The introduction of drugs with antipsychotic activity in the 1950s allowed the treatment of schizophrenia symptoms, such as delusions and hallucinations. The chronicity of these treatments induces extrapyramidal effects such as tardive dyskinesia, characterized by involuntary and stereotyped orofacial movements of great functional and social impact. Tardive dyskinesia has been the subject of several studies due to its potential irreversibility and its uncomfortable nature for patients exposed to treatment with typical antipsychotics for a long time. One of the hypotheses to explain the pathophysiology of tardive dyskinesia is based on the increased sensitivity of dopaminergic receptors generated by the compensatory increase in dopamine synthesis against the constant blockade of type D2 receptors by typical antipsychotics (haloperidol). There would also be an increase in inflammatory processes and oxidative stress. Clinical studies from our group show that some cannabinoids have an atypical antipsychotic profile, that is, they do not induce extrapyramidal symptoms. Preclinical studies show that cannabidiol attenuates the involuntary mouth movements induced by chronic treatment with haloperidol and treatment with levodopa of parkinsonian animals. The antidyskinetic action of cannabidiol is associated with its interaction with PPAR³ (gamma-type peroxisome proliferator) receptors, which play a role in modulating the inflammatory response and oxidative stress. Cannabigerol has not yet been tested in the tardive dyskinesia model. Laboratory results demonstrate that doxycycline, a second-generation tetracycline, has an antipsychotic-like effect and prevents amphetamine-induced impairment in predictive tests for antipsychotic-like effect. Doxycycline attenuates levodopa-induced dyskinesia (LID), and has anti-inflammatory and antioxidant action. However, in a tardive dyskinesia model, doxycycline did not show benefits. When combined with CBD in this model, it prevented the anti-dyskinetic potential of CBD. Additionally, unpublished data from the group show that in a LID model, doxycycline decreases endogenous endocannabinoid concentrations. Based on these premises, this study aims to investigate the antidyskinetic effect of cannabidiol and cannabigerol, alone or in combination, as well as the effect of doxycycline on the antidyskinetic potential of these compounds, in a preclinical model using chronic treatment with haloperidol. A redose curve and the analysis of the potential mechanism of these compounds will be performed through (i) expression of the FosB protein in the striatum of the animals, in order to characterize typical or atypical antipsychotic activity of the compounds; (ii) evaluation of the interaction of cannabinoid compounds with PPAR³ receptors; (iii) analysis of the concentrations of the endocannabinoids anandamide and 2AG, after treatment with CBD, CBG and doxycycline. This study will add knowledge about cannabinoids and their interaction with doxycycline, with possible clinical implications.
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