Protective role of endocannabinoid signaling in an animal model of haloperidol-induced tardive dyskinesia.

Tardive dyskinesia (TD) is a side effect associated with the long-term use of certain antipsychotics. Considering the modulatory role of the endocannabinoid system upon dopaminergic neurotransmission, the present study tested the hypothesis that increasing endocannabinoid (anandamide and 2-arachidonoylglycerol) levels attenuates haloperidol-induced TD (vacuous chewing movements, VCMs) in male Wistar rats. The animals received administration of chronic haloperidol (38 mg/kg; 29 days) followed by acute FAAH (URB597, 0.1-0.5 mg/kg) or MAGL (JZL184, 1-10 mg/kg) inhibitors before VCM quantification. The underlying mechanisms were evaluated by pre-treatments with a CB ₁ receptor antagonist (AM251, 1 mg/kg) or a TRPV ₁ channel blocker (SB366791, 1 mg/kg). Moreover, CB ₁ receptor expression was evaluated in the striatum of high-VCM animals. As expected, haloperidol induced VCMs only in a subset of rats. Either FAAH or MAGL inhibition reduced VCMs. These effects were prevented by CB ₁ receptor antagonism, but not by TRPV1 blockage. Remarkably, CB ₁ receptor expression was increased high-VCM rats, with a positive correlation between the levels of CB ₁ expression and the number of VCMs. In conclusion, increasing endocannabinoid levels results in CB ₁ receptor-mediated protection against haloperidol-induced TD in rats. The increased CB ₁ receptor expression after chronic haloperidol treatment suggests a counter-regulatory protective mechanism.
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