed negative correlations between either DA levels or immunoreactivity of the GAD67, in the Sn, both with the MAO-A activity in the striatum; and correlations between the immunoreactivities of the receptor D2, TDA, and GAD67 in the striatum. Taken together, these results may suggest that the animals, which resisted the development of DO after haloperidol treatment, showed an integration between dopaminergic modulators and makers; and this integration seems to be dependent on the time treatment.