Rationale
Cannabis users display a constellation of withdrawal symptoms upon drug discontinuation, including sleep disturbances, irritability,
and possibly memory deficits. In cannabinoid-dependent rodents, the CB1 antagonist rimonabant precipitates somatic withdrawal and enhances forskolin-stimulated adenylyl cyclase activity in cerebellum,
an effect opposite that of acutely administered ∆9-tetrahydrocannabinol (THC), the primary constituent in cannabis.
Objectives
Here, we tested whether THC-dependent mice undergoing rimonabant-precipitated withdrawal display short-term spatial memory
deficits, as assessed in the Morris water maze. We also evaluated whether rimonabant would precipitate adenylyl cyclase superactivation
in hippocampal and cerebellar tissue from THC-dependent mice.
Results
Rimonabant significantly impaired spatial memory of THC-dependent mice at lower doses than those necessary to precipitate
somatic withdrawal behavior. In contrast, maze performance was near perfect in the cued task, suggesting sensorimotor function
and motivational factors were unperturbed by the withdrawal state. Finally, rimonabant increased adenylyl cyclase activity
in cerebellar, but not in hippocampal, membranes.
Conclusions
The memory disruptive effects of THC undergo tolerance following repeated dosing, while the withdrawal state leads to a rebound
deficit in memory. These results establish spatial memory impairment as a particularly sensitive component of cannabinoid
withdrawal, an effect that may be mediated through compensatory changes in the cerebellum.
Keywords Abstinence – Adenylate cyclase – Cannabinoids – Cerebellum – Hippocampus – Learning and memory – Water maze – Withdrawal – Working memory
Funding sources: This research was supported by the National Institute on Drug Abuse (R01DA015683, R01DA02396, R01DA003672,
R01DA014227, P01DA009789, and T32DA07027).