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

https://doi.org/10.1016/j.pbb.2021.173193Get rights and content

Highlights

  • Haloperidol induced tardive dyskinesia (vacuous chewing movements, VCMs) in rats.

  • VCMs occurred only in a subset of animals, as reported in clinical studies.

  • Endocannabinoid hydrolysis inhibitors ameliorated VCMs.

  • These effects were prevented by CB1, but not TRPV1, blockade.

  • VCM intensity correlated with CB1 receptor expression in the striatum.

Abstract

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 CB1 receptor antagonist (AM251, 1 mg/kg) or a TRPV1 channel blocker (SB366791, 1 mg/kg). Moreover, CB1 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 CB1 receptor antagonism, but not by TRPV1 blockage. Remarkably, CB1 receptor expression was increased high-VCM rats, with a positive correlation between the levels of CB1 expression and the number of VCMs. In conclusion, increasing endocannabinoid levels results in CB1 receptor-mediated protection against haloperidol-induced TD in rats. The increased CB1 receptor expression after chronic haloperidol treatment suggests a counter-regulatory protective mechanism.

Introduction

Antipsychotic drugs are of major importance for the treatment of schizophrenia. Their core mechanism of action entails antagonism or partial agonism at dopamine D2 receptors (Kapur and Mamo, 2003). Antipsychotics can be classified as first generation drugs, which include chlorpromazine and haloperidol, and second generation (“atypical”) drugs, whose prototype is clozapine. Although first-generation antipsychotics are still widely used, they are prone to induce serious side effects (Ellenbroek, 2012), such as tardive dyskinesia (TD), characterized by involuntary movements affecting mainly the orofacial region, with manifestations of chewing movements, tongue protrusion and excessive blinking (Arya et al., 2019). TD occurs in around 10 to 20% of patients treated with antipsychotics and may last for years after the end of treatment (Casey, 1999; Woods et al., 2010).

The mechanisms underlying TD are not well understood (Loonen and Ivanova, 2013). The prevailing hypothesis posits that the chronic blockade of dopaminergic receptors results in a compensatory hyperdopaminergic state in the dorsal striatum (Turrone et al., 2003). In experimental settings, TD can be properly modeled in laboratory rodents (rats and mice). The long-term treatment with haloperidol leads a subset of animals to develop a TD-like response termed vacuous chewing movements (VCM), an animal model with robust face, construct and predictive validity (Gobira et al., 2013b).

Dopamine signaling and function in the basal ganglia can be modulated by various neurochemical mechanisms, such as the endocannabinoid system (Fernández-Ruiz, 2009). This signaling system comprises the cannabinoid receptors CB1 and CB2; the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG); and their associated metabolizing enzymes, fatty acid amine hydrolase (FAAH) and monoacylglycerol lipase (MAGL), which are primarily responsible for the hydrolysis of anandamide and 2-AG, respectively (Pertwee et al., 2010). In addition to CB1 and CB2 receptors, endocannabinoids bind to other targets, such as the transient receptor potential vanilloid type-1 channel (TRPV1), formerly known as the “vanilloid receptor” (Pertwee et al., 2010; Fatahi et al., 2018). Both CB1 and TRPV1 are densely expressed in striatal neurons, where they modulate dopaminergic activity (Julian et al., 2003; Marinelli et al., 2003) and levodopa-induced dyskinesia (Morgese et al., 2007). Moreover, direct CB1 receptor activation inhibits haloperidol-induced VCMs in rats (Röpke et al., 2014). However, the effects of endocannabinoid hydrolysis inhibitor have remained to be investigated.

Therefore, the present study tested the hypothesis that the selective inhibition of endocannabinoid hydrolyzing enzymes reduces VCMs in rats. We also investigated if the effects of FAAH and MAGL inhibitors depend on activation of CB1 receptor and TRPV1 channel. Finally, we tested the effect of long-term haloperidol treatment on CB1 expression in the striatum. The main findings implicate endocannabinoid-mediated CB1 receptor facilitation as a potential mechanism to ameliorate TD.

Section snippets

Animals

Male Wistar rats weighing 200–220 g were kept under controlled temperature (24 °C) in a light dark cycle of 12 h, with free access to water and food. The experimental procedures were approved by the Committee on Ethics in the Use of Animals from the Federal University of Minas Gerais (CEUA-UFMG) under protocol 220/2014.

Drugs

Haloperidol decanoate (Haldol®, Janssen-Cilag) was diluted in sesame oil; the FAAH inhibitor, [3-(3-carbamoylphenyl)phenyl]-N-cyclohexylcarbamate (URB597; Tocris), the MAGL

Results

In an initial experiment, haloperidol-treated animals were classified into separate groups accordingly to their VCM scores as high or low VCMs. Recapitulating the clinical profile, haloperidol increased VCM only in a subset of rats (F2,27 = 136.8, p < 0.0001, Fig. 1). Next, the FAAH inhibitor, URB597, or the MAGL inhibitor, JZL184, was administered to an independent cohort of animals submitted to chronic haloperidol treatment. As shown in Fig. 2, upper panel, URB597 inhibited VCM at the doses

Discussion

The present study tested the hypothesis that facilitating endocannabinoid signaling inhibits haloperidol-induced TD in an animal model. The results show that the selective inhibition of the endocannabinoid-hydrolyzing enzymes reduces VCMs in haloperidol-treated rats. This effect was prevented by a CB1 receptor antagonist, but not by a TRPV1 channel blocker. Finally, chronic haloperidol administration increased CB1 receptor expression in the striatum, which positively correlated with the number

Conclusion

In conclusion, endocannabinoid hydrolysis inhibition reduces haloperidol-induced VCMs in a CB1-dependent manner. Moreover, chronic haloperidol administration increases CB1 receptor expression in the striatum, which directly correlates with VCM levels, suggesting a compensatory mechanism. Compounds that inhibit endocannabinoid hydrolysis warrants further investigation as potential pharmacological approaches to ameliorate TD resulting from long-term antipsychotic treatment.

Ethical approval

The experimental procedures were approved by the Committee on Ethics in the Use of Animals from the Federal University of Minas Gerais (CEUA-UFMG) under protocol 220/2014.

Funding

This study was financed by CNPq [grant number 406122/2016-4] and FAPESP [grant number 2017/24304-0]. FAM is recipient of a CNPq productivity fellowship (level 2).

Availability of data and materials

All data and images are presented in the main body of the manuscript or as supplementary material. Additional data, material and information are available on request.

CRediT authorship contribution statement

JR and THFV: Performed research. Analyzed data. Wrote the paper. LPI and LA: Analyzed data. Wrote the paper. FMR and FAM: Designed study. Analyzed data. Wrote the paper. All authors read and approved the manuscript and all data were generated in-house and that no paper mill was used.

Declaration of competing interest

The authors have no conflict of interest to declare.

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