This Resource Is a peer-reviewed article by Gobi et al. published in the 2005-12-13 issue of the Proceedings of the National Academy of Sciences. The authors show, quoting from the Abstract: '[how] URB597, a selective inhibitor of the enzyme fatty-acid amide hydrolase, which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide, exerts potent antidepressant-like effects in the mouse tail-suspension test and the rat forced-swim test... These actions are prevented by the CB1 antagonist rimonabant, are accompanied by increased brain anandamide levels... The findings support a role for anandamide in mood regulation and point to fatty-acid amide hydrolase as a previously uncharacterized target for antidepressant drugs.'

Antidepressant-Like Activity and Modulation of Brain Monoaminergic Transmission by Blockade of Anandamide Hydrolysis

Conditioned gaping produced by high dose Δ9-tetrahydracannabinol: Dysregulation of the hypothalamic endocannabinoid system.

The brain's endocannabinoid system plays a crucial role in reward processes by mediating appetitive learning and encoding the reinforcing properties of substances. Evidence also suggests that endocannabinoids are an important constituent of neuronal substrates involved in emotional responses to stress. Thus, it is critical to understand how the endocannabinoid system and stress may affect reward processes given their importance in substance use disorders. We examined the relationship between factors that regulate endocannabinoid system signaling (i.e., cannabinoid receptor genes and prolonged cannabis exposure) and stress on fMRI BOLD response to reward cues using multivariate statistical analysis. We found that proxies for endocannabinoid system signaling (i.e., endocannabinoid genes and chronic exposure to cannabis) and stress have differential effects on neural response to cannabis cues. Specifically, a single nucleotide polymorphism (SNP) variant in the cannabinoid receptor 1 (CNR1) gene, early life stress, and current perceived stress modulated reward responsivity in long-term, heavy cannabis users, while a variant in the fatty acid amide hydrolase (FAAH) gene and current perceived stress modulated cue-elicited response in non-using controls. These associations were related to distinct neural responses to cannabis-related cues compared to natural reward cues. Understanding the contributions of endocannabinoid system factors and stress that lead to downstream effects on neural mechanisms underlying sensitivity to rewards, such as cannabis, will contribute towards a better understanding of endocannabinoid-targeted therapies as well as individual risks for cannabis use disorder.

The contributions of the endocannabinoid system and stress on the neural processing of reward stimuli.

Cannabis (and its main psychoactive component, THC) is one of the most widely-used drugs in the world, and recent expansion of its legal status has made it available in a variety of formulations and at a potency unrivaled in history. While its medicinal properties are gaining scientific support, so too is its potential to lead to abuse and dependence. Both initiation of cannabis use and frequent cannabis use are most prevalent in adolescence, and compared to adults, cannabis use by adolescents is associated with a greater likelihood of developing cannabis dependence and cannabis use disorder. Given the ethical limitations surrounding research that provides cannabis to non-users or non-adults, animal models of drug use can be valuable tools for the study of causes and consequences related to drug use, as well as allowing for investigating brain mechanisms underlying these factors. However, only recently have models in which animals reliably use cannabis (THC) at levels above its respective vehicle and at levels which produce consistent behavioral and physiological effects become available, and in no case has age-related differences in this use been examined. Thus, one goal of the current study was to directly compare the self-administration of edible THC (a route of administration used by humans and a formulation increasing in popularity) between adolescent and adult mice. Adolescents also appear to be differentially sensitive to various effects of several classes of drugs, and they have been shown to be less sensitive to the aversive effects of cannabis, thereby putting them at greater risk for elevated and continued use. Evidence also suggests that, in addition to the risk associated with adolescent cannabis use, having initial positive subjective experiences resulting from its use is a strong predictor of subsequent cannabis dependence. Thus, the second goal of the current study was to use the place conditioning paradigm to examine the reward- (or aversion-) inducing properties of THC in adolescent and adult C57BL/6J mice, using both the traditional experimenter-administered THC (via injection) as well as edible THC self-administration. Prior to initiating these THC studies, sensitivity of the place conditioning procedure to age-related differences in drug-induced reward was validated using cocaine, yielding locomotor stimulation in both ages and a decreased sensitivity to cocaine’s rewarding properties in adolescent mice. When provided limited access to edible THC dough in doses ranging from 0.0 to 6.0 mg/kg, mice showed a dose-dependent reduction in consumption across access sessions, and this reduction was more rapid in adult mice at the highest doses, suggesting that adolescent mice might have been less sensitive to its aversive properties. These same mice, as well as a separate group of mice receiving injection (also 0.0 to 6.0 mg/kg THC), were given place conditioning sessions, alternating between THC dough and control dough or THC injection and vehicle injection, for 6 days per week and were tested once per week across a total of 3 weeks. Mice conditioned using edible THC showed a neutral response (neither reward nor aversion) at all doses. However, mice conditioned using injected THC showed a conditioned place aversion to the highest dose, which was more pronounced in adult mice. Interestingly, in mice self-administering edible THC, the dose of THC consumed was related to the outcome of place conditioning, such that a conditioned place preference was observed for adult mice which shifted their consumption of 3.0 mg/kg edible THC downward relative to those mice with full consumption of 3.0 mg/kg, and for adolescent mice which had the highest degree of consumption of 6.0 mg/kg edible THC relative to those mice with the lowest consumption of 6.0 mg/kg. Furthermore, initial place preference outcomes at the individual level at test 1 predicted subsequent doses of edible THC consumed, suggesting mice adjust their self-administration of edible THC based on the subjective experience it produces. Besides its impact in place conditioning, THC also had differential effects on body weight and locomotor activity based on age and route of administration. Collectively, this project demonstrates that adolescent mice are less sensitive to the hedonic properties of both cocaine and THC, and that differences in edible THC self-administration between ages, and between individuals within an age, are likely related the subjective experience of its rewarding and aversive properties.

Determination of the rewarding capacity of edible and injected ∆9-tetrahydrocannabinol in adolescent and adult mice

Cannabinoid receptor 1 (CB1R) has been one of the major targets in medication development for treating substance use disorders (SUDs). Early studies indicated that rimonabant, a selective CB1R antagonist with an inverse agonist profile, was highly promising as a therapeutic for SUDs. However, its adverse side effects, such as depression and suicidality, led to its withdrawal from clinical trials worldwide in 2008. Consequently, much research interest shifted to developing neutral CB1R antagonists based on the recognition that rimonabant’s side effects may be related to its inverse agonist profile. In this article, we first review rimonabant’s research background as a potential pharmacotherapy for SUDs. Then, we discuss the possible mechanisms underlying its therapeutic anti-addictive effects versus its adverse effects. Lastly, we discuss the rationale for developing neutral CB1R antagonists as potential treatments for SUDs, the supporting evidence in recent research, and the challenges of this strategy. We conclude that developing neutral CB1R antagonists without inverse agonist profile may represent attractive strategies for the treatment of SUDs.

/pdf/neutral-cb1-receptor-antagonists-as-pharmacotherapies-for-35ok1u1n.pdf

Neutral CB1 Receptor Antagonists as Pharmacotherapies for Substance Use Disorders: Rationale, Evidence, and Challenge

Unlike other drugs of abuse, Δ9-tetrahydrocanabinol (THC) is generally aversive in rodent conditioned place preference models, but little is known about how stress may modify THC affective properties. We evaluate the potential of footshock stress to enhance the rewarding effects of THC and the fatty acid amide hydrolase inhibitor, URB597, as it has been shown to enhance their anxiolytic effects. The effect of footshock stress 24 h prior to each conditioning trial on the rewarding/aversive effects of THC (1, 0.1, 0.5 mg/kg, ip) and URB597 (0.3 mg/kg, ip) was evaluated in an unbiased place conditioning procedure in rats. Subsequently, the same stressor was given immediately prior to conditioning with THC (1 and 0.1 mg/kg). Locomotor activity was also measured during conditioning. A dose of 1 mg/kg THC, but not 0.1–0.5 mg/kg, produced a conditioned place aversion (CPA) that was not modified by footshock delivered 24 h prior to conditioning trials; however, footshock delivered immediately prior to conditioning trials prevented that CPA. Lower doses of THC and URB597 produced no place conditioning regardless of footshock conditions. A dose of 1 mg/kg THC produced locomotor suppression during conditioning trials that was prevented by footshock delivered 24 h before and reversed to locomotor activation by footshock delivered immediately before conditioning. Unlike the effect of footshock on THC- and URB597-induced anxiolytic effects, footshock does not promote THC or URB597-induced reward in a conditioned place preference paradigm. However, footshock stress reverses the sedative effects of 1 mg/kg THC.

Effect of footshock stress on place conditioning produced by Δ9-tetrahydrocannabinol and the fatty acid amide hydrolase (FAAH) inhibitor, URB597, in Sprague-Dawley rats

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Effect of footshock stress on place conditioning produced by Δ9-tetrahydrocannabinol and the fatty acid amide hydrolase (FAAH) inhibitor, URB597, in Sprague-Dawley rats