Bidirectional regulation of novelty-induced behavioral inhibition by the endocannabinoid system

The balance between novelty seeking and safety assessment is a key feature of adaptive behavior, and alterations in this equilibrium can lead to neuropsychiatric disorders. Excessive novelty seeking is a main form of pathological impulsivity, which is among the symptoms that define attention deficit hyperactivity disorder (ADHD). There is growing evidence that the endocannabinoid system (ECS) plays an important role in the control of this balance, but little is known about the underlying neuronal mechanisms. In this study, we aimed at dissecting the neurocircuits under the control of the ECS in novelty-induced behavioral inhibition. To reach this goal, we combined pharmacological, genetic and behavioral tools. Mice were repeatedly exposed to novel palatable food or a novel object and their responses to these stimuli were analyzed over several days. The results confirmed that systemic blockade of cannabinoid type-1 (CB(1)) receptors strongly decreases palatable food intake, but its impact onto the response to novelty is less pronounced. Using conditional mutant mice lacking the CB(1) receptor either in cortical glutamatergic or in GABAergic neurons, we found that the ECS exerts opposite functions on the balance between novelty seeking and behavioral inhibition. Whereas CB(1) receptors expressed in cortical glutamatergic neurons favors novelty seeking, CB(1)-dependent control of inhibitory GABAergic neurons promotes behavioral inhibition. These data show a tightly regulated influence of the ECS on impulsive behaviors and suggest the involvement of endocannabinoid signaling in the pathophysiological modulation of ADHD and related disorders.