Cannabidiol but not cannabidiolic acid reduces behavioural sensitisation to methamphetamine in rats, at pharmacologically effective doses

Abstract

Rationale: Cannabidiol (CBD) and cannabidiolic acid (CBDA) are non-psychoactive components of the cannabis plant. CBD has been well characterised to have anxiolytic and anticonvulsant activity, whereas the behavioural effects of CBDA are less clear. Preclinical and clinical data suggests that CBD has antipsychotic properties and reduces methamphetamine self-administration in rats. An animal model that is commonly used to mimic the neurochemical changes underlying psychosis and drug dependence is methamphetamine (METH) sensitisation, where repeated administration of the psychostimulant progressively increases the locomotor effects of METH.

Objective: The aim of this study was to determine whether CBD or CBDA attenuate METH-induced sensitisation of locomotor hyperactivity in rats.

Methods: Eighty-six male Sprague Dawley rats underwent METH sensitisation protocol where they were subjected to daily METH (1 mg/kg on days 2 and 8, 5 mg/kg on days 3-7; i.p.) injections for 7 days. After 21 days of withdrawal, rats were given a prior injection of CBD (0, 40 and 80 mg/kg; i.p.) or CBDA (0, 0.1, 10 and 1000 µg/kg; i.p.) and challenged with acute METH (1 mg/kg; i.p.). Locomotor activity was then measured for 60 min.

Results: Rats displayed robust METH sensitisation as evidenced by increased locomotor activity to METH challenge in METH-pretreated versus SAL-pretreated rats. CBD (40 and 80 mg/kg) reduced METH-induced sensitisation. There was no effect of any CBDA doses on METH sensitisation or acute METH-induced hyperactivity.

Conclusion: These results demonstrate that CBD, but not CBDA, reduces METH sensitisation of locomotor activity in rats at pharmacologically effective doses, thus reinforcing evidence that CBD has anti-addiction and antipsychotic properties.

Keywords: Cannabidiol; Cannabidiolic acid; Locomotor activity; Methamphetamine; Psychosis; Sensitisation.

Fig. 1

Schematic of experimental procedure and timeline for METH sensitisation protocol. Experiment 1 tested CBD treatment; experiment 2 tested CBDA treatment. Abbreviations: METH, methamphetamine; SAL, saline; VEH, vehicle; CBD, cannabidiol; CBDA, cannabidiolic acid; Loco, locomotor activity

Fig. 2

Locomotor sensitisation to repeated METH administration. Both figures represent comparisons between saline-pretreated rats (SM) and METH-pretreated rats (MM) after a METH challenge injection. a Experiment 1 (CBD): #p < 0.001 when comparing MM with SM group on challenge day and day 8; *p < 0.001 when comparing the challenge day with both day 2 and day 8 in both groups. b Experiment 2 (CBDA): ##p < 0.001 comparing MM rats with SM on challenge day, and #p = 0.043 on day 8; *p < 0.001 when comparing the challenge day with both day 2 and day 8 within the MM rats. (Challenge day, i.e. METH challenge 30 min after treatment with VEH)

Fig. 3

Mean (± SEM) of locomotor activity after CBD or vehicle administration on METH challenge days and number of photocell beam breaks per each 10-min bins following CBD or vehicle pretreatment. a **p < 0.001 when compared to rats treated with VEH in the METH-pretreated (MM) group, #p < 0.001 when compared within VEH treatment of METH-pretreated rats (MM) to saline control (SM) on challenge day, *p = 0.02 when compared to rats treated with VEH in the saline control (SM) group. b Time-course of locomotor activity within saline-pretreated rats after METH challenge injections (SM). *p < 0.05, significant difference between CBD40 and VEH/CBD80. c Time-course of locomotor activity within METH-pretreated rats after METH challenge injections.*p = 0.05, significant difference between CBD80 and VEH at 11–20 min time bins; **p < 0.05, significant difference of CBD40 and CBD80 from VEH at 51–60 min time bins; ^#p < 0.05, significant difference between 51–60 time bins and 0–10, 11–20 and 21–30 min time bins within CBD40 and CBD80

Fig. 4

Mean (± SEM) of locomotor activity after CBDA or vehicle administration on METH challenge days and number of photocell beam breaks per each 5-min bins following pretreatment with VEH, CBDA0.1, CBDA10 and CBDA1000 for METH-pretreated group (MM) and its control (SM). a #p < 0.001 when compared the VEH from METH-pretreated rats (MM) to saline control (SM) on challenge day. b and c revealed no significant effect of CBDA on beam break activity over the 60-min test session in both SM (p =0.619) and MM (p =0.415) groups