The effects of cannabidiol on cue- and stress-induced reinstatement of
cocaine seeking behaviour are reverted by the CB1 receptor antagonist
AM4113
Abstract
BACKGROUND AND PURPOSE: Pharmacological treatments are unavailable to
patients with cocaine use disorders. Efforts to develop
pharmacotherapies have led to the study of cannabidiol, a constituent of
the C. sativa plant. However, the specific effects and mechanisms of
action of cannabidiol in a rodent model of extinction-based abstinence
and drug seeking relapse remain unclear. EXPERIMENTAL APPROACH: In this
study, cannabidiol was provided during extinction training to male CD-1
mice trained to self-administer cocaine. We evaluated the reinstatement
of cocaine seeking induced by cues, stress, and drug priming. To
ascertain the participation of CB1 receptors in these behavioural
changes, we administered the neutral CB1 antagonist AM4113 before each
reinstatement session. KEY RESULTS The results document that cannabidiol
did not modulate extinction learning. After cannabidiol treatment,
increased levels of CB1 receptor protein were found in the prelimbic and
orbitofrontal parts of the prefrontal cortex, as well as in the ventral
striatum; an effect paralleled by a reduction of ∆FosB accumulation and
increased GluR2 AMPA receptor subunits. Furthermore, cue-induced
reinstatement of cocaine seeking was prevented in cannabidiol-treated
mice. Unexpectedly, cannabidiol facilitated stress-induced reinstatement
of cocaine-maintained responding. Cocaine-primed reinstatement remained
unaltered by cannabidiol. Both, the blockade of cue-induced
reinstatement and the facilitation of stress-induced reinstatement were
abolished by AM4113 in cannabidiol-treated mice. CONCLUSION AND
IMPLICATIONS: Our results reveal a series of complex CB1-related changes
induced by cannabidiol with opposite implications for the reinstatement
of cocaine seeking behaviour that may limit therapeutic opportunities.