Bi‐directional modulation of food habit expression by the endocannabinoid system

Abstract

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.

Endocannabinoid contributions to alcohol habits and motivation: Relevance to treatment

“…AM404 (R&D Systems [Minneapolis, MN] and Fisher Scientific [Waltham, MA]) was administered at 10 mg/kg, a dose reported to decrease presumably goal‐directed ethanol self‐administration . AM251 (Fisher Scientific) was administered at 1 mg/kg based on our previous work demonstrating reduced habitual food seeking at this dose . JZL184 (Sigma‐Aldrich and Cayman Chemical [Ann Arbor, MI]) was administered at 2, 8, and 18 mg/kg based on previously reported effects on habitual food seeking (2 and 18 mg/kg) and anxiety‐like behavior (8 mg/kg) .…”

“…AM251 (Fisher Scientific) was administered at 1 mg/kg based on our previous work demonstrating reduced habitual food seeking at this dose . JZL184 (Sigma‐Aldrich and Cayman Chemical [Ann Arbor, MI]) was administered at 2, 8, and 18 mg/kg based on previously reported effects on habitual food seeking (2 and 18 mg/kg) and anxiety‐like behavior (8 mg/kg) . URB597 (Sigma‐Aldrich) was administered at 0.5 mg/kg …”

“…Once mice achieved the performance criterion on the FR1 schedule, VI training began. VI schedules were determined by randomly selecting the duration of the interval from an exponential array that had an average of 30 seconds for the VI30 schedule and an average of 60 seconds for the VI60 schedule. The first active nosepoke response made after the interval elapsed resulted in delivery of the dipper full of ethanol solution.…”

“…Contingency degradation tests were conducted as previously described . Briefly, these sessions appeared similar to the operant training session, but dippers of ethanol were noncontingently delivered.…”

“…We applied a novel statistical technique for classifying individual animals' pattern of responding as goal‐directed or habitual . Response rate for each mouse during the contingency degradation session was compared with that mouse's response rate for all previous VI60 sessions using a generalized linear model (GLM) with a Poisson distribution, which is the most appropriate distribution for count data.…”