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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 Open the ORCID record for Jaiyeola Abiola Kajero [Opens in a new window] ,
Soraya Seedat ,
Jude U. Ohaeri ,
Abidemi Akindele  and
Oluwagbemiga Aina
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]
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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.

Keywords

Tardive dyskinesiahaloperidolcannabidiolantioxidantsprooxidants
Type
Original Article
Information
Acta Neuropsychiatrica , Volume 36 , Issue 5 , October 2024 , pp. 265 - 275
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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.

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Figure 0

Table 1. Pharmacological administration schedule

Figure 1

Fig. 1. Vacuous chewing movements.

Figure 2

Table 2. Brain antioxidant indices