THC inhibits the expression of ethanol-induced locomotor sensitization in mice

Accepted Manuscript THC inhibits the expression of ethanol-induced locomotor sensitization in mice Renato Filev, Douglas S. Engelke, Dartiu X. da Silveira, Luiz E. Mello, Jair G. SantosJunior PII:

S0741-8329(16)30287-7

DOI:

10.1016/j.alcohol.2017.06.004

Reference:

ALC 6735

To appear in:

Alcohol

Received Date: 9 November 2016 Revised Date:

19 June 2017

Accepted Date: 22 June 2017

Please cite this article as: Filev R., Engelke D.S., da Silveira D.X., Mello L.E. & Santos-Junior J.G., THC inhibits the expression of ethanol-induced locomotor sensitization in mice, Alcohol (2017), doi: 10.1016/ j.alcohol.2017.06.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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THC inhibits the expression of ethanol-induced locomotor sensitization in mice Renato Filev a*, Douglas S. Engelke a, d, Dartiu X. da Silveira b, Luiz E. Mello a, and Jair G. Santos-Junior c a

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Department of Physiology – Laboratory of Neurobiology, UNIFESP, R. Pedro de Toledo, 669 – 3rd floor, 04039-032, São Paulo, SP Brazil

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Department of Psychiatry and Medical Psychology, UNIFESP, R. Borges Lagoa, 570 – Vila Clementino, São Paulo – SP, 04038-000 Brazil c

Department of Physiological Sciences, Faculdade de Ciências Médicas Santa Casa de São Paulo, Rua Dr. Cesário Motta Jr., 61 – São Paulo – SP – Cep: 01221-020 Brazil

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*Corresponding author:

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Current address: Department of Neurobiology and Anatomy, McGovern Medical School, The University of Texas Health Science Center, 6431 Fannin St., Room 7.512, Houston, Texas 77030.

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Renato Filev Laboratório de Neurobiologia Edifício de Pesquisas II – UNIFESP R. Pedro de Toledo 669–3° andar, 04039-032 São Paulo, SP Brasil Phone: +55 11 5576 4969 E-mail: [email protected]

Authors’ e-mails Renato Filev: [email protected] Douglas Senna Engelke: [email protected] Dartiu Xavier da Silveira: [email protected] Luiz Eugênio Mello: [email protected] Jair Guilherme Santos-Junior: [email protected]

ACCEPTED MANUSCRIPT Abstract The motivational circuit activated by ethanol leads to behavioral changes that recruit the endocannabinoid system (ECS). Case reports and observational studies suggest that the use of Cannabis sp. mitigates problematic ethanol consumption in humans. Here, we verified

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the effects of the two main phytocannabinoid compounds of Cannabis sp., cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), in the expression of ethanol-induced locomotor sensitization in mice. Male adult DBA/2 mice were exposed to locomotor

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sensitization by daily intraperitoneal injections of ethanol (2.5 g/kg) for 12 days; control

groups received saline. After the acquisition phase, animals were treated with cannabinoids:

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CBD (2.5 mg/kg); THC (2.5 mg/kg); CBD + THC (1:1 ratio), or vehicle for 4 days with no access to ethanol during this period. One day after the last cannabinoid injection, all animals were challenged with ethanol (2.0 g/kg) to evaluate the expression of the locomotor sensitization. Mice treated with THC alone or THC + CBD showed reduced expression of

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locomotor sensitization, compared to the vehicle control group. No effects were observed with CBD treatment alone. Our findings showing that phytocannabinoid treatment prevents the expression of behavioral sensitization in mice provide insight into the potential

Highlights

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therapeutic use of phytocannabinoids in alcohol-related problems.

THC, the main compound in cannabis, interferes in an ethanol-related behavior.

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THC inhibits the expression of locomotor sensitization induced by ethanol.

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Activation of the endocannabinoid system may be important in ethanol therapies.

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Keywords: alcohol; cannabis; sensitization; dependence; endocannabinoid system; behavior

ACCEPTED MANUSCRIPT Introduction The endocannabinnoid system (ECS) plays an important regulatory role in several neurotransmission systems (Basavarajappa, 2007; Mechoulam & Parker, 2013), including those involved in motivational circuitry (Friemel, Zimmer, & Schneider, 2014; Maldonado,

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Valverde, & Berrendero, 2006; Parolaro, Vigano, Realini, & Rubino, 2007). The ECS has been linked with drug-associated behavior and neuronal plasticity related to the motivational process (Maldonado et al., 2006; Parsons & Hurd, 2015; Prud’homme, Cata, & Jutras-

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Aswad, 2015). For example, chronic exposure to ethanol has been associated with changes in endocannabinoid signaling (Basavarajappa, 2007; Wang, Liu, Harvey-White, Zimmer, &

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Kunos, 2003), and blockade of endocannabinoid receptors has been shown to reduce ethanol intake (Arnone et al., 1997; Cippitelli et al., 2005; Colombo et al., 2007; Gallate & McGregor, 1999; Maccioni, Colombo, & Carai, 2010; Wang et al., 2003). Animal models of locomotor sensitization have been used to assess motivational

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salience provoked by recurrent exposure to drugs of abuse, such as ethanol (Abrahao et al., 2013; Coelhoso et al., 2013; Robinson & Berridge, 2008; Steketee & Kalivas, 2011). Repeated administration of ethanol induces progressive and persistent increase of locomotor

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activity, even after prolonged periods of withdrawal (Boehm, Goldfarb, Serio, Moore, & Linsenbardt, 2008; Coelhoso et al., 2013; Steketee & Kalivas, 2011). Sensitization to ethanol

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increases dopamine release and neuronal plasticity in the striatum (Abrahao et al., 2013; Oleson & Cheer, 2012), a region known to regulate motivational behaviors (Koob & Volkow, 2016). Evidence suggests that ethanol-induced plasticity is modulated by the ECS (Hungund, Szakall, Adam, Basavarajappa, & Vadasz, 2003; Lovinger, 2010; Maldonado et al., 2006), but whether exogenous manipulation of the ECS can affect the behavioral expression of ethanol-induced sensitization remained unknown until now. To address this question, we used two of the main phytocannabinoid compounds found in Cannabis sativa: delta-9tetrahydrocannabinol (THC), which acts as a direct agonist of cannabinoid receptors, and

ACCEPTED MANUSCRIPT cannabidiol (CBD), which indirectly increases the levels of endocannabinoids (Devinsky et al., 2014; Mechoulam & Parker, 2013). Methods A total of 84 animals were submitted to this protocol (40 received ethanol and 44

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received saline). DBA/2 mice were originally acquired from The Jackson Laboratory. The animals were bred and raised in the Instituto de Farmacologia e Biologia Molecular (INFAR) – Universidade Federal de São Paulo, Brazil. In this study, the related strain was designated

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as DBA/2 to indicate that the animals used were born after three generations of breeding from the initial matrix (DBA/2J) received from The Jackson Laboratory. Male adult mice were

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separated into groups of 8 subjects and kept in home cages (40 × 34 × 17 cm) in a light/dark cycle (12/12 h, lights on at 7:00 AM), with free access to food and water. The study was carried out in strict accordance with the recommendations established by the National

animals.

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Institute of Health (Publications No. 8023, revised 1978) for the care and use of laboratory

Ethanol 15% (Synth®) was diluted in saline (NaCl 0.9% in water solution), and was administered in doses of 2.0 g/kg and 2.5 g/kg, intraperitoneally (i.p.). CBD and THC,

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originally obtained from the National Institute of Health of the United States, were kindly

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provided by Prof. Elisaldo Carlini (Preventive Medicine Department/Universidade Federal de São Paulo – UNIFESP). A single dose of 2.5 mg/kg of CBD and THC was tested. This dose was selected according to previous studies demonstrating no deleterious effects on locomotor activity (El-Alfy et al., 2010; Long et al., 2010; Tai et al., 2015). DMSO 8% (SigmaAldrich®), Tween 20 1% (Biorad®), and saline were used in the cannabinoids dilution. Mice were handled daily for 1 week before experimental procedures, in order to reduce stress. Locomotor activity was recorded by a video camera located in the top of the open field that used as the sensitization apparatus. The distance traveled by the mice was

ACCEPTED MANUSCRIPT measured in centimeters by Ethovision® software (Amsterdam, The Netherlands). All experiments were carried out during the afternoon. The apparatus used as sensitization context was made in wood boxes painted with acrylic white paint (22.5 × 23 cm × 35 cm). Animals were habituated to the experimental room for 30 min before the start of the

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experiment. The behavioral test was performed immediately after the injection. Brightness in the experimental room was 100 lux. The sensitization apparatus was cleaned with ethanol (70%) between each animal, to remove possible odor cues.

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Locomotor sensitization was carried out as proposed by Stephen Boehm II and colleagues (2008) (Fig. 1). The baseline activity was registered on the first day of the

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experiment, when the animals received an i.p. injection of saline and were immediately placed in the sensitization context for 15 min. On the second day, animals received the first ethanol injection (2.0 g/kg, i.p.) and were promptly placed in the sensitization context for 15 min. This procedure allowed us to record the acute locomotor effects of ethanol

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administration. From the 2nd to the 11th day of the experiment, mice received saline or ethanol (2.5 g/kg) (i.p.) and were returned directly to their home cages. On the 12th day, the acquisition of locomotor sensitization was registered after ethanol (2 g/kg, i.p.)

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administration and a sequential 15 min of exposure to the sensitization context.

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After the acquisition phase, both groups (saline and ethanol) were randomized into four groups (N = 10–12 per group), described below: •

Saline: Vehicle (Saline_VEH) – animals received saline during the acquisition phase and vehicle for 4 days as treatment; Cannabidiol (Saline_CBD) – animals received saline during the acquisition phase and 2.5 mg/kg CBD for 4 days as treatment; Tetrahydrocannabinol (Saline_THC) – animals received saline during the acquisition phase and 2.5 mg/kg THC for 4 days as treatment; Tetrahydrocannabinol + Cannabidiol

ACCEPTED MANUSCRIPT (Saline_THC + CBD) – animals received saline during the acquisition phase and a mixture of 2.5 mg/kg of THC and CBD (1:1) for 4 days as treatment. •

Ethanol: Vehicle (Ethanol_VEH) – animals received ethanol during the acquisition phase and vehicle for 4 days as treatment; Cannabidiol (Ethanol_CBD) – animals received

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ethanol during the acquisition phase and 2.5 mg/kg CBD for 4 days as treatment;

Tetrahydrocannabinol (Ethanol_THC) – animals received ethanol during the acquisition phase and 2.5 mg/kg THC for 4 days as treatment; Tetrahydrocannabinol + Cannabidiol

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(Ethanol_THC + CBD) – animals received ethanol during the acquisition phase and a mixture of 2.5 mg/kg of THC and CBD (1:1) for 4 days as treatment.

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The VEH group received 5% DMSO, 1% Tween 20 in saline 0.9%. THC was administered, combined with CBD at a ratio of 1:1, at a dose of 2.5 mg/kg. Treatments were performed daily during 4 days after the acquisition phase.

One day after the phytocannabinoids treatment, all experimental groups, including

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saline control groups, were challenged with ethanol. Animals received ethanol injections (2.0 g/kg, i.p.) and were immediately placed in the sensitization context for 15 min, in order to measure the expression of locomotor sensitization.

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All groups had been previously analyzed using the Shapiro-Wilk test and showed

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normal distribution in this evaluation. Analysis of variance tests (ANOVA) were conducted for the experimental analysis. Two-way ANOVA with repeated measures was performed to evaluate the baseline and acquisition of locomotor sensitization. In this test, baseline, 1st, and 12th acquisitions were considered the factor of time (repeated measures), the saline or ethanol was considered factor 1 (sensitization), and the vehicle or phytocanabinoid injection (vehicle, CBD, THC, THC + CBD) was considered factor 2 (treatment). For the expression phase, two-way ANOVA was performed considering two factors (factor 1: saline or ethanol during acquisition phase, and factor 2: vehicle or phytocannabinoid). After all experimental

ACCEPTED MANUSCRIPT analyses, the Newman-Keuls post hoc test was used to verify the specific differences between the groups. The level of significance adopted was p < 0.05 All statistical analyses were made using the software Statistica 12®. Results

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In the baseline day, as expected, no differences were detected by the two-way

ANOVA with repeated measures, since no interaction between the factors ‘sensitization’ and ‘treatment’ were found (F(3,76) = 1.1697, p = 0.32691). The result demonstrates that there was

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no difference in basal locomotor prior to the ethanol treatment.

During the acquisition phase, all ethanol-treated animals presented increased

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locomotion when comparing day 1 and day 12 (factor time: F(2,152) = 167.56, p < 0.0001; factor sensitization: F(1,76) = 278.24, p < 0.0001; interaction: F(6,152) = 2.9396, p = 0.0096). The Newman-Keuls post hoc test detected differences in the locomotor activity between day 1 and day 12 in all ethanol-treated animals (all p values < 0.05), indicating that ethanol

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treatment was able to increase locomotor activity during the acquisition phase. Next, the phytocannabinoid treatment groups were randomly organized in the 12th day. Fig. 2A shows the locomotor activity for each group during the baseline, acquisition day 1, and acquisition

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day 12. A previous dose-response study evaluated the effects of CBD on the expression of

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sensitization induced by ethanol. Doses of 2.5, 5.0, 10, and 50 mg/kg of CBD did not alter the expression of locomotor activity in ethanol-sensitized animals (data not shown). In the expression phase, the groups were analyzed considering two factors: factor 1 –

sensitization, and factor 2 – treatment. The two-way ANOVA detected differences between groups in all factors and their interaction (factor 1: F(1,76) = 20.644, p = 0.00002; factor 2: F(3,76) = 6.7467, p = 0.0004; interaction: F(3,76) = 2.7957, p = 0.04). Our post hoc analyses demonstrated that sensitized THC-treated animals, alone and combined with CBD (Ethanol_THC and Ethanol_THC + CBD), expressed lower locomotor activity when

ACCEPTED MANUSCRIPT compared with the sensitized vehicle and CBD-treated animals (Ethanol_VEH, Ethanol_CBD) (p < 0.05), and similar locomotion of the saline-treated animals in the acquisition phase (p > 0.05), as shown in Fig. 2B. These results suggest that THC inhibits the expression of sensitization to ethanol. Our results also suggest CBD alone had no effect on

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the locomotor activity in this paradigm. Discussion

Our results demonstrated, for the first time, that THC, alone and combined with CBD,

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inhibits the expression of locomotor sensitization induced by ethanol in mice. Sensitization is considered a first step in neuroplasticity associated with drug dependence (Koob & Volkow,

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2016). Some authors have proposed that the sensitization response mimics the transition from use to abuse and dependence (Robinson & Berridge, 2008). The mesolimbic sensitization seems to be important in the maintenance of use and relapse (Steketee & Kalivas, 2011). Therefore, the ECS could be an important target concerning ethanol dependence treatment,

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despite the limited numbers of studies evaluating this hypothesis (Maldonado et al., 2006; Pava & Woodward, 2012; Prud’homme et al., 2015; Sloan, Gowin, Ramchandani, Hurd, & Le Foll, 2017).

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In rodents, a dose of 10 mg/kg of THC promotes an acute hypolocomotor effect

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30 min later (El-Alfy et al., 2010; Long et al., 2010), but this effect does not remain 24 h after the injection. THC does not induce locomotor sensitization in rodents per se (Ginovart et al., 2012). There is no evidence that 2.5 mg/kg THC delivered for 4 days promotes a hypolocomotor persistent effect. The pharmacological manipulation of ECS may affect brain areas related to the development of drug-related sensitization. Based on our findings, it is possible to suggest that THC inhibited the expression of sensitization to ethanol in mice. An alternative explanation for the blockade of ethanol sensitization described here is that withdrawal of THC would reduce locomotion during the test day. However, we did not

ACCEPTED MANUSCRIPT observe any effects on locomotion in the non-sensitized mice treated with THC. In addition, there is no evidence showing that THC withdrawal affects locomotion in rodents 24 h after repeated administration (Aceto, Scates, Lowe, & Martin, 1995; Cook, Lowe, & Martin, 1998). Instead, the majority of the studies that evaluate cannabinoid withdrawal have induced

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it by using a CB1 antagonist (Hutcheson et al., 1998; Lichtman, Fisher, & Martin, 2001; Tai et al., 2015). In the present study, no cannabinoid antagonist was used; there is no evidence that THC in the dose and period of treatment used here induced withdrawal effects in rodents.

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The decreased locomotor activity observed in the THC-treated group may be

explained by a cross-tolerance effect, as previously described in the literature (Dar, 2014;

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Pava & Woodward, 2012; Siemens & Doyle, 1979; Sprague & Craigmill, 1976). Chronic THC can decrease the acute ataxic effect of ethanol, and chronic ethanol can decrease the acute THC hypolocomotor effect (Pava & Woodward, 2012). However, in our study, an opposite effect was found – THC pretreatment, ceased 24 h before the ethanol challenge day,

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attenuates the locomotor activity in ethanol-sensitized animals. Therefore, it is possible that THC attenuates the increased locomotion induced by ethanol by functional tolerance of CB1. Previous treatment with a CB1 agonist reduces ethanol effects in nucleus accumbens (Perra

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et al., 2005). Additionally, chronic ethanol exposures configure CB1 down-regulation in

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brain areas related to motivational behavior (Basavarajappa, 2007), while CB1 up-regulation was verified after ethanol withdrawal in sensitized mice (Coelhoso et al., 2013). Thus, agonists may attenuate the CB1 increase in the ethanol-withdrawal period. In addition, animals injected with saline during the acquisition phase and treated with THC did not show locomotor activity changes when challenged with ethanol. Ultimately, further questions about cross-tolerance should be conducted, considering proper experimental design toward this specific question.

ACCEPTED MANUSCRIPT The relationship between ECS and the development of ethanol dependence is well established (Henderson-Redmond, Guindon, & Morgan, 2016; Maldonado et al., 2006; Oleson & Cheer, 2012). Previous studies focusing on the use of cannabinoid receptor antagonists have shown a disruption of several ethanol-related behaviors (Cippitelli et al.,

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2005; Maccioni et al., 2010; Wang et al., 2003). However, clinical trials have not shown an efficacy of ECS antagonism for alcoholism treatment (George et al., 2010; Soyka et al.,

2008). In contrast, case reports discuss the possible Cannabis use for alcoholism treatment

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(Mikuriya, 2004). These contradictory results encouraged us to evaluate agonists of ECS in the locomotor sensitization paradigm. Interestingly, an observational study has demonstrated

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a potential effect of smoked Cannabis in reducing crack cocaine consumption (Labigalini, Rodrigues, & Da Silveira, 1999). Moreover, evidence suggests that the use of cannabinoids for therapeutic proposes does not elicit problematic consumption from other substances (Labigalini et al., 1999; Prud’homme et al., 2015; Sloan et al., 2017; Walsh et al., 2017).

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Based on these observations, we hypothesized that the activation of ECS could inhibit the ethanol response in an animal model of ethanol sensitization. In conclusion, the present study suggests that THC treatment could be helpful to

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suppress the mechanisms involved in early stages of drug dependence and escalation of drug

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behavior. Further studies should be performed to investigate the neural circuits and mechanisms by which THC suppresses behavioral sensitization induced by ethanol. Funding

This work was supported by the Fundação de Amparo à Pesquisa do Estado de São

Paulo (FAPESP – 2009/16307-2). Acknowledgments We acknowledge Prof. Elisaldo de Araújo Carlini, who kindly provided the cannabinoid substances for this research.

ACCEPTED MANUSCRIPT Conflict of interest

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The authors declare that there were no conflicts of interest.

ACCEPTED MANUSCRIPT Figure legends Fig. 1. Diagram of the experimental design of locomotor sensitization paradigm and cannabinoid treatment.

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Fig. 2. (A) Locomotor activity before (baseline) and during acquisition of ethanol-induced locomotor sensitization (first day – ACQ1 and last day – ACQ12). The data were expressed as mean ± S.E.M. *p < 0.05 in relation to the respective ACQ1, ¥ p < 0.05 in relation to saline groups, and #p < 0.01 in relation to ethanol greater than saline in ACQ12. (B) Locomotor activity after ethanol challenge (expression of locomotor sensitization). Data were expressed as mean ± S.E.M. *p < 0.05 in relation to the Ethanol_VEH group. N = 10–12 per group. VEH = vehicle; CBD = cannabidiol; THC = tetrahydrocannabinol; ACQ = acquisition.

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