Hostname: page-component-cd9895bd7-p9bg8 Total loading time: 0 Render date: 2024-12-22T18:56:34.948Z Has data issue: false hasContentIssue false

The effects of cannabidiol on behavioural and oxidative stress parameters induced by prolonged haloperidol administration

Published online by Cambridge University Press:  04 November 2022

Jaiyeola Abiola Kajero*
Affiliation:
Federal Neuropsychiatric Hospital, Yaba, Lagos, Nigeria Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
Soraya Seedat
Affiliation:
Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
Jude U. Ohaeri
Affiliation:
Department of Psychological Medicine, College of Medicine, University of Nigeria Enugu Campus, Enugu, Nigeria
Abidemi Akindele
Affiliation:
Department of Pharmacology, Therapeutics and Toxicology, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, Lagos, Nigeria
Oluwagbemiga Aina
Affiliation:
Department of Biochemistry and Nutrition, Nigerian Institute of Medical Research, Yaba, Lagos, Nigeria
*
Author for correspondence: Jaiyeola Abiola Kajero, Email: [email protected]
Rights & Permissions [Opens in a new window]

Abstract

Objectives:

We investigated the influence of oral cannabidiol (CBD) on vacuous chewing movements (VCM) and oxidative stress parameters induced by short- and long-term administration of haloperidol in a rat model of tardive dyskinesia (TD).

Methods:

Haloperidol was administered either sub-chronically via the intraperitoneal (IP) route or chronically via the intramuscular (IM) route to six experimental groups only or in combination with CBD. VCM and oxidative stress parameters were assessed at different time points after the last dose of medication.

Results:

Oral CBD (5 mg/kg) attenuated the VCM produced by sub-chronic administration of haloperidol (5 mg/kg) but had minimal effects on the VCM produced by chronic administration of haloperidol (50 mg/kg). In both sub-chronic and chronic haloperidol groups, there were significant changes in brain antioxidant parameters compared with CBD only and the control groups. The sub-chronic haloperidol-only group had lower glutathione activity compared with sub-chronic haloperidol before CBD and the control groups; also, superoxide dismutase, catalase, and 2,2-diphenyl-1-picrylhydrazyl activities were increased in the sub-chronic (IP) haloperidol only group compared with the CBD only and control groups. Nitric oxide activity was increased in sub-chronic haloperidol-only group compared to the other groups; however, the chronic haloperidol group had increased malondialdehyde activity compared to the other groups.

Conclusions:

Our findings indicate that CBD ameliorated VCM in the sub-chronic haloperidol group before CBD, but marginally in the chronic haloperidol group before CBD. There was increased antioxidant activity in the sub-chronic group compared to the chronic group.

Type
Original Article
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.
Copyright
© The Author(s), 2022. Published by Cambridge University Press on behalf of Scandinavian College of Neuropsychopharmacology

Significant Outcomes

  • Prolonged administration of haloperidol for 3 months produced a more sustained form of VCM

  • Sustained administration of haloperidol was associated with reduced antioxidant activity suggesting increased oxidative stress with increased duration of administration of haloperidol

  • CBD had minimal impact on VCM induced by chronic administration of haloperidol compared to VCM induced by sub-chronic administration of haloperidol

Limitations of Study

Introduction

Tardive dyskinesia (TD) is a difficult-to-treat chronic involuntary movement disorder associated with dopamine receptor blocking agents, mostly antipsychotics (Rana et al., Reference Rana, Chaudry and Blanchet2013; Cloud et al., Reference Cloud, Zutshi and Factor2014; Kim et al., Reference Kim, MacMaster and Schwartz2014) and anti-emetics (e.g., metoclopramide) (Merrill et al., Reference Merrill, Lyon and Matiaco2013). Onset is usually delayed with orofacial dyskinesia being the most prominent presentation although athetosis, dystonia, chorea, motor tics, and myoclonus are also common (Mahmoudi et al., Reference Mahmoudi, Blanchet and Lévesque2013; Kim et al., Reference Kim, MacMaster and Schwartz2014; Kamyar et al., Reference Kamyar, Razavi, Vahdati Hasani, Mehri, Foroutanfar and Hosseinzadeh2016; Cornett et al., Reference Cornett, Novitch, Kaye, Kata and Kaye2017). Effective management of emergent TD is important because the symptoms and signs impact negatively on the quality of life of patients and on medication compliance (Lee et al., Reference Lee, Kang, Choi, Park, Lim, Min, Kim and Kim2009; Syu et al., Reference Syu, Ishiguro, Inada, Horiuchi, Tanaka, Ishikawa, Arai, Itokawa, Niizato, Iritani, Ozaki, Takahashi, Kakita, Takahashi, Nawa, Keino-Masu, Arikawa-Hirasawa and Arinami2010 Su et al., Reference Su, Xu, Fan, Du and Hu2012; Creed et al., Reference Creed, Hamani, Bridgman, Fletcher and Nobrega2012; Chang & Fung, Reference Chang and Fung2014; Kim et al., Reference Kim, MacMaster and Schwartz2014).

The risk of developing TD increases with age. Other factors associated with TD include the presence of affective symptoms, female sex, organic brain disorders, and the presence of negative and cognitive symptoms in schizophrenia (Woerner et al., Reference Woerner, Alvir, Saltz, Lieberman and Kane1998; Syu et al., Reference Syu, Ishiguro, Inada, Horiuchi, Tanaka, Ishikawa, Arai, Itokawa, Niizato, Iritani, Ozaki, Takahashi, Kakita, Takahashi, Nawa, Keino-Masu, Arikawa-Hirasawa and Arinami2010; Rana et al., Reference Rana, Chaudry and Blanchet2013; Sarró et al., Reference Sarró, Pomarol-Clotet, Canales-Rodríguez, Salvador, Gomar, Ortiz-Gil, Landín-Romero, Vila-Rodríguez, Blanch and McKenna2013; Kim et al., Reference Kim, MacMaster and Schwartz2014; Ryu et al., Reference Ryu, Yoo, Kim, Choi, Baek, Ha, Kwon and Hong2015; Solmi et al., Reference Solmi, Pigato, Kane and Correll2018). The prevalence of TD is also higher in patients on typical compared to those on atypical antipsychotics (Rana et al., Reference Rana, Chaudry and Blanchet2013 Kim et al., Reference Kim, MacMaster and Schwartz2014; Chang & Fung, Reference Chang and Fung2014; Cloud et al., Reference Cloud, Zutshi and Factor2014; Cornett et al., Reference Cornett, Novitch, Kaye, Kata and Kaye2017), with a global mean prevalence rate of 30% with conventional antipsychotics and 21% for atypical antipsychotics (Carbon et al., Reference Carbon, Hsieh, Kane and Correll2017). While it was previously thought that atypical antipsychotics would ameliorate the risk of TD, recent data have been less promising (Mahmoudi et al., Reference Mahmoudi, Blanchet and Lévesque2013; Cloud et al., Reference Cloud, Zutshi and Factor2014; Shireen, Reference Shireen2016; Bordia et al., Reference Bordia, Zhang, Perez and Quik2016; Loughlin et al., Reference Loughlin, Lin, Abler and Carroll2019; Sartim et al., Reference Sartim, Guimarães and Joca2016; Patterson-Lomba et al., Reference Patterson-Lomba, Ayyagari and Carroll2019).

In low- and middle-income countries, typical antipsychotics often constitute most antipsychotic prescriptions, for example, in Nigeria this is almost 80%, with trifluoperazine being the most prescribed antipsychotic (54.2%) (Bakare et al., Reference Bakare, Igwe, Odinka and Iteke2011; Onah et al., Reference Onah, Abdulmalik and Kaigamma2018). The prevalence of TD may also be higher than in western countries. A recent study at a Nigerian teaching hospital reported a prevalence of 5.8% (Nkporbu et al., Reference Nkporbu, Okeafor, Stanley, Onya and Stanley2016), while an earlier study at a psychiatric hospital recorded a prevalence of 27% (Gureje, Reference Gureje1987). The high rate of polypharmacy prescription patterns in Nigeria and in sub-Saharan Africa in general may also contribute to the development of adverse drug effects, including TD, because in most cases polypharmacy consists of a long-acting intramuscular depot combined with either a typical or atypical antipsychotic drugs (Adeponle et al., Reference Adeponle, Obembe, Nnaji, Adeyemi and Suleiman2008; Tesfaye et al., Reference Tesfaye, Debencho, Kisi and Tareke2016; Igbinomwanhia et al., Reference Igbinomwanhia, Olotu and James2017).

Although the pathophysiology of TD is still being unravelled, studies have implicated dopamine receptor supersensitivity (DRS) with receptor upregulation, γ-aminobutyric acid (GABA) depletion, cholinergic deficiency, lower expression of serotonin (5HT-2A) receptors, neurotoxicity and oxidative stress, changes in synaptic plasticity, defective neuroadaptive signalling, and lack of antipsychotic metabolising enzymes, as putative mechanisms (Rana et al., Reference Rana, Chaudry and Blanchet2013; Cornett et al., Reference Cornett, Novitch, Kaye, Kata and Kaye2017; Creed et al., Reference Creed, Hamani, Bridgman, Fletcher and Nobrega2012; Cloud et al., Reference Cloud, Zutshi and Factor2014; Kim et al., Reference Kim, MacMaster and Schwartz2014; Bordia et al., Reference Bordia, Zhang, Perez and Quik2016). Genetic factors may also play an important role in TD with documented associations between TD and polymorphisms of the dopamine D3 (DRD3), serine-9-Glycine (Ser9Gly), heparan sulfate proteoglycan 2, perlecan (HSPG2), and serotonin 2A and 2C receptor genes (Graff-Guerrero et al., Reference Graff-Guerrero, Mizrahi, Agid, Marcon, Barsoum, Rusjan and Kapur2009). In addition, Val66Met, a naturally occurring polymorphism in the brain-derived neurotropic factor gene, may be associated with the development and severity of TD in Caucasians, and the transcriptional factor Nur77, a central regulator of T cell immunometabolism (also known as NGFI-B or Nr4a1) has also been implicated in the development of TD (Tiwari et al., Reference Tiwari, Deshpande, Lerer and Nimgaonkar2008; Chang & Fung, Reference Chang and Fung2014; Cornett et al., Reference Cornett, Novitch, Kaye, Kata and Kaye2017; Syu et al., Reference Syu, Ishiguro, Inada, Horiuchi, Tanaka, Ishikawa, Arai, Itokawa, Niizato, Iritani, Ozaki, Takahashi, Kakita, Takahashi, Nawa, Keino-Masu, Arikawa-Hirasawa and Arinami2010; Liebmann et al., Reference Liebmann, Hucke, Koch, Eschborn, Ghelman, Chasan, Glander, Schädlich, Kuhlencord, Daber, Eveslage, Beyer, Dietrich, Albrecht, Stoll, Busch, Wiendl, Roth, Kuhlmann and Klotz2018).

A prolonged dosing regime is strongly associated with increased receptor occupancy levels and chronic blockade of dopamine D2 and D3 receptors (Naidu & Kulkarni, Reference Naidu and Kulkarni2001a; Margolese et al., Reference Margolese, Chouinard, Kolivakis, Beauclair and Miller2005; Kasantikul & Kanchanatawan, Reference Kasantikul and Kanchanatawan2007; Seigneurie et al., Reference Seigneurie, Sauvanaud and Limosin2016). Persistent receptor blockade has also been linked to the upregulation of dopamine receptors and DRS (Nel & Harvey, Reference Nel and Harvey2003; Ginovart et al., Reference Ginovart, Wilson, Hussey, Houle and Kapur2009; Yin et al., Reference Yin, Barr, Ramos-Miguel and Procyshyn2016). This blockade also leads to increased dopamine turnover which is associated with overproduction of free radicals, such as the quinone/semiquinone metabolites by monoamine oxidases and auto-oxidation of dopamine molecules (Wyatt, Reference Wyatt1999; Cho & Lee, Reference Cho and Lee2013). This induces apoptosis and neuronal death of the GABA interneurons that regulate balance between direct and indirect basal ganglia pathways (Gunne et al., Reference Gunne, Häggström and Sjöquist1984; Margolese et al., Reference Margolese, Chouinard, Kolivakis, Beauclair and Miller2005; Gittis et al., Reference Gittis, Leventhal, Fensterheim, Pettibone, Berke and Kreitzer2011), leading to symptoms of TD. The same overproduction of free radicals can also damage the glutamatergic neurons, disrupting the synaptic plasticity of glutamatergic synapses on striatal interneurons, and causing an imbalance between direct and indirect basal ganglia pathways, thus producing abnormal output to the sensorimotor cortex (Cadet & Perumal, Reference Cadet and Perumal1990; Teo et al., Reference Teo, Edwards and Bhatia2012).

Cannabidiol (CBD) is a phytocannabinoid with multiple complex actions on the central nervous system (Zuardi, Reference Zuardi2008; Peres et al., Reference Peres, Lima, Hallak, Crippa, Silva and Abílio2018). Though CBD’s mechanism of action is not fully understood, studies have suggested that it is a non-competitive negative allosteric modulator of CB1 and CB2 receptors (Peres et al., Reference Peres, Lima, Hallak, Crippa, Silva and Abílio2018; Laprairie et al., Reference Laprairie, Bagher, Kelly and Denovan-Wright2015; Martínez-Pinilla et al., Reference Martínez-Pinilla, Varani, Reyes-Resina, Angelats, Vincenzi, Ferreiro-Vera and Franco2017). It is also an agonist at the transient receptor potential channels of the vanilloid subtype 1 (TRPV1) (Bisogno et al., Reference Bisogno, Hanuš, De Petrocellis, Tchilibon, Ponde, Brandi and Di Marzo2001). CBD inhibits enzymatic hydrolysis and uptake of anandamide and regulates mitochondria activity; all these actions mediate the anti-inflammatory and antioxidant effects of CBD (Bisogno et al., Reference Bisogno, Hanuš, De Petrocellis, Tchilibon, Ponde, Brandi and Di Marzo2001; Peres et al., Reference Peres, Lima, Hallak, Crippa, Silva and Abílio2018; Valvassori et al., Reference Valvassori, Budni, Varela and Quevedo2013; Campos et al., Reference Campos, Fogaça, Sonego and Guimarães2016). It also enhances neurotransmission mediated by the serotonin 5-HT1A receptor by acting as an allosteric modulator at this receptor, and this action may be responsible for its anxiolytic effects (Rock et al., Reference Rock, Bolognini, Limebeer, Cascio, Anavi-Goffer, Fletcher, Mechoulam, Pertwee and Parker2012; Sartim et al., Reference Sartim, Guimarães and Joca2016; Lee et al., Reference Lee, Bertoglio, Guimarães and Stevenson2017).

In addition, CBD regulates the peroxisome proliferator-activated receptor γ (PPARγ) and PPARγ ligands are known to display anti-inflammatory actions (O’Sullivan et al., Reference O’Sullivan, Sun, Bennett, Randall and Kendall2009; Sonego et al., Reference Sonego, Prado, Vale, Sepulveda-Diaz, Cunha, Tirapelli, Del Bel, Raisman-Vozari and Guimarães2018). CBD also antagonises D2 receptors (Graff-Guerrero et al., Reference Graff-Guerrero, Mizrahi, Agid, Marcon, Barsoum, Rusjan and Kapur2009), which may contribute to its antipsychotic effects (Seeman, Reference Seeman2016).

We hypothesised in an animal model of TD that chronic exposure to haloperidol through IM administration of slow-releasing haloperidol for 3 months would lead to more sustained VCM compared with sub-chronic IP haloperidol administered for 21 days. Our prototype antioxidant (CBD) would, therefore, be less effective in a slow-releasing IM haloperidol group compared to a sub-chronic IP haloperidol group. We also proposed that there would be an increase in oxidative stress in the slow-releasing IM haloperidol group compared to the IP haloperidol group, as measured by several oxidative stress indices.

Materials and methods

Animals

Male adult Wistar rats (n = 53) were obtained from a colony of the Nigerian Institute of Medical Research (NIMR), Yaba, Lagos, Nigeria. The animals were kept in clean polypropylene cages in well-ventilated and hygienic compartments, maintained under standard environmental conditions, and fed with standard rodent pellets (Ladokun Feed Plc., Ibadan, Nigeria) and water ad libitum. The animals were acclimatised for a period of 2 weeks before experimental procedures were undertaken in accordance with the United States National Institutes of Health Guidelines for Care and Use of Laboratory Animals in Biomedical Research (National Research Council, 2011). The study is the second component of a larger study approved by the Institutional Review Board (IRB) of NIMR, Yaba, Lagos, Nigeria (IRB/16/329), and the Stellenbosch University Health Research Ethics Committee: Animal Care and Use (SU-ACUD16-00137).

Drugs

CBD [(-)-Cannabidiol, GMP (Cannabidiolum); CBD] (VAKOS X, a.s., Permova 28a, Praha, Czech Republic) was supplied in fine granule form with the amount administered weekly calculated and dissolved in 70% ethanol, as recommended by the manufacturer, and diluted with distilled water. CBD was administered orally. Rapid-acting parenteral haloperidol at 5 mg/ml was administered intraperitoneally, while slow-releasing parenteral haloperidol 50 mg/ml (Janseen Pharmaceuticals, Beerse, Belgium) was administered through the intramuscular route.

Experimental design

There were six experimental groups (n = 53): sub-chronic haloperidol administration (SC-HAL) (n = 9); sub-chronic haloperidol before CBD administration (SC-HAL-CBD) (n = 10); CBD only (n = 9); chronic haloperidol administration (CH-HAL) (n = 8); chronic haloperidol before CBD administration (CH-HAL-CBD) (n = 7) and the control group (n = 10).

The administration of pharmacological agents was as follows: SC-HAL (haloperidol at 5 mg/kg IP), SC-HAL-CBD (haloperidol 5 mg/kg IP before administration of CBD at 5 mg/kg p.o.), CBD (CBD at 5 mg/kg p.o.), control (2 ml distilled water p.o.), CH-HAL (Haloperidol decanoate at 50 mg/kg IM), and CH-HAL-CBD (haloperidol decanoate at 50 mg/kg IM before administration of CBD at 5 mg/kg p.o.) (Table 1).

Table 1. Pharmacological administration schedule

For the SC-HAL, CBD, and the control groups, the agents were administered once daily for 21 days (Sasaki et al., Reference Sasaki, Hashimoto, Maeda, Inada, Kitao, Fukui and Iyo1995; Naidu & Kulkarni, Reference Naidu and Kulkarni2001a, Reference Naidu and Kulkarni2001b, Bishnoi & Boparai, Reference Bishnoi and Boparai2012). A dose of 5 mg/kg of haloperidol was administered IP (Bishnoi and Boparai, Reference Bishnoi and Boparai2012) in SC-HAL group. Effective doses of CBD in rats’ range between 2.5 and 10 mg/kg (Guimarães et al., Reference Guimarães, Chiaretti, Graeff and Zuardi1990). VCM was assessed at 8 h, 24 h, and 8 days after the last dose of medication. Assessment on day 8 was to ensure that the VCM model was established.

For SC-HAL-CBD, the first pharmacological agent (haloperidol) was administered for 21 days, and the second pharmacological agent (CBD) was commenced 24 to 48 h after the first was discontinued and this was administered for a further 21 days. VCM was assessed after the last dose of pharmacological agent at 8 h, 24 h, and on the 8th day. The rats in SC-HAL-CBD were pre-treated with haloperidol to induce VCM before the administration of CBD to ascertain if CBD ameliorated haloperidol-induced VCM.

For the C-HAL group, slow-releasing IM haloperidol decanoate 50 mg/kg was administered monthly (Andreassen et al., Reference Andreassen, Meshul, Moore and Jørgensen2001) on three consecutive occasions and VCM was assessed on day 28, and day 36 after the last administration of IM haloperidol. For the CH-HAL-CBD, slow-releasing intramuscular haloperidol decanoate 50 mg/kg monthly for three consecutive months was also administered, but administration of CBD 5 mg/kg for 21 days was commenced 24 to 48 h after the last dose of intramuscular haloperidol. VCM was assessed at 24 h and 8th day after the last dose of CBD (Table 1).

SC-HAL and SC-HAL-CBD were classified as IP haloperidol groups and received IP haloperidol either only or in combination with CBD, while CH-HAL and CH-HAL-CBD were classified as IM haloperidol groups and received IM haloperidol either only or in combination with CBD.

Vacuous chewing movement assessment

Vacuous chewing movement (VCM, mouth openings in the vertical plane not directed toward physical material) was assessed by placing each animal in an individual transparent glass plexiform cage. Each animal was allowed to acclimatise for 5 min before counting started. The number of VCM was counted for 10 min (Crowley et al., Reference Crowley, Adkins, Pratt, Quackenbush, Van Den Oord, Moy, Wilhelmsen, Cooper, Bogue, McLeod and Sullivan2012). The VCM results reported corresponding to the last VCM measurement taken before the animals were killed for each group.

Animals were killed 24 h after all the behavioural assessment were carried out for all groups. They were first anesthetised with phenobarbitone before cervical dislocation and then dissected by opening the abdomen. The brain was isolated and dissected on ice where 10% w/v of brain sample (0.03 M sodium phosphate buffer, pH 7.4) was homogenised. The homogenates generated from processed brain tissue were then used for oxidative stress indices determination.

The following antioxidant indices were determined spectrometrically: malondialdehyde (MDA), glutathione (GSH), catalase activity (CAT), superoxide dismutase activity (SOD), nitric oxide (NO) scavenging activity, and 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging assay. Methodologies used in determining antioxidant indices were described in detail in our previously published study (Kajero et al., Reference Kajero, Seedat, Ohaeri, Akindele and Aina2020).

Statistical analysis

Data were analysed using the IBM SPSS Statistics for Windows, Version 28.0 (Armonk, NY: IBM Corp.). Continuous variables such as VCM, behavioural assays and antioxidant levels, when normally distributed were presented using means and standard deviations as measures of central tendency and dispersion. Kolmogorov–Smirnov test was used to identify skewed variables. A comparison of the equality of means between groups was done using a one way-ANOVA test. When the F-statistic was significant (<0.05), depending on the violation of the homogeneity of variance, the Tukey’s HSD test or Games Howell post hoc test was used to identify the differences between groups. Where the data were not normally distributed, a comparison of medians was done using the Kruskal–Walli’s test. Box and whisker plots were used in the presentation of continuous variables as a figure.

Results

Effects on VCMs

There was a significant difference in mean VCM count before and after the administration of medications in the SC-HAL group (<0.001) and CH-HAL group (<0.001). There was also a statistically significant difference in mean VCM among the six groups (p < 0.000) (Fig. 1).

Fig. 1. Vacuous chewing movements.

SC-HAL: sub-chronic haloperidol administration; SC-HAL-CBD: sub-chronic haloperidol before CBD administration; CBD: cannabidiol; CH-HAL: chronic haloperidol administration; CH-HAL-CBD: chronic haloperidol before CBD administration; Control : 2 ml distilled water.

Post hoc analysis revealed a significant difference between SC-HAL and SC-HAL-CBD groups (p = 0.015), SC-HAL and CBD groups (p = 0.009), SC-HAL and control groups (p = 0.011), SC-HAL and SC-HAL-CBD groups (p = 0.036), CBD and CH-HAL groups (p = 0.002), and CH-HAL and CH-HAL-CBD groups (p = 0.049).

Antioxidant assays

Brain oxidative stress indices

In the brain, antioxidant indices in the IP haloperidol and the IM haloperidol groups were compared with the oral CBD only and control groups. There were significant changes in brain oxidative stress indices between the sub-chronic (IP) haloperidol (SC-HAL), chronic (IM) haloperidol (CH-HAL), oral CBD, and control: CAT (p = 0.000), SOD (p = 0.000), GSH (p = 0.000), (scavenging activity in DPPH assay) (p = 0.000), NO (p = 0.000), MDA (p = 0.000). The sub-chronic (IP) haloperidol-only (SC-HAL) group showed higher activity of antioxidant parameters relative to the other groups, except in respect of GSH where the SC-HAL group had significantly lower activity compared with the other groups (Table 2).

Table 2. Brain antioxidant indices

Post hoc comparison of sub-chronic administration of haloperidol groups (SC-HAL and SC-HAL-CBD) and chronic administration of haloperidol groups (CH-HAL and CH-HAL-CBD) with oral CBD only and control groups.

Brain SOD

Post hoc analysis revealed significant differences between SC-HAL and SC-HAL-CBD groups (p = 0.001), SC-HAL and CBD groups (p = 0.015), SC-HAL and control groups (p = 0.006), SC-HAL and CH-HAL groups (p = 0.010), SC-HAL and CH-HAL-CBD groups (p = 0.001), and SC-HAL-CBD and control groups (p = 0.022).

Brain CAT

There were significant difference between SC-HAL and SC-HAL-CBD groups (p = 0.014), SC-HAL and CBD groups (p = 0.001), SC-HAL and control groups (p = 0.018), SC-HAL and CH-HAL groups (p = 0.007) SC-HAL and CH-HAL-CBD groups (p = 0.035), and CBD and control groups (p = 0.001).

Brain GSH

SC-HAL group had a significantly lower activity of brain GSH than other groups with significant between-group differences for the SC-HAL and SC-HAL-CBD groups (p = 0.014), and SC-HAL and control groups (p = 0.001). SC-HAL-CBD and the control groups (p = 0.011), CBD and control groups (p = 0.009), and control and CH-HAL-CBD groups (p = 0.012).

Brain NO

Post hoc analysis revealed significant differences in NO activity between SC-HAL and SC-HAL-CBD groups (p = 0.000), SC-HAL and control groups (p = 0.000), the SC-HAL and control groups (p = 0.000), SC-HAL and CH-HAL groups (p = 0.000), SC-HAL and CH-HAL-CBD groups (p = 0.000), and CBD and control groups (p = 0.037).

Brain MDA

Post hoc analysis revealed significant differences in MDA activity between SC-HAL and SC-HAL-CBD groups (p = 0.001) and SC-HAL and control groups (p = 0.004), SC-HAL and CH-HAL (SCHAL < CHAL, p = 0.031), and SC-HAL and CH-HAL-CBD groups (p = 0.001). There was also a statistically significant difference in MDA activity between SC-HAL-CBD and CH-HAL groups (p = 0.001), CBD and CH-HAL groups (CBD < CHAL, p = 0.002), control and CH-HAL groups (control < CHAL, p = 0.001), and CH-HAL and CH-HAL-CBD groups (p = 0.001). CH-HAL had the highest activity followed by SC-HAL.

Brain scavenging activity (DPPH assay)

There were significant differences between SC-HAL and SC-HAL-CBD groups (p = 0.001), SC-HAL and control groups (p = 0.016), SC-HAL and CH-HAL groups (p = 0.000), SC-HAL and CBD groups (p = 0.000), SC-HAL-CBD and CH-HAL groups (p = 0.000), SC-HAL-CBD and CH-HAL-CBD groups (p = 0.000), CBD and control groups (p = 0.042), CBD and CH-HAL groups (p < 0.001), control and CH-HAL groups (p = 0.001), control and CH-HAL-CBD groups (p = 0.024), and CH-HAL and CH-HAL-CBD groups (p = 0.024).

Discussion

This study is the second report in a series of studies on the effectiveness of CBD in ameliorating symptoms of VCM induced by haloperidol in an animal model of TD. We investigated the effects of chronic exposure to haloperidol in the form of IM-administered slow-releasing haloperidol without any other pharmacological agent for 3 months and of sub-chronic administration of IP haloperidol without any other pharmacological agent for 21 days, on the severity of VCM. We then investigated the effectiveness of CBD in ameliorating VCM induced by chronic and sub-chronic exposure to haloperidol. We also evaluated the influence of chronic and sub-chronic administration of haloperidol on oxidative stress indices.

Effects of interventions on VCM

Our results show that sub-chronic haloperidol only produced significantly more VCM than the other groups except for chronic haloperidol only. We can also infer from our study that CBD when given after the administration of sub-chronic haloperidol ameliorates haloperidol-induced VCM. We previously established the ability of CBD to prevent VCM when administered simultaneously with haloperidol (Kajero et al., Reference Kajero, Seedat, Ohaeri, Akindele and Aina2020). Attenuation of haloperidol-induced VCM by CBD may be explained by its antioxidant and neuroprotective effects (Malfait et al., Reference Malfait, Gallily, Sumariwalla, Malik, Andreakos, Mechoulam and Feldmann2000; Peres et al., Reference Peres, Levin, Suiama, Diana, Gouvêa, Almeida, Santos, Lungato, Zuardi, Hallak, Crippa and Almeida2016). CBD also promotes neurogenesis (Valvassori et al., Reference Valvassori, Elias, De Souza, Petronilho, Dal-Pizzol, Kapczinski, Trzesniak, Tumas, Dursun, Nisihara Chagas, Hallak, Zuardi, Quevedo and Crippa2011; Gallegos et al., Reference Gallegos2015) and may interact with the 5HT1A and 5HT2A receptor subtypes in the basal ganglia (Russo et al., Reference Russo, Burnett, Hall and Parker2005) to ameliorate dopaminergic system dysfunction (Gomes et al., Reference Gomes, Del Bel and Guimarães2013).

We further observed that CBD barely mitigated chronic haloperidol administration-induced VCM. This is most likely due to the chronic exposure to haloperidol leading to prolonged receptor occupation and consequently increased dopamine turnover in regions of the brain with high density of catecholamine, such as the basal ganglia, and overproduction of free radicals with damage to neuronal cells (Wyatt, Reference Wyatt1999; Margolese et al., Reference Margolese, Chouinard, Kolivakis, Beauclair and Miller2005; Gittis et al., Reference Gittis, Leventhal, Fensterheim, Pettibone, Berke and Kreitzer2011; Cho & Lee, Reference Cho and Lee2013, leading to symptoms of TD. Previous studies have investigated acute parenteral administration of reserpine (Peres et al., Reference Peres, Levin, Suiama, Diana, Gouvêa, Almeida, Santos, Lungato, Zuardi, Hallak, Crippa and Almeida2016), acute (IP) haloperidol (Gomes et al., Reference Gomes, Del Bel and Guimarães2013), and sub-chronic administration of IP haloperidol (Sonego et al., Reference Sonego, Gomes, Del Bel and Guimaraes2016).

In respect of IP and oral haloperidol administered for 21 days, in accordance with our previous report (Kajero et al., Reference Kajero, Seedat, Ohaeri, Akindele and Aina2020), the occupation of D2 receptors may not have been prolonged enough to induce severe oxidative stress and permanent damage to the GABA interneurons and glutamatergic neurons. The VCM we observed with these two routes of administration may be due to blockage of D2 receptors in the caudate, putamen, and the globus pallidus (Rupniak et al., Reference Rupniak, Jenner and Marsden1986; Van Harten et al., Reference Van Harten, Matroos, Hoek and Kahn1996), and complex reciprocal interactions between dopamine and acetylcholine (ACH) receptors. These complex interactions may lead to hypercholinergic activity in the striatum and may more closely mirror early-onset dyskinesia in humans than late-onset dyskinesia (Waddington, Reference Waddington1990; Egan et al., Reference Egan, Hurd, Ferguson, Bachus, Hamid and Hyde1996; Marchese et al., Reference Marchese, Bartholini, Casu, Ruiu, Casti, Congeddu, Tambaro and Pani2004; Blanchet et al., Reference Blanchet, Parent, Rompré and Lévesque2012).

Antioxidant indices in the brain: (sub-chronic and chronic haloperidol groups compared with CBD only and controls)

We found an elevation of SOD activity in the haloperidol-only group compared to the other groups. This may represent a compensatory mechanism to oxidative stress produced by sub-chronic haloperidol administration. SOD acts as first line of defence against oxidative stress by converting super oxide radicals to hydrogen peroxide which is, in turn, converted to water and oxygen by catalase and glutathione peroxidase (Dakhale et al., Reference Dakhale, Khanzode, Khanzode, Saoji, Khobragade and Turankar2004; Kunz et al., Reference Kunz, Gama, Andreazza, Salvador, Ceresér, Gomes and Kapczinski2008). We also observed an increase in the activity of SOD in the control group compared to sub-chronic haloperidol before CBD. The activity of SOD as a scavenger of free radicals may increase in the presence of excessive production of free radicals as the system attempts to maintain a healthy redox balance (Harris, Reference Harris1992; Dakhale et al., Reference Dakhale, Khanzode, Khanzode, Saoji, Khobragade and Turankar2004; Boskovic et al., Reference Boskovic, Vovk, Kores Plesničar, Grabnar, Vovk, Kores Plesnicar and Boskovic2011). The relatively low SOD activity in the group that received sub-chronic haloperidol before adjunctive CBD and in the CBD-only group suggests that CBD may ameliorate the oxidative stress produced by haloperidol by modifying redox imbalance (Atalay et al., Reference Atalay, Jarocka-karpowicz, Skrzydlewska and Skrzydlewskas2020), possibly through some other mechanism.

We did not find any significant difference when chronic haloperidol only and chronic haloperidol before CBD groups were compared, suggesting chronic administration of haloperidol only did not exhibit more SOD activity than chronic haloperidol before CBD, unlike what we observed between sub-chronic haloperidol only group and sub-chronic haloperidol before CBD. Administration of CBD after chronic haloperidol administration also did not have any influence on SOD production, unlike what we observed in sub-chronic haloperidol before CBD. Boskovic et al. (Reference Boskovic, Vovk, Kores Plesničar, Grabnar, Vovk, Kores Plesnicar and Boskovic2011), in a clinical study, observed a decrease in antioxidant enzyme activity with prolonged use of antipsychotics and increased age in patients with schizophrenia.

Catalase is an efficient antioxidant produced in the peroxisome (small membrane-enclosed organelles important in metabolic reactions) with a remarkably high turnover rate and may have been induced in the IP haloperidol-only group to catalyse the conversion of increased hydrogen peroxide (H2O2) produced by SOD to water and oxygen (Sies, Reference Sies2015; Kurutas, Reference Kurutas2016). CBD may have effectively reduced the free radical production in the group administered sub-chronic haloperidol before adjunctive CBD. Popovic et al. (Reference Popovic, Janicijevic-Hudomal, Kaurinovic, Rasic, Trivic and Vojnović2009) observed an increase in catalase activity in their study examining the effects of acute administration of haloperidol in animals in a stressful environment. Though their dose of haloperidol differed from our study, most other studies have reported a decreased level of catalase activity in haloperidol-only groups (Naidu et al., Reference Naidu, Singh and Kulkarni2002; Patil et al., Reference Patil, Dhawale, Gound and Gadakh2012; Thakur et al., Reference Thakur, Prakash, Bisht and Bansal2015). Differences in dosage, duration, and sequence of medication administration may influence enzyme activity in these studies.

There was no significant difference in catalase activity between the chronic haloperidol only, CBD only, and control groups, suggesting that chronic haloperidol only did not induce increase CAT activity unlike what we observed with sub-chronic haloperidol only where CAT was increased to compensate for the increase in oxidative stress. The brain has 50 times lower catalase and SOD than the liver (Cobley et al., Reference Cobley, Fiorello and Bailey2018), and this may have limited its ability to increase CAT and SOD production in response to increased oxidative stress over a long period. No prior studies of the influence of CBD on behavioural and biochemical parameters associated with long-term administration of IM haloperidol decanoate have, to our knowledge, been published.

Glutathione peroxidase (GPx) is the enzyme responsible for the conversion of reduced GSH to the oxidised form (GSSG) with the help of hydrogen peroxide which is converted to water and oxygen in the process (Burk & Hill, Reference Burk and Hill2010; Ursini & Maiorino, Reference Ursini and Maiorino2013). Increased activity of GPx will therefore lead to a decrease in the level of GSH. The low level of reduced GSH in the sub-chronic haloperidol only compared to the sub-chronic haloperidol with adjunctive CBD groups suggests increased activity of GPx. It is plausible that the three antioxidants (SOD, CAT, and GSH) acted in concert to keep free radicals at low levels. Other investigators observed an enhancement of the activity of GPx and reductase enzymes by CBD (Massi et al., Reference Massi, Vaccani, Bianchessi, Costa, Macchi and Parolaro2006).

The control group had a higher GSH level than the other groups indicating reduced GPx activity and less oxidative stress in the control group. There was no significant difference between chronic haloperidol only and chronic haloperidol before CBD groups in contrast to the sub-chronic haloperidol only and sub-chronic haloperidol before CBD groups, suggesting CBD did not have an influence on GPx activity or GSH level in chronic haloperidol administration. There is a paucity of studies in this regard though an earlier study also observed a decrease in antioxidant enzymes and non-enzymatic GSH in the brain after long-term administration of haloperidol (Boskovic et al., Reference Bošković, Grabnar, Terzič, Kores Plesničar and Vovk2013).

Pro-oxidants (sub-chronic and chronic haloperidol groups compared with CBD only and control)

NO is an unusual messenger molecule with multiple molecular targets; it normally controls neurotransmission and vascular tone. It is also important in the regulation of gene and messenger ribonucleic acid (mRNA) transcription and can promote post-translational modifications of proteins (O’Dell et al., Reference O’Dell, Hawkins, Kandel and Arancio1991; Schuman & Madison, Reference Schuman and Madison1991; Pozdnyakov et al., Reference Pozdnyakov, Lloyd, Reddy and Sitaramayya1993; Pantopoulos & Hentze, Reference Pantopoulos and Hentze1995; Khan et al., Reference Khan, Harrison, Olbrych, Alexander and Medford1996; Gudi et al., Reference Gudi, Hong, Vaandrager, Lohmann and Pilz1999; Förstermann & Sessa, Reference Förstermann and Sessa2012). Under physiologic conditions, NO (a free radical) and its metabolites are neutralised through reactions with various thiols (e.g., GSH) to form stable S-nitrosothiols. If produced in excess because of lipid peroxidation, thiols may be overwhelmed leading to increased production of free radicals and oxidative stress (Gegg et al., Reference Gegg, Beltran, Salas-Pino, Bolanos, Clark, Moncada and Heales2003; Andreazza et al., Reference Andreazza, Kauer-Sant’Anna, Frey, Bond, Kapczinski, Young and Yatham2008).

The higher activity of NO in the brain observed in the sub-chronic haloperidol-only group in relation to other groups indicates increased oxidative stress in this compared to other groups. The reduced NO activity in the CBD-only group and the sub-chronic group with adjunct CBD administration suggests that CBD can ameliorate oxidative stress when combined with haloperidol by reducing NO production. Some investigators have reported on the ability of CBD to inhibit inducible NO synthase and therefore reduce NO production (Costa et al., Reference Costa, Colleoni, Conti, Parolaro, Franke, Trovato and Giagnoni2004; Esposito et al., Reference Esposito, De Filippis, Maiuri, De Stefano, Carnuccio and Luvone2006; Rajesh et al., Reference Rajesh, Mukhopadhyay, Bátkai, Haskó, Liaudet, Drel, Obrosova and Pacher2007; Chen et al., Reference Chen, Hou, Chen, Wang, Yang, He, Zhou and Li2016).

The chronic haloperidol administration-only group had significantly less NO activity than the sub-chronic haloperidol-only group and did not have more NO activity than either chronic haloperidol before CBD, CBD only, or the control indicating chronic haloperidol group did not alter NO balance or CBD did not affect NO activity in the IM haloperidol groups. Some investigators have reported that chronic administration of haloperidol followed by withdrawal is associated with reduced NO and lower striatal cGMP levels (Iwahashi et al., Reference Iwahashi, Yoneyama, Ohnishi, Nakamura, Miyatake, Suwaki, Hosokawa and Ichikawa1996; Harvey & Bester, Reference Harvey and Bester2000). In contrast, other studies found up-regulation of NOS activity in the rat striatum after dopamine receptor blockade, suggesting that this may contribute to the motor side effects of antipsychotic agents (Morris et al., Reference Morris, Simpson, Mundell, Maceachern, Johnston and Nolan1997; Sammut et al., Reference Sammut, Bray and West2007). More studies are needed to clarify the relationship between prolonged administration of haloperidol and NO.

There is evidence that increase in free radicals can lead to dysfunction of oxidative stress enzymes causing membrane damage and elevating lipid peroxidation products such as MDA, especially in the spinal fluid (Zhang & Yao, Reference Zhang and Yao2013). Interestingly, we observed higher MDA activity in the chronic haloperidol-only group compared to other groups, sub-chronic haloperidol group also had more MDA activity compared to other groups except for the chronic haloperidol-only group, suggesting a greater increase in free radical production and lipid peroxidation compared to other interventions. This is in the same direction as other studies (Consroe et al., Reference Consroe, Laguna, Allender, Snider, Stern, Sandyk, Kennedy and Schram1991; Kudo & Ishizaki, Reference Kudo and Ishizaki1999; Patil et al., Reference Patil, Dhawale, Gound and Gadakh2012; Kamyar et al., Reference Kamyar, Razavi, Vahdati Hasani, Mehri, Foroutanfar and Hosseinzadeh2016; Zendulka et al., Reference Zendulka, Dovrtělová, Nosková, Turjap, Šulcová, Hanuš and Juřica2016). It is also an indication that increased MDA activity in the brain may be associated with prolonged duration of administration of haloperidol and severity of VCM. We also observed a decrease in MDA in the sub-chronic (IP) haloperidol before CBD group compared to sub-chronic haloperidol-only group indicating CBD inhibited lipid peroxidation and probably prevented membrane damage when given after haloperidol.

The chronic haloperidol before CBD group MDA measurements also had less activity than the chronic haloperidol-only group, further confirming the ability of CBD to inhibit lipid peroxidation in various organs, as described in other studies (Luvone et al., Reference Luvone, Esposito, Esposito, Santamaria, Di Rosa and Izzo2004; Mechoulam et al., Reference Mechoulam, Peters, Murillo-rodriguez, Hanus and Campus2007; Pisanti et al., Reference Pisanti, Malfitano, Ciaglia, Lamberti, Ranieri, Cuomo, Abate, Faggiana, Proto, Fiore, Laezza and Bifulco2017). These observations support our hypothesis that neuronal cell damage is induced by prolonged administration of haloperidol. There are no other studies, as far as we are aware, of the effects of CBD on chronic administration of haloperidol on the brain’s antioxidant system.

DPPH (2,2-diphenyl-1-picrylhydrazyl) (sub-chronic and chronic haloperidol groups compared with CBD only and control)

The DPPH assay was developed to evaluate free radical scavenging activity of antioxidants in organic solvents but has been used to assess antioxidant capacity of hydrolysed porcine tissues (Sanchez-Moreno et al., Reference Sánchez-Moreno, Larrauri and Saura-Calixto1998; Kedare & Singh, Reference Kedare and Singh2011; Damgaard et al., Reference Damgaard, Otte, Meinert and Jensen2014). In our study, we used DPPH to assess the total antioxidant activity in the brain. In the sub-chronic group, brain homogenates scavenging activities in DPPH were increased in the sub-chronic haloperidol-only group compared to the sub-chronic haloperidol before CBD group, suggesting an increase in antioxidant activity (SOD and CAT in this study) as a compensatory mechanism for the increased free radical production observed in this group. Rao & Balachandran (Reference Rao and Balachandran2002) proposed that disequilibrium between free radical metabolism and the antioxidant system can produce excessive ROS.

The ROS system contains enzymes, such as SOD, GPx, and CAT. DPPH, a stable radical (Kedare & Singh, Reference Kedare and Singh2011), interacts with the ROS antioxidant system. Sub-chronic haloperidol only in our study generated more oxidative enzymes compared to sub-chronic haloperidol before CBD, the control, and chronic haloperidol only. This may explain why scavenging activities were increased in our brain samples with sub-chronic haloperidol administration only. Our observations of low scavenging activity in DPPH in the brain in the chronic haloperidol-only group compared to other groups is not surprising as SOD and CAT activities in the chronic haloperidol only group were consistently low. We also detected a high scavenging activity in the chronic haloperidol before CBD group which confirms reduced antioxidant enzyme activity in this group and at the same time suggests that CBD contributed to antioxidant activities in the IM haloperidol before CBD group. This confirmed our earlier suggestions that prolonged administration of haloperidol maintained a consistently high level of free radicals and diminished the ability of the brain to generate antioxidant enzymes (Boskovic et al., Reference Bošković, Grabnar, Terzič, Kores Plesničar and Vovk2013). CBD probably helped to alleviate the increased MDA activity observed in the chronic haloperidol only.

In summary, we found that CBD ameliorates established VCM induced by sub-chronic haloperidol administration but was marginally effective in ameliorating VCM induced by chronic haloperidol administration, confirming our first hypothesis that prolonged administration of haloperidol through the IM route induced a more severe form of VCM compared to 21-day IP haloperidol administration. We can thus infer that there is an association between long-term administration of haloperidol and increased activity of MDA and reduced activity of antioxidants. Therefore, slow-releasing chronic haloperidol diminished the ability of the brain to compensate for persistent oxidative stress. Our results also suggest that CBD may be exerting its effect primarily by modifying the activities of GSH and MDA.

Acknowledgements

Dr Opeyemi Awofeso was involved in data analysis. Mr Sunday Adenekan and Mr Abiodun Doherty helped with the biochemical analysis while Mr Chiadika Chimeremeze, Mr Hafeez Shittu, Hasnat Osibote, Damilola Oshunyinka, and Abisola Kolawole were the laboratory assistants who worked with the team in the conduct of the experiments.

Authors Contributions

Both Jaiyeola kajero and Soraya Seedat conceived and design the work. Jaiyeola Kajero, Abidemi Akindele, and Oluwagbemiga Aina were responsible for data collection, analysis, and interpretation. Jaiyeola Kajero was responsible for drafting the article. Soraya Seedat, Jude Ohaeri, and Abidemi Akindele were responsible for critical revision of the article and Soraya Seedat was responsible for final approval of the version to be published.

Financial support

This research is supported by the South African Research Chair in PTSD hosted by the Stellenbosch University, funded by the Department of Science and Technology South Africa, and administered by the National Research Foundation as well as the South African Medical Research Council Unit on the Genomics of Brain Disorders. This work was also supported by Cannabis Science Inc.

Conflicts of Interest

None.

Disclosure statement

Cannabis Science Inc., however, did not contribute towards the development of the protocol, the experiments, the analysis, or the interpretation of data.

Animal Welfare Ethical Statement

The animals were properly housed in clean polypropylene cages with well-ventilated and hygienic compartments, fed with standard rodent pellets (Ladokun Feed Plc., Ibadan, Nigeria) and water ad libitum, and kept in surroundings appropriate to their species and acclimatised for a period of 2 weeks before experimental procedures were undertaken in accordance with the United States National Institutes of Health Guidelines for Care and Use of Laboratory Animals in Biomedical Research (National Research Council, 2011). The study was approved by the Institutional Review Board (IRB) of NIMR, Yaba, Lagos, Nigeria (IRB/16/329) and Stellenbosch University’s Health Research Ethics Committee: Animal Care and Use (SU-ACUD16-00137).

Ethical Standards

The authors assert that all procedures contributing to this work comply with the South African National Standard (SANS) on the care and use of laboratory animals.

References

Adeponle, AB, Obembe, AO, Nnaji, F, Adeyemi, SO and Suleiman, GT (2008) Psychotropic drugs prescription at two regional psychiatric hospitals in northern Nigeria. West African Journal of Medicine 27(2), 106110.Google ScholarPubMed
Andreassen, OA, Meshul, CK, Moore, C and Jørgensen, HA (2001) Oral dyskinesias and morphological changes in rat striatum during long-term haloperidol administration. Psychopharmacology (Berl). 157(1), 1119.CrossRefGoogle ScholarPubMed
Andreazza, AC, Kauer-Sant’Anna, M, Frey, BN, Bond, DJ, Kapczinski, F, Young, LT and Yatham, LN (2008) Oxidative stress markers in bipolar disorder: a meta-analysis. Journal of Affective Disorders 111(2-3), 135144. doi: 10.1016/j.jad.2008.04.013.CrossRefGoogle ScholarPubMed
Atalay, S, Jarocka-karpowicz, I, Skrzydlewska, E and Skrzydlewskas, E (2020) Antioxidative and anti-inflammatory properties of cannabidiol. Antioxidants 9(1), 120. doi: 10.3390/antiox9010021.Google Scholar
Bakare, MO, Igwe, MN, Odinka, PC and Iteke, O (2011) Neuropsychiatric diagnosis and psychotropic medication prescription patterns in a mental hospital-based child and adolescent psychiatric service in Nigeria. Journal of Health Care for the Poor and Underserved 22(3), 751755. doi: 10.1353/hpu.2011.0078.CrossRefGoogle Scholar
Bishnoi, M and Boparai, RK (2012) An animal model to study the molecular basis of tardive dyskinesia. Methods in Molecular Biology 829, 193201. doi: 10.1007/978-1-61779-458-2_12.CrossRefGoogle Scholar
Bisogno, T, Hanuš, L, De Petrocellis, L, Tchilibon, S, Ponde, DE, Brandi, I, … Di Marzo, V (2001) Molecular targets for cannabidiol and its synthetic analogues: Effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. British Journal of Pharmacology. doi: 10.1038/sj.bjp.0704327.CrossRefGoogle Scholar
Blanchet, PJ, Parent, MT, Rompré, PH and Lévesque, D (2012) Relevance of animal models to human tardive dyskinesia. Behavioral and Brain Functions 8(1), 12. doi: 10.1186/1744-9081-8-12.CrossRefGoogle ScholarPubMed
Bordia, T, Zhang, D, Perez, XA and Quik, M (2016) Striatal cholinergic interneurons and D2 receptor-expressing GABAergic medium spiny neurons regulate tardive dyskinesia. Experimental Neurology 286, 3239. doi: 10.1016/j.expneurol.2016.09.009.CrossRefGoogle ScholarPubMed
Boskovic, M, Vovk, TT, Kores Plesničar, B, Grabnar, I, Vovk, TT, Kores Plesnicar, B and Boskovic, M (2011) Oxidative stress in schizophrenia. Current Neuropharmacology 9(2), 301312. doi: 10.2174/157015911795596595.Google ScholarPubMed
Bošković, M, Grabnar, I, Terzič, T, Kores Plesničar, B and Vovk, T (2013) Oxidative stress in schizophrenia patients treated with long-acting haloperidol decanoate. Psychiatry Research 210(3), 761768. doi: 10.1016/j.psychres.2013.08.035.CrossRefGoogle ScholarPubMed
Burk, RF and Hill, KE (2010) Glutathione Peroxidases. In Comprehensive Toxicology, Second Edition. doi: 10.1016/B978-0-08-046884-6.00413-9.CrossRefGoogle Scholar
Burnham, R, McNeil, S, Hegedus, C and Gray, DS (2006) Fibrous myopathy as a complication of repeated intramuscular injections for chronic headache. Pain Research & Management 11(4), 249252. doi: 10.1155/2006/198751.CrossRefGoogle ScholarPubMed
Busanello, A, Peroza, LR, Wagner, C, Sudati, JH, Pereira, RP, Prestes, ADS et al. (2012) Resveratrol reduces vacuous chewing movements induced by acute treatment with fluphenazine. Pharmacology Biochemistry and Behavior 101(2), 307310.CrossRefGoogle ScholarPubMed
Cadet, JL and Perumal, AS (1990) Chronic treatment with prolixin causes oxidative stress in rat brain. Biological Psychiatry 28(8), 738740. doi: 10.1016/0006-3223(90)90461-A.CrossRefGoogle ScholarPubMed
Campos, AC, Fogaça, MV, Sonego, AB and Guimarães, FS (2016) Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacological Research 112, 119127. doi: 10.1016/j.phrs.2016.01.033.CrossRefGoogle ScholarPubMed
Carbon, M, Hsieh, CH, Kane, JM and Correll, CU (2017) Tardive dyskinesia prevalence in the period of second-generation antipsychotic use: a meta-analysis. The Journal of Clinical Psychiatry 78(3), e264e278. doi: 10.4088/JCP.16r10832.CrossRefGoogle ScholarPubMed
Chang, FCF and Fung, VSC (2014) Clinical significance of pharmacogenomic studies in tardive dyskinesia associated with patients with psychiatric disorders. Pharmacogenomics and Personalized Medicine 7, 317328. doi: 10.2147/PGPM.S52806.Google ScholarPubMed
Chen, J, Hou, C, Chen, X, Wang, D, Yang, P, He, X, Zhou, J and Li, H (2016) Protective effect of cannabidiol on hydrogen peroxide-induced apoptosis, inflammation and oxidative stress in nucleus pulposus cells. Molecular Medicine Reports 14(3), 23212327. doi: 10.3892/mmr.2016.5513.CrossRefGoogle ScholarPubMed
Cho, CH and Lee, HJ (2013) Oxidative stress and tardive dyskinesia: Pharmacogenetic evidence. Progress in Neuro-Psychopharmacology and Biological Psychiatry 46, 207213. doi: 10.1016/j.pnpbp.2012.10.018.CrossRefGoogle ScholarPubMed
Cloud, LJ, Zutshi, D and Factor, SA (2014) Tardive dyskinesia: therapeutic options for an increasingly common disorder. Neurotherapeutics 11(1), 166176. doi: 10.1007/s13311-013-0222-5.CrossRefGoogle ScholarPubMed
Cobley, JN, Fiorello, ML and Bailey, DM (2018) 13 reasons why the brain is susceptible to oxidative stress. Redox Biology 15, 490503. doi: 10.1016/j.redox.2018.01.008.CrossRefGoogle ScholarPubMed
Consroe, P, Laguna, J, Allender, J, Snider, S, Stern, L, Sandyk, R, Kennedy, K and Schram, K (1991) Controlled clinical trial of cannabidiol in Huntington’s disease. Pharmacology Biochemistry and Behavior 40(3), 701708. doi: 10.1016/0091-3057(91)90386-G.CrossRefGoogle ScholarPubMed
Cornett, EM, Novitch, M, Kaye, AD, Kata, V and Kaye, AM (2017) Medication-induced tardive dyskinesia: a review and update. The Ochsner Journal 17(2), 162174. doi: 10.1043/TOJ-16-0108.Google Scholar
Costa, B, Colleoni, M, Conti, S, Parolaro, D, Franke, C, Trovato, AE and Giagnoni, G (2004) Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw. Naunyn-Schmiedeberg’s Archives of Pharmacology 369(3), 294299. doi: 10.1007/s00210-004-0871-3.CrossRefGoogle ScholarPubMed
Creed, MC, Hamani, C, Bridgman, A, Fletcher, PJ and Nobrega, JN (2012) Contribution of decreased serotonin release to the antidyskinetic effects of deep brain stimulation in a rodent model of tardive dyskinesia: comparison of the subthalamic and entopeduncular nuclei. Journal of Neuroscience 32(28), 95749581. doi: 10.1523/JNEUROSCI.1196-12.2012.CrossRefGoogle Scholar
Crowley, JJ, Adkins, DE, Pratt, AL, Quackenbush, CR, Van Den Oord, EJ, Moy, SS, Wilhelmsen, KC, Cooper, TB, Bogue, MA, McLeod, HL, Sullivan, PF (2012) Antipsychotic-induced vacuous chewing movements and extrapyramidal side effects are highly heritable in mice. Pharmacogenomics Journal 12(2), 147155. doi: 10.1038/tpj.2010.82.CrossRefGoogle ScholarPubMed
Dakhale, G, Khanzode, S, Khanzode, S, Saoji, A, Khobragade, L and Turankar, A (2004) Oxidative damage and schizophrenia: the potential benefit by atypical antipsychotics. Neuropsychobiology 49(4), 205209. doi: 10.1159/000077368.CrossRefGoogle ScholarPubMed
Damgaard, TD, Otte, JAH, Meinert, L and Jensen, K (2014) Antioxidant capacity of hydrolyzed porcine tissues 282-288. Food Science & Nutrition 2(3), 282288. doi: 10.1002/fsn3.106.CrossRefGoogle Scholar
Egan, MF, Hurd, Y, Ferguson, J, Bachus, SE, Hamid, EH and Hyde, TM (1996) Pharmacological and neurochemical differences between acute and tardive vacuous chewing movements induced by haloperidol. Psychopharmacology 127(1-2), 337345. doi: 10.1007/bf02806012.CrossRefGoogle ScholarPubMed
Esposito, G, De Filippis, D, Maiuri, MC, De Stefano, D, Carnuccio, R and Luvone, T (2006) Cannabidiol inhibits inducible nitric oxide synthase protein expression and nitric oxide production in β-amyloid stimulated PC12 neurons through p38 MAP kinase and NF-κB involvement. Neuroscience Letters 399(1-2), 9195. doi: 10.1016/j.neulet.2006.01.047.CrossRefGoogle ScholarPubMed
Förstermann, U and Sessa, WC (2012) Nitric oxide synthases: regulation and function. European Heart Journal 33(7), 829837. doi: 10.1093/eurheartj/ehr304.CrossRefGoogle Scholar
Gallegos, M and SR (2015) Cannabinoids in neuroinflammation, oxidative stress and neuro excitotoxicity. Pharmaceutica Analytica Acta 6(3). doi: 10.4172/2153-2435.1000346.CrossRefGoogle Scholar
Gegg, ME, Beltran, B, Salas-Pino, S, Bolanos, JP, Clark, JB, Moncada, S and Heales, SJR (2003) Differential effect of nitric oxide on glutathione metabolism and mitochondrial function in astrocytes and neurones: implications for neuroprotection/neurodegeneration? Journal of Neurochemistry 86(1), 228237. doi: 10.1046/j.1471-4159.2003.01821.x.CrossRefGoogle ScholarPubMed
Ginovart, N, Wilson, AA, Hussey, D, Houle, S and Kapur, S (2009) D2-receptor upregulation is dependent upon temporal course of D2-occupancy: a longitudinal [11C]-raclopride PET study in cats. Neuropsychopharmacology 34(3), 662671. doi: 10.1038/npp.2008.116.CrossRefGoogle ScholarPubMed
Gittis, AH, Leventhal, DK, Fensterheim, BA, Pettibone, JR, Berke, JD and Kreitzer, AC (2011) Selective inhibition of striatal fast-spiking interneurons causes Dyskinesias. Journal of Neuroscience 31(44), 1572715731. doi: 10.1523/JNEUROSCI.3875-11.2011.CrossRefGoogle ScholarPubMed
Goldberg, TE, Greenberg, RD, Griffin, SJ, Gold, JM, Kleinman, JE, Pickar, D, Schulz, SC and Weinberger, DR (1993) The effect of clozapine on cognition and psychiatric symptoms in patients with schizophrenia. British Journal of Psychiatry 162(1), 4348. doi: 10.1192/bjp.162.1.43.CrossRefGoogle ScholarPubMed
Gomes, FV, Del Bel, EA and Guimarães, FS (2013) Cannabidiol attenuates catalepsy induced by distinct pharmacological mechanisms via 5-HT1A receptor activation in mice. Progress in Neuro-Psychopharmacology and Biological Psychiatry 46, 4347. doi: 10.1016/j.pnpbp.2013.06.005.CrossRefGoogle ScholarPubMed
Graff-Guerrero, A, Mizrahi, R, Agid, O, Marcon, H, Barsoum, P, Rusjan, P, … Kapur, S (2009) The dopamine D2 receptors in high-affinity state and D 3 receptors in schizophrenia: A clinical [11C]-(+)-PHNO PET study. Neuropsychopharmacology. doi: 10.1038/npp.2008.199.CrossRefGoogle Scholar
Gudi, T, Hong, GK, Vaandrager, AB, Lohmann, SM and Pilz, RB (1999) Nitric oxide and cGMP regulate gene expression in neuronal and glial cells by activating type II cGMP-dependent protein kinase. The FASEB Journal 13(15), 21432152. doi: 10.1096/fasebj.13.15.2143.CrossRefGoogle ScholarPubMed
Guimarães, FS, Chiaretti, TM, Graeff, FG and Zuardi, AW (1990) Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology 100, 558559. doi: 10.1007/BF02244012.CrossRefGoogle ScholarPubMed
Gunne, LM, Häggström, JE and Sjöquist, B (1984) Association with persistent neuroleptic-induced dyskinesia of regional changes in brain GABA synthesis. Nature 309(5966), 347349. doi: 10.1038/309347a0.CrossRefGoogle ScholarPubMed
Gureje, O (1987) Tardive dyskinesia in schizophrenics: prevalence, distribution and relationship to neurological, soft, signs in Nigerian patients. Acta Psychiatrica Scandinavica 76(5), 523528. doi: 10.1111/j.1600-0447.1987.tb02913.x.CrossRefGoogle ScholarPubMed
Harris, ED (1992) Regulation of antioxidant enzymes. Journal of Nutrition 6(suppl_3), 26752683. doi: 10.1093/jn/122.suppl_3.625.Google ScholarPubMed
Harvey, BH and Bester, AM (2000) Withdrawal-associated changes in peripheral nitrogen oxides and striatal cyclic GMP after chronic haloperidol treatment. Behavioural Brain Research 111(1-2), 203211. doi: 10.1016/S0166-4328(00)00156-X.CrossRefGoogle ScholarPubMed
Igbinomwanhia, NG, Olotu, SO and James, BO (2017) Prevalence and correlates of antipsychotic polypharmacy among outpatients with schizophrenia attending a tertiary psychiatric facility in Nigeria. Therapeutic Advances in Psychopharmacology 7(1), 310. doi: 10.1177/2045125316672134.CrossRefGoogle ScholarPubMed
Iwahashi, K, Yoneyama, H, Ohnishi, T, Nakamura, K, Miyatake, R, Suwaki, H, Hosokawa, K and Ichikawa, Y (1996) Haloperidol inhibits neuronal nitric oxide synthase activity by preventing electron transfer. Neuropsychobiology 33(2), 7679. doi: 10.1159/000119253.CrossRefGoogle ScholarPubMed
Kajero, JA, Seedat, S, Ohaeri, J, Akindele, A and Aina, O (2020) Investigation of the effects of cannabidiol on vacuous chewing movements, locomotion, oxidative stress and blood glucose in rats treated with oral haloperidol. The World Journal of Biological Psychiatry 21(8), 612626. doi: 10.1080/15622975.2020.1752934.CrossRefGoogle ScholarPubMed
Kamyar, M, Razavi, BM, Vahdati Hasani, F, Mehri, S, Foroutanfar, A and Hosseinzadeh, H (2016) Crocin prevents haloperidol-induced orofacial dyskinesia: possible an antioxidant mechanism. Iranian Journal of Basic Medical Sciences 19(10), 10701079. doi: 10.22038/ijbms.2016.7732.Google ScholarPubMed
Kasantikul, D and Kanchanatawan, B (2007) Antipsychotic-induced tardive movement disorders: a series of twelve cases. Journal of the Medical Association of Thailand 90(1), 188194.Google ScholarPubMed
Kedare, SB and Singh, RP (2011) Genesis and development of DPPH method of antioxidant assay. Journal of Food Science and Technology 48(4), 412422. doi: 10.1007/s13197-011-0251-1.CrossRefGoogle ScholarPubMed
Khan, BV, Harrison, DG, Olbrych, MT, Alexander, RW and Medford, RM (1996) Nitric oxide regulates vascular cell adhesion molecule 1 gene expression and redox-sensitive transcriptional events in human vascular endothelial cells. Proceedings of the National Academy of Sciences USA 93(17), 91149119. doi: 10.1073/pnas.93.17.9114.CrossRefGoogle ScholarPubMed
Kim, J, MacMaster, E and Schwartz, TL (2014) Tardive dyskinesia in patients treated with atypical antipsychotics: case series and brief review of etiologic and treatment considerations. Drugs in Context 3, 19. doi: 10.7573/dic.212259.CrossRefGoogle ScholarPubMed
Kudo, S and Ishizaki, T (1999) Pharmacokinetics of haloperidol. An update. Clinical Pharmacokinetics 37(6), 435456. doi: 10.2165/00003088-199937060-00001.CrossRefGoogle ScholarPubMed
Kunz, M, Gama, CS, Andreazza, AC, Salvador, M, Ceresér, KM, Gomes, FA, … Kapczinski, F (2008) Elevated serum superoxide dismutase and thiobarbituric acid reactive substances in different phases of bipolar disorder and in schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry. doi: 10.1016/j.pnpbp.2008.07.001.CrossRefGoogle Scholar
Kurutas, EB (2016) The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: current state. Nutrition Journal 15(1), 122. doi: 10.1186/s12937-016-0186-5.Google ScholarPubMed
Laprairie, RB, Bagher, AM, Kelly, MEM and Denovan-Wright, EM (2015) Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. British Journal of Pharmacology 172(20). doi: 10.1111/bph.13250.CrossRefGoogle ScholarPubMed
Lee, HJ, Kang, SG, Choi, JE, Park, YM, Lim, SW, Min, KR, Kim, SH and Kim, L (2009) No evidence for association between tyrosine hydroxylase gene Val81Met polymorphism and susceptibility to tardive dyskinesia in schizophrenia. Psychiatry Investigation 6(2), 108111. doi: 10.4306/pi.2009.6.2.108.CrossRefGoogle ScholarPubMed
Lee, JLC, Bertoglio, LJ, Guimarães, FS and Stevenson, CW (2017) Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorders. British Journal of Pharmacology 174(19), 32423256. doi: 10.1111/bph.13724.CrossRefGoogle ScholarPubMed
Liebmann, M, Hucke, S, Koch, K, Eschborn, M, Ghelman, J, Chasan, AI, Glander, S, Schädlich, M, Kuhlencord, M, Daber, NM, Eveslage, M, Beyer, M, Dietrich, M, Albrecht, P, Stoll, M, Busch, KB, Wiendl, H, Roth, J, Kuhlmann, T and Klotz, L (2018) Nur77 serves as a molecular brake of the metabolic switch during T cell activation to restrict autoimmunity. Proceedings of the National Academy of Sciences 115(34), E8017–E8026. doi: 10.1073/pnas.1721049115.CrossRefGoogle Scholar
Loughlin, AM, Lin, N, Abler, V and Carroll, B (2019) Tardive dyskinesia among patients using antipsychotic medications in customary clinical care in the United States. PLOS ONE 14(6), e0216044. doi: 10.1371/journal.pone.0216044.CrossRefGoogle ScholarPubMed
Luvone, T, Esposito, G, Esposito, R, Santamaria, R, Di Rosa, M and Izzo, AA (2004) Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on β-amyloid-induced toxicity in PC12 cells. Journal of Neurochemistry 89(1), 134141. doi: 10.1111/j.1471-4159.2003.02327.x.Google Scholar
Mahmoudi, S, Blanchet, PJ and Lévesque, D (2013) Haloperidol-induced striatal Nur77 expression in a non-human primate model of tardive dyskinesia. European Journal of Neuroscience 38(1), 21922198. doi: 10.1111/ejn.12198.CrossRefGoogle Scholar
Malfait, AM, Gallily, R, Sumariwalla, PF, Malik, AS, Andreakos, E, Mechoulam, R and Feldmann, M (2000) The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proceedings of the National Academy of Sciences USA 97(17), 9561–9566. doi: 10.1073/pnas.160105897.CrossRefGoogle Scholar
Marchese, G, Bartholini, F, Casu, MA, Ruiu, S, Casti, P, Congeddu, E, Tambaro, S and Pani, L (2004) Haloperidol versus risperidone on rat, early onset, vacuous chewing. Behavioural Brain Research 149(1), 916. doi: 10.1016/S0166-4328(03)00192-X.CrossRefGoogle ScholarPubMed
Margolese, HC, Chouinard, G, Kolivakis, TT, Beauclair, L and Miller, R (2005) Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 1: pathophysiology and mechanisms of induction. The Canadian Journal of Psychiatry 50(9), 541547. doi: 10.1177/070674370505000907.CrossRefGoogle Scholar
Martínez-Pinilla, E, Varani, K, Reyes-Resina, I, Angelats, E, Vincenzi, F, Ferreiro-Vera, C, … Franco, R (2017) Binding and signaling studies disclose a potential allosteric site for cannabidiol in cannabinoid CB2 receptors. Frontiers in Pharmacology 8(OCT). doi: 10.3389/fphar.2017.00744.CrossRefGoogle Scholar
Massi, P, Vaccani, A, Bianchessi, S, Costa, B, Macchi, P and Parolaro, D (2006) The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells. Cellular and Molecular Life Sciences 63(17), 20572066. doi: 10.1007/s00018-006-6156-x.CrossRefGoogle ScholarPubMed
Mechoulam, R, Peters, M, Murillo-rodriguez, E, Hanus, L and Campus, EK (2007) Cannabidiol – recent advances. Chemistry & Biodiversity 4(8), 16781692. doi: 10.1002/cbdv.200790147.CrossRefGoogle ScholarPubMed
Merrill, RM, Lyon, JL and Matiaco, PM (2013) Tardive and spontaneous dyskinesia incidence in the general population. BMC Psychiatry 13(1), 1. doi: 10.1186/1471-244X-13-152.CrossRefGoogle ScholarPubMed
Morris, BJ, Simpson, CS, Mundell, S, Maceachern, K, Johnston, HM and Nolan, AM (1997) Dynamic changes in NADPH-diaphorase staining reflect activity of nitric oxide synthase: evidence for a dopaminergic regulation of striatal nitric oxide release. Neuropharmacology 36(11-12), 15891599. doi: 10.1016/S0028-3908(97)00159-7.CrossRefGoogle ScholarPubMed
Naidu, PS and Kulkarni, SK (2001a) Effect of 5-HT1A and 5- HT2A/2C receptor modulations on neuroleptic-induced vacuous chewing movements. European Journal of Pharmacology 428(1), 8186.CrossRefGoogle ScholarPubMed
Naidu, PS and Kulkarni, SK (2001b) Possible involvement of prostaglandins in haloperidol-induced orofacial dyskinesia in rats. European Journal of Pharmacology 430(2-3), 295298.CrossRefGoogle ScholarPubMed
Naidu, PS, Singh, A and Kulkarni, SK (2002) Carvedilol attenuates neuroleptic-induced orofacial dyskinesia: possible antioxidant mechanisms. British Journal of Pharmacology 136(2), 193200. doi: 10.1038/sj.bjp.0704717.CrossRefGoogle ScholarPubMed
National Research Council (2011) Guide for the care and use of laboratory animals, 8th edn. Washington, DC: The National Academies Press.Google Scholar
Nel, A and Harvey, BH (2003) Haloperidol-induced dyskinesia is associated with striatal NO synthase suppression: reversal with olanzapine. Behavioural Pharmacology 14(3), 251255. doi: 10.1097/00008877-200305000-00010.CrossRefGoogle ScholarPubMed
Nkporbu, AK, Okeafor, CU, Stanley, CN, Onya, OO and Stanley, PC (2016) Prevalence and pattern of drug induced movement disorders in University of Port Harcourt Teaching Hospital: a 3-year review. EC Neurology 4(1), 3640.Google Scholar
O’Dell, TJ, Hawkins, RD, Kandel, ER and Arancio, O (1991) Tests of the roles of two diffusible substances in long-term potentiation: evidence for nitric oxide as a possible early retrograde messenger. Proceedings of the National Academy of Sciences USA 88(24), 1128511289. doi: 10.1073/pnas.88.24.11285.CrossRefGoogle ScholarPubMed
O’Sullivan, SE, Sun, Y, Bennett, AJ, Randall, MD and Kendall, DA (2009) Time-dependent vascular actions of cannabidiol in the rat aorta. European Journal of Pharmacology. doi: 10.1016/j.ejphar.2009.03.010.CrossRefGoogle Scholar
Onah, PO, Abdulmalik, A and Kaigamma, AY (2018) Antipsychotic drugs prescription pattern among patients with schizophrenia in a Federal Neuropsychiatric Hospital Maiduguri, Northeast Nigeria. Journal of Advances in Medical and Pharmaceutical Sciences 19(1), 18. doi: 10.9734/jamps/2018/40478.CrossRefGoogle Scholar
Pantopoulos, K and Hentze, MW (1995) Nitric oxide signaling to iron-regulatory protein: direct control of ferritin mRNA translation and transferrin receptor mRNA stability in transfected fibroblasts. Proceedings of the National Academy of Sciences USA 92(5), 12671271. doi: 10.1073/pnas.92.5.1267.CrossRefGoogle ScholarPubMed
Patil, R, Dhawale, K, Gound, H and Gadakh, R (2012) Protective effect of leaves of Murraya koenigii on reserpine-induced orofacial dyskinesia. Iranian Journal of Pharmaceutical Research 11(2), 635641. doi: 10.22037/ijpr.2012.1096.Google ScholarPubMed
Patterson-Lomba, O, Ayyagari, R and Carroll, B (2019) 62 predictors of tardive dyskinesia in psychiatric patients taking concomitant antipsychotics. CNS Spectrums 24(1), 207208. doi: 10.1017/S1092852919000488.CrossRefGoogle Scholar
Peres, FF, Levin, R, Suiama, MA, Diana, MC, Gouvêa, DA, Almeida, VVD, Santos, CM, Lungato, L, Zuardi, AW, Hallak, JEC, Crippa, JA, Almeida, VVD (2016) Cannabidiol prevents motor and cognitive impairments induced by reserpine in rats. Frontiers in Pharmacology 7, 343. doi: 10.3389/fphar.2016.00343.CrossRefGoogle ScholarPubMed
Peres, FF, Lima, AC, Hallak, JEC, Crippa, JA, Silva, RH and Abílio, VC (2018) Cannabidiol as a promising strategy to treat and prevent movement disorders? Frontiers in Pharmacology 9, 482. doi: 10.3389/fphar.2018.00482.CrossRefGoogle ScholarPubMed
Pisanti, S, Malfitano, AM, Ciaglia, E, Lamberti, A, Ranieri, R, Cuomo, G, Abate, M, Faggiana, G, Proto, MC, Fiore, D, Laezza, C, Bifulco, M (2017) Cannabidiol: state of the art and new challenges for therapeutic applications. Pharmacology & Therapeutics 175, 133150. doi: 10.1016/j.pharmthera.2017.02.041.CrossRefGoogle ScholarPubMed
Popovic, M, Janicijevic-Hudomal, S, Kaurinovic, B, Rasic, J, Trivic, S and Vojnović, M (2009) Antioxidant effects of some drugs on immobilization stress combined with cold restraint stress. Molecules 14(11), 45054516. doi: 10.3390/molecules14114505.CrossRefGoogle ScholarPubMed
Pozdnyakov, N, Lloyd, A, Reddy, VN and Sitaramayya, A (1993) Nitric oxide-regulated endogenous ADP-ribosylation of rod outer segment proteins. Biochemical and Biophysical Research Communications 192(2), 610615. doi: 10.1006/bbrc.1993.1459.CrossRefGoogle ScholarPubMed
Rajesh, M, Mukhopadhyay, P, Bátkai, S, Haskó, G, Liaudet, L, Drel, VR, Obrosova, IG and Pacher, P (2007) Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption. American Journal of Physiology 293(1), H610H619. doi: 10.1152/ajpheart.00236.2007.Google ScholarPubMed
Rana, AQ, Chaudry, ZM and Blanchet, PJ (2013) New and emerging treatments for symptomatic tardive dyskinesia. Drug Design, Development and Therapy 7, 13291340. doi: 10.2147/DDDT.S32328.CrossRefGoogle ScholarPubMed
Rao, AV and Balachandran, B (2002) Role of oxidative stress and antioxidants in neurodegenerative diseases. Nutritional Neuroscience 5(5), 291309. doi: 10.1080/1028415021000033767.CrossRefGoogle ScholarPubMed
Rock, EM, Bolognini, D, Limebeer, CL, Cascio, MG, Anavi-Goffer, S, Fletcher, PJ, Mechoulam, R, Pertwee, RG and Parker, LA (2012) Cannabidiol, a nonpsychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT 1A somatodendritic autoreceptors in the dorsal raphe nucleus. British Journal of Pharmacology 165(8), 26202634. doi: 10.1111/j.1476-5381.2011.01621.x.CrossRefGoogle ScholarPubMed
Rupniak, NMJ, Jenner, P and Marsden, CD (1986) Acute dystonia induced by neuroleptic drugs. Psychopharmacology 88, 403–419. doi: 10.1007/BF00178501.CrossRefGoogle ScholarPubMed
Russo, EB, Burnett, A, Hall, B and Parker, KK (2005) Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochemical Research 30(8), 10371043.CrossRefGoogle ScholarPubMed
Ryu, S, Yoo, JH, Kim, JH, Choi, JS, Baek, JH, Ha, K, Kwon, JS and Hong, KS (2015) Tardive dyskinesia and tardive dystonia with second-generation antipsychotics in non-elderly schizophrenic patients unexposed to first-generation antipsychotics a cross-sectional and retrospective study. Journal of Clinical Psychopharmacology 35(1), 1321. doi: 10.1097/JCP.0000000000000250.CrossRefGoogle ScholarPubMed
Sammut, S, Bray, KE and West, AR (2007) Dopamine D2 receptor-dependent modulation of striatal NO synthase activity. Psychopharmacology (Berl) 191(3), 793803. doi: 10.1007/s00213-006-0681-z.CrossRefGoogle ScholarPubMed
Sánchez-Moreno, C, Larrauri, JA and Saura-Calixto, F (1998) A procedure to measure the antiradical efficiency of polyphenols. Journal of the Science of Food and Agriculture 76, 270276. doi: 10.1002/(SICI)1097-0010(199802)76:2<270::AID-JSFA945>3.0.CO;2-9.3.0.CO;2-9>CrossRefGoogle Scholar
Sarró, S, Pomarol-Clotet, E, Canales-Rodríguez, EJ, Salvador, R, Gomar, JJ, Ortiz-Gil, J, Landín-Romero, R, Vila-Rodríguez, F, Blanch, J, McKenna, PJ (2013) Structural brain changes associated with tardive dyskinesia in schizophrenia. British Journal of Psychiatry 203(1), 5157. doi: 10.1192/bjp.bp.112.114538.CrossRefGoogle ScholarPubMed
Sartim, AG, Guimarães, FS and Joca, SRL (2016) Antidepressant-Like effect of cannabidiol injection into the ventral medial prefrontal cortex-Possible involvement of 5-HT1A and CB1 receptors. Behavioural Brain Research 303, 218–227. doi: 10.1016/j.bbr.2016.01.033.CrossRefGoogle Scholar
Sasaki, H, Hashimoto, K, Maeda, Y, Inada, T, Kitao, Y, Fukui, S and Iyo, M (1995) Rolipram, a selective c-AMP phosphodiesterase inhibitor suppresses oro-facial dyskinetic movements in rats. Life Science Part 1 Physiology & Pharmacology 56(25), 443447. doi: 10.1016/0024-3205(95)00218-U.Google ScholarPubMed
Schuman, EM and Madison, DV (1991) A requirement for the intercellular messenger nitric oxide in long-term potentiation. Science 80(5037), 2541506. doi: 10.1126/science.1720572.Google Scholar
Seeman, P (2016) Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsychotic clinical dose. Translational Psychiatry 6(10), e920e920. doi: 10.1038/tp.2016.195.CrossRefGoogle ScholarPubMed
Seigneurie, AS, Sauvanaud, F and Limosin, F (2016) Prevention and treatment of tardive dyskinesia caused by antipsychotic drugs. LʼEncéphale 42(3), 248254. doi: 10.1016/j.encep.2015.12.021.CrossRefGoogle ScholarPubMed
Shireen, E (2016) Experimental treatment of antipsychotic-induced movement disorders. Journal of Experimental Pharmacology 8, 110. doi: 10.2147/JEP.S63553.CrossRefGoogle ScholarPubMed
Sies, H (2015) Oxidative stress: a concept in redox biology and medicine. Redox Biology 4, 180183. doi: 10.1016/j.redox.2015.01.002.CrossRefGoogle ScholarPubMed
Solmi, M, Pigato, G, Kane, JM and Correll, CU (2018) Clinical risk factors for the development of tardive dyskinesia. Journal of the Neurological Sciences 389, 2127. doi: 10.1016/j.jns.2018.02.012.CrossRefGoogle ScholarPubMed
Sonego, AB, Gomes, FV, Del Bel, EA and Guimaraes, FS (2016) Cannabidiol attenuates haloperidol-induced catalepsy and c-Fos protein expression in the dorsolateral striatum via 5-HT1A receptors in mice. Behavioural Brain Research 309, 2228. doi: 10.1016/j.bbr.2016.04.042.CrossRefGoogle ScholarPubMed
Sonego, AB, Prado, DS, Vale, GT, Sepulveda-Diaz, JE, Cunha, TM, Tirapelli, CR, Del Bel, EA, Raisman-Vozari, R and Guimarães, FS (2018) Cannabidiol prevents haloperidol-induced vacuos chewing movements and inflammatory changes in mice via PPARγ receptors. Brain Behavior and Immunity 74, 241251. doi: 10.1016/j.bbi.2018.09.014.CrossRefGoogle ScholarPubMed
Su, CJ, Xu, XQ, Fan, Y, Du, RH and Hu, G (2012) Aquaporin-4 knockout abolishes apomorphine-induced tardive dyskinesia following chronic treatment with neuroleptics. CNS Neuroscience & Therapeutics 18(12), 10241026. doi: 10.1111/cns.12020.CrossRefGoogle ScholarPubMed
Syu, A, Ishiguro, H, Inada, T, Horiuchi, Y, Tanaka, S, Ishikawa, M, Arai, M, Itokawa, M, Niizato, K, Iritani, S, Ozaki, N, Takahashi, M, Kakita, A, Takahashi, H, Nawa, H, Keino-Masu, K, Arikawa-Hirasawa, E, Arinami, T (2010) Association of the HSPG2 gene with neuroleptic-induced tardive dyskinesia. Neuropsychopharmacology 35(5), 11551164. doi: 10.1038/npp.2009.220.CrossRefGoogle ScholarPubMed
Teo, JT, Edwards, MJ and Bhatia, K (2012) Tardive dyskinesia is caused by maladaptive synaptic plasticity: a hypothesis. Movement Disorders 27(10), 12051215. doi: 10.1002/mds.25107.CrossRefGoogle ScholarPubMed
Tesfaye, S, Debencho, N, Kisi, T and Tareke, M (2016) Prevalence of antipsychotic polypharmacy and associated factors among outpatients with schizophrenia attending Amanuel Mental Specialized Hospital, Addis Ababa, Ethiopia. Psychiatry Journal 2016, 16. doi: 10.1155/2016/6191074.CrossRefGoogle ScholarPubMed
Thakur, KS, Prakash, A, Bisht, R and Bansal, PK (2015) Beneficial effect of candesartan and lisinopril against haloperidol-induced tardive dyskinesia in rat. Journal of the Renin-Angiotensin-Aldosterone System 16(4), 917929. doi: 10.1177/1470320313515038.CrossRefGoogle ScholarPubMed
Tiwari, AK, Deshpande, SN, Lerer, B and Nimgaonkar, VL (2008) schizophrenia subjects: role of oxidative stress pathway genes. Biotechnology 92, 278279.Google Scholar
Ursini, F and Maiorino, M (2013) Glutathione peroxidases, Encyclopedia of biological chemistry, 2nd. doi: 10.1016/B978-0-12-378630-2.00383-2.Google Scholar
Valvassori, SS, Budni, J, Varela, RB and Quevedo, J (2013) Contributions of animal models to the study of mood disorders. Revista Brasileira De Psiquiatria 35(suppl 2), S121S131. doi: 10.1590/1516-4446-2013-1168.CrossRefGoogle Scholar
Valvassori, SS, Elias, G, De Souza, B, Petronilho, F, Dal-Pizzol, F, Kapczinski, F, Trzesniak, C, Tumas, V, Dursun, S, Nisihara Chagas, MH, Hallak, JE, Zuardi, AW, Quevedo, J, Crippa, JA (2011) Effects of cannabidiol on amphetamine-induced oxidative stress generation in an animal model of mania. Journal of Psychopharmacology 25(2), 274279. doi: 10.1177/0269881109106925.CrossRefGoogle Scholar
Van Harten, PN, Matroos, GE, Hoek, HW and Kahn, RS (1996) The prevalence of tardive dystonia, tardive dyskinesia, parkinsonism and akathisia: The Curaçao extrapyramidal syndromes study: I. Schizophrenia Research 19(2–3). doi: 10.1016/0920-9964(95)00096-8.CrossRefGoogle ScholarPubMed
Waddington, JL (1990) Spontaneous orofacial movements induced in rodents by very long-term neuroleptic drug administration: phenomenology, pathophysiology and putative relationship to tardive dyskinesia. Psychopharmacology 101(4), 431447. doi: 10.1007/BF02244220.CrossRefGoogle ScholarPubMed
Woerner, MG, Alvir, JMJ, Saltz, BL, Lieberman, JA and Kane, JM (1998) Prospective study of tardive dyskinesia in the elderly: rates and risk factors. American Journal of Psychiatry 155(11), 15211528. doi: 10.1176/ajp.155.11.1521.CrossRefGoogle ScholarPubMed
Wyatt, RJ (1999) Tardive dyskinesia: possible involvement of free radicals and treatment with vitamin E. Schizophrenia Bulletin 31, 731740.Google Scholar
Yin, J, Barr, A, Ramos-Miguel, A and Procyshyn, R (2016) Antipsychotic induced dopamine supersensitivity psychosis: a comprehensive review. Current Neuropharmacology 15(1), 174183. doi: 10.2174/1570159x14666160606093602.CrossRefGoogle Scholar
Zendulka, O, Dovrtělová, G, Nosková, K, Turjap, M, Šulcová, A, Hanuš, L and Juřica, J (2016) Cannabinoids and cytochrome P450 interactions. Current Drug Metabolism 17(3), 206226. doi: 10.2174/1389200217666151210142051.CrossRefGoogle ScholarPubMed
Zhang, XY and Yao, JK (2013) Oxidative stress and therapeutic implications in psychiatric disorders. Progress in Neuro-Psychopharmacology and Biological Psychiatry 46, 197199. doi: 10.1016/j.pnpbp.2013.03.003.CrossRefGoogle ScholarPubMed
Zuardi, AW (2008) Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Revista Brasileira de Psiquiatria 30(3), 271280.CrossRefGoogle ScholarPubMed
Figure 0

Table 1. Pharmacological administration schedule

Figure 1

Fig. 1. Vacuous chewing movements.

Figure 2

Table 2. Brain antioxidant indices