One hallmark of addiction is compulsive drug use despite the desire to quit. Compulsive, habitual drug seeking and drug taking may be due to disruptions in the neural circuits that mediate goal-directed actions. Given that specific aspects of deficient goal-directed behavior has been observed to predict the likelihood of relapse to drug use, understanding the neural mechanisms underlying the formation and expression of habitual behaviors may offer novel insights into the pathophysiology of substance use disorders, and may offer opportunities for novel treatments. In Chapter 1, I discuss theoretical aspects of habitual behavior in humans and animal models, and summarize relevant studies on the neurobiology and neurocircuitry associated with habits. An influential study demonstrated the necessity of the endocannabinoid system to habitual behaviors, because transgenic cannabinoid receptor type 1 (CB 1) knockout mice do not exhibit habitual behavior. The endocannabinoid system may be essential for the formation of habitual behaviors, the expression of habitual behaviors, or both, and importantly it may provide effective targets for treating excessive habitual drug seeking behavior observed in alcohol use disorder.
Here, we investigated the contributions of the CB 1 receptor and other components of the endocannabinoid system to the expression of habitual behavior for food and for alcohol. We observed a reduction in habitual food and alcohol seeking responses with administration of a CB 1 receptor antagonist, and with administration of a drug that inhibits the putative endocannabinoid transporter, AM404. We suggest that the endocannabinoid transporter is essential for the release and the reuptake of endocannabinoids. Consistent with this hypothesis, pharmacologically increasing the endocannabinoid 2-arachidonoyl glycerol (2-AG) prior to administration of AM404 restored habitual responding for food. Moreover, the novel diacyl glycerol lipase inhibitor DO34, which reduces the synthesis of 2-AG, produced similar reductions in habitual responding for alcohol suggesting that AM404-mediated reductions in habitual responding are due to decreased release of 2-AG. Notably, AM404 was able to reduce alcohol seeking and consumption in mice that were insensitive to lithium chloride-induced devaluation of alcohol, which bolsters the clinical relevance of these findings. Conversely, administration of JZL184, a monoacyl glycerol lipase inhibitor that increases synaptic levels of 2-AG, increased motivation to respond for alcohol on a progressive ratio schedule of reinforcement. These results demonstrate a critical role for endocannabinoid signaling in the motivation to seek alcohol, as well as for the expression of appetitive habitual behaviors.
While previous studies have established the necessity of the CB 1 receptor for the formation of habits, it is currently unknown which endocannabinoid ligand contributes the required CB 1 receptor signaling. The two endocannabinoid ligands that are most studied are anandamide and 2-AG. In Chapter 4, we examine whether increasing 2-AG or anandamide selectively during habit training would accelerate the formation of habitual responding for food. We hypothesized that increasing endocannabinoid tone would make habits form more quickly, but instead we observed preserved goal-directed behavior. We additionally observed preserved goal-directed behavior when a CB 1 receptor antagonist was administered during habit learning. These results suggest that dysregulation of CB 1 receptor signaling is sufficient to prevent the formation of habits.
In summary, these data presented in this dissertation provide novel insight regarding the contributions of the endocannabinoid system to the formation and expression of habitual responding for food and for alcohol. These results suggest that phafinacological manipulations of endocannabinoid signaling could be effective therapeutics for treating alcohol use disorder and perhaps other psychiatric conditions that are associated with compulsive habitual actions.
|Advisor:||Taylor, Jane Rebecca|
|School Location:||United States -- Connecticut|
|Source:||DAI-B 80/07(E), Dissertation Abstracts International|
|Keywords:||Addiction, Alcohol, Contingency Degradation, Endocannabinoid, Habit, Mice|
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