Gianessi_2021_Eur.J.Neurosci__

Emerging data indicates that endocannabinoid signaling is critical to the formation of habitual behavior. Previous work demonstrated that antagonism of cannabinoid receptor type 1 (CB1R) with AM251 during operant training impairs habit formation, but it is not known if this behavioral effect is specific to disrupted signaling of the endocannabinoid ligands anandamide or 2-arachidonoyl glycerol (2-AG). Here, we used selective pharmacological compounds during operant training to determine the impact of fatty acid amide hydrolase (FAAH) inhibition to increase anandamide (and other n-acylethanolamines) or monoacylglycerol lipase (MAGL) inhibition to increase 2-AG levels on the formation of habitual behaviors in mice using a food-reinforced contingency degradation procedure. We found, contrary to our hypothesis, that inhibition of FAAH and of MAGL disrupted the formation of habits. Next, AM251 was administered during training to verify that impaired habit formation could be assessed using contingency degradation. AM251-exposed mice responded at lower rates during training and at higher rates in the test. To understand the inconsistency with published data, we performed a proof-of-principle dose-response experiment to compare AM251 in our vehicle-solution to the published vehicle-suspension on response rates. We found consistent reductions in response rate with increasing doses of AM251 in solution and an inconsistent dose-response relationship with AM251 in suspension. Together, our data suggest that further characterization of the role of CB1R signaling in the formation of habitual responding is warranted and that augmenting endocannabinoids may have clinical utility for prophylactically preventing aberrant habit formation such as that hypothesized to occur in substance use disorders.