Alterations in behavioral flexibility by cannabinoid CB1 receptor agonists and antagonists

Rationale: Cannabinoid CB1 receptors are expressed in the prefrontal cortex, but their role in mediating executive functions such as behavioral flexibility is unclear. Objective: The present study examined the effect of pharmacological activation or blockade of the cannabinoid CB1 receptors on behavioral flexibility using a strategy set-shifting task conducted on a cross maze. Materials and Methods: In experiment 1, rats initially were trained to turn left or right while ignoring the visual cue to obtain a food; on the second test day, rats had to inhibit the previously learned rule and approach the cue to obtain the food. In experiment 2, the order of discrimination training was reversed. Results: Administration of the cannabinoid CB1 receptor agonist HU-210 before the set-shift on day 2 elicited dose-dependent effects on performance. A 20-mu g/kg dose of HU-210 increased perseverative errors, whereas the effects of a lower, 5-mu g/kg dose caused differential effects depending on whether rats were required to shift from a response to a visual-cue discrimination strategy or vice versa. Conversely, administration of a 2-mg/kg, but not a 5-mg/kg dose of the CB1 receptor antagonist AM251 reduced perseverative errors. Conclusions: These data demonstrate a biphasic and dose-sensitive role for the cannabinoid system in behavioral flexibility, which in turn may have clinical implications for the role of the endocannabinoid system in psychiatric disorders where behavioral flexibility is compromised.