The genetic versus pharmacological invalidation of the cannabionoid CB1 receptor results in differential effects on ‘non-associative’ memory and forebrain monoamine concentrations in mice

Gunnar Thiemann1, Catherine Ledent2, Areles Molleman1, Ruediger Hasenoehrl1. 1University of Hertfordshire, Hatfield, Herts., United Kingdom, 2Universite Libre de Bruxelles, Brussels, Belgium.

The endocannabinoid CB1 receptor has been implicated in the inhibitory control of associative processing. Accordingly, cannabinoid receptor agonists tend to impair learning, whereas cannabinoid receptor antagonists enhance cognition (Castellano et al., 2003). Almost all experiments aimed at investigating the role of (endo)cannabinoids in mnemonic functions were conducted with animal models of ‘associative’ learning, i.e., examining cannabinoid effects on acquisition, retention and extinction of tasks with explicitly defined stimulus-response contingencies. The role of endocannabinoids in ‘non-associative’ learning remains to be elucidated. Here, we examined the effects of a genetic versus pharmacological blockade of the CB1 cannabinoid receptor in terms of acquisition and retention of a habituation task and changes in cerebral monoamines in mice (3-month-old male and female CB1 receptor-knockout (CB1R-/-) mice and male wild-type (CB1R+/+) controls, weighing 25-35g). Habituation was defined by a decrease in vertical activity (rearing) in an unfamiliar open field over time. Data were analyzed pair-wise with Mann-Whitney U-tests. The experiments were approved by the UK Home Office.

The results can be summarized as follows: (i.) The chronic (CB1R-/-) and acute invalidation of the CB1 receptor with SR141716A (SR; 3mg/kg IP) resulted in enhanced behavioural habituation during the first exposure to the open field, indicative of improved acquisition of the task [number of rearing: controls, 10.84±1.16; CB1R-/-, 4.80±0.96 (p≤0.03); SR, 6.04±1.16 (p≤0.05]; (ii.) CB1R-/- mice, but not SR-treated animals, showed enhanced long-term retention of the habituation task when they were tested 48 hrs [% of controls: CB1R-/-, -30.49±1.77 (p=0.01); SR, -2.43±4.56 (n.s.)] and 1 week subsequent to the first exposure to the open field [% of controls: CB1R-/-, -20.51±3.04 (p=0.04); SR, +3.72±3.54 (n.s.)], respectively; (iii.) The facilitation of long-term habituation in CB1R-/- mice was accompanied by decreased 5-HT concentrations [controls, 1.01±0.17ng/mg; CB1R-/-, 0.68±0.14ng/mg (p=0.05)] and increased 5-HT turnover rates in hippocampus [5-HIAA/5-HT: controls, 1.35±0.10; CB1R-/-, 2.01±0.11 (p=0.046)]; (iv.) SR-treated animals displayed ‘antidepressant-like’ alterations of cerebral monoamines, i.e., most monoamine parameters were increased, especially in dorsal striatum and hippocampus.

The present findings show that a genetic invalidation of the CB1 receptor can cause a facilitation of behavioural habituation, which represents a form of ‘non-associative’ learning. Thus, it is feasible that under normal conditions the cannabinoid system may have a paramount role in facilitating extinction and/or forgetting processes (Marsicano et al., 2002). The data also support the assumption of a SR (rimonabant)-sensitive receptive site that is different from the ‘classical’ CB1 receptor and that might be instrumental for the inhibitory control of the acquisition but not retention of non-associative learning tasks

Castellano C. et al. (2003) Curr Drug Targets CNS Neurol Disord 2:389–402

Marsicano G. et al. (2002) Nature 418:530-534