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Emerging data indicate 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. [ABSTRACT FROM AUTHOR]

Individuals with alcohol use disorder exhibit compulsive habitual behaviors that are thought to be, in part, a consequence of chronic and persistent use of alcohol. The endocannabinoid system plays a critical role in habit learning and in ethanol self-administration, but the role of this neuromodulatory system in the expression of habitual alcohol seeking is unknown. Here, we investigated the role of the endocannabinoid system in established alcohol habits using contingency degradation in male C57BL/6 mice. We found that administration of the novel diacyl glycerol lipase inhibitor DO34, which decreases the biosynthesis of the endocannabinoid 2-arachidonoyl glycerol (2-AG), reduced habitual responding for ethanol and ethanol approach behaviors. Moreover, administration of the endocannabinoid transport inhibitor AM404 or the cannabinoid receptor type 1 antagonist AM251 produced similar reductions in habitual responding for ethanol and ethanol approach behaviors. Notably, AM404 was also able to reduce ethanol seeking and consumption in mice that were insensitive to lithium chloride-induced devaluation of ethanol. Conversely, administration of JZL184, a monoacyl glycerol lipase inhibitor that increases levels of 2-AG, increased motivation to respond for ethanol on a progressive ratio schedule of reinforcement. These results demonstrate an important role for endocannabinoid signaling in the motivation to seek ethanol, in ethanol-motivated habits, and suggest that pharmacological manipulations of endocannabinoid signaling could be effective therapeutics for treating alcohol use disorder. [ABSTRACT FROM AUTHOR]

Serotonin (5-hydroxytryptamine; 5-HT) coordinates behavioral responses to stress through a variety of presynaptic and postsynaptic receptors distributed across functionally diverse neuronal networks in the central nervous system. Efferent 5-HT projections from the dorsal raphe nucleus (DRN) to the bed nucleus of the stria terminalis (BNST) are generally thought to enhance anxiety and aversive learning by activating 5-HT 2C receptor (5-HT 2C R) signaling in the BNST, although an opposing role for postsynaptic 5-HT 1A receptors has recently been suggested. In the present study, we sought to delineate a role for postsynaptic 5-HT 1A receptors in the BNST in aversive behaviors using a conditional knockdown of the 5-HT 1A receptor. Both males and females were tested to dissect out sex-specific effects. We found that male mice have significantly reduced fear memory recall relative to female mice and inactivation of 5-HT 1A receptor in the BNST increases contextual fear conditioning in male mice so that they resemble the females. This coincided with an increase in neuronal excitability in males, suggesting that 5-HT 1A receptor deletion may enhance contextual fear recall by disinhibiting fear memory circuits in the BNST. Interestingly, 5-HT 1A receptor knockdown did not significantly alter anxiety-like behavior in male or female mice, which is in agreement with previous findings that anxiety and fear are modulated by dissociable circuits in the BNST. Overall, these results suggest that BNST 5-HT 1A receptors do not significantly alter behavior under basal conditions, but can act as a molecular brake that buffer against excessive activation of aversive circuits in more threatening contexts.