The compulsive, habitual behaviors that have been observed in individuals diagnosed with substance use disorders may be due to disruptions in the neural circuits that mediate goal-directed actions. The endocannabinoid system has been shown to play a critical role in habit learning, but the role of this neuromodulatory system in habit expression is unclear. Here, we investigated the role of the endocannabinoid system in established habitual actions using contingency degradation in male C57BL/6 mice. We found that administration of the endocannabinoid transport inhibitor AM404 reduced habitual responding for food and that antagonism of cannabinoid receptor type 1 (CB1), but not transient receptor potential cation subfamily V (TRPV1), receptors produced a similar reduction in habitual responding. Moreover, pharmacological stimulation of CB1 receptors increased habitual responding for food. Co-administration of an enzyme inhibitor that selectively increases the endocannabinoid 2-arachidonoyl glycerol (2-AG) with AM404 partially restored habitual responding for food. Together, these findings demonstrate an important role for the endocannabinoid system in the expression of habits and provide novel insights into potential pharmacological strategies for reducing habitual behaviors in mental disorders.
Bibliographical noteFunding Information:
This study was supported by public health service grants AA012870, DA041480, and DA043443. Additional support was provided by a NARSAD award, the Charles B.G. Murphy Fund, and the State of CT Department of Mental Health Services. Graphical abstract made with Motifolio drawing toolkits (www.motifolio.com). We thank Peter Harris for additional assistance with the graphical abstract.
- 2-arachidonoyl glycerol
- CB1 receptor
- goal-directed behaviors