An alternate pathway is possible, whereby 2-AG could be formed by the sequential actions of phospholipase A1 and lysophospholipase C enzymes. The primary route for 2-AG hydrolysis in neurons is afforded by the enzyme monoacylglycerol lipase. Recently, a pharmacologically distinct monoglyceride lipase activity in microglial cells has been reported. In order to understand better the role endocannabinoids might have in CB1-regulated behaviors, a number of pharmacological tools, which target events in endocannabinoid metabolism, have been developed. Anandamide deactivation is prevented by the transport inhibitors AM404, UCM707, OMDM-1 and OMDM-2, and VDM11, and the FAAH-selective anandamide hydrolysis inhibitors URB597and OL-135. 2-AG hydrolysis is blocked by the MGL inhibitor URB602. Pharmacological inhibition of endocannabinoid deactivation has been shown to produce anxiolytic, analgesic, and antidepressant-like effects. The antidepressant-like effects of anandamide deactivation inhibitors will be discussed in detail later in the present article.Limited, but compelling evidence indicates that the endocannabinoid system is altered during stress-related states in both rodents and humans. The chronic mild or chronic unpredictable stress protocol are two related models of depression that produce sequelae reminiscent of those observed in humans afflicted with the disease. These include, among others, a reduction in body weight gain and ingestion of palatable foods. In rats subjected to 3 weeks of CUS, Hill and colleagues found a significant reduction of 2-AG content, as well as levels of CB1 receptor protein in the hippocampus. Stressed animals also showed impairment of reversal learning in the Morris water maze,mobile vertical rack which was corrected by administration of the cannabinoid agonist HU 210, suggesting that this effect was due to decreased endocannabinoid signaling. Similarexperiments in our lab have shown that after 10 weeks of CMS, CB1 receptor mRNA is increased in the prefrontal cortex and decreased in the rat midbrain.
Anandamide levels in the hippocampus, prefrontal cortex, midbrain, thalamus, and striatum were not significantly altered in these studies. 2-AG was similarly unchanged in the hippocampus, prefrontal cortex, midbrain, and striatum, but was reduced in the thalamus of stress-exposed rats.In a study of 20 human subjects, Hungund et al. found an increase in both CB1 receptor mRNA and CB1 receptor-stimulated [35S]GTPγS binding in the dorsolateral prefrontal cortex of subjects with a life-time diagnosis of major depression who committed suicide, compared to normal controls who died by accident or natural causes. Miller and colleagues reported reduced serum 2-AG levels in drug-free females diagnosed with major depression compared to demographically-matched controls, with levels of 2-AG negatively correlated to the duration of the depressive episode. In the latter study, serum anandamide was not associated with major depression, but was negatively correlated with measures of anxiety. The results of these studies of both rodents and humans provide evidence that endocannabinoid signaling is changed – at least in some brain regions and, perhaps, in the periphery – during depression. The alterations observed in the hippocampus, prefrontal cortex, and thalamus are of particular interest, given the likely involvement of these neural structures in the regulation of emotion. In humans, Δ 9 -THC, the natural cannabinoid agonist that is the major psychoactive component of marijuana, produces subjective feelings of relaxation and euphoria, but also promotes anxiety and dysphoria in a context- and dose-dependent manner. Similarly, when administered to rodents, exogenous cannabinoid agonists produce mixed effects on mood related behavior. Low doses of cannabinoid agonists are usually anxiolytic, while moderate to high doses are anxiogenic, but these dose-dependent effects are also contingent on other factors, including strain, age, sex, environment and previous experience with the drug. In mice, Δ 9 -THC produced anxiolytic effects in the light/dark box at a dose of 0.3 mg-kg−1 , i.p., but at 5 mg-kg−1 , i.p., induced anxiogenic effects.
HU 210, a highly potent cannabinoid receptor agonist, at a dose of 0.1 mg-kg−1 , i.p., has also been reported to produce anxiogenic effects in the defensive-withdrawal test after acute administration, but, when this same dose was administered for 10 days it exerted antidepressant-like effects in the novelty suppressed feeding and forced swim tests. Comparable dose- and context-dependent effects on mood-related behavior in the elevated-plus maze and social interaction tests have been noted following treatment with another synthetic cannabinoid agonist, CP 55,940.Data from experiments with CB1 knockout mice suggest that prevention of cannabinoid signaling either increases or has no effect on anxiety- and depression-related behaviors, depending on the conditions of the test. Notably, in these studies, CB1 knockout mice displayed increased anxiety-like behavior compared to wild-type controls under conditions that are stressful to the animals . Additionally, CB1 receptor knockout mice have increased sensitivity to develop anhedonia in the CUS model of depression, and display several other behavioral responses that are similar to the symptoms of melancholic depression . Likewise, several researchers have reported that administration of the CB1 receptor antagonists SR141716 and AM251 produced anxiogenic-like effects. By contrast, few groups reported anxiolytic- and antidepressant-like effects of CB1 receptor antagonists. However, in clinical trials of rimonabant for the treatment of obesity, anxiety and depression are among the most frequent adverse events reported. Together, these studies suggest that CB1 receptor signaling is important for coping behavior, especially during intense or prolonged stress. As described in the previous section, changes in endocannabinoid activity might occur during depression in animal models and, possibly, in humans. Furthermore, direct activation or reduction of CB1 receptor signaling has important effects on mood and stress-related behaviors. These findings raise the intriguing possibility that modulation of endogenous cannabinoid signaling could be a useful target for depression therapy.
Indeed, enhancement of endocannabinoid signaling by pharmacological inhibitors of anandamide degradation has been shown to modulate stress-related behavior in assays for antidepressant-like drug activity – the forced swim test and tail suspension test – and in a rodent model of depression – chronic mild stress . The anandamide transport inhibitor, AM404, at a dose of 5 mg-kg−1 , was reported to decrease immobility time in the rat FST. Likewise, the fatty acid amide hydrolase inhibitor, URB597 , decreased immobility – presumably by increasing swimming behavior – in the rat FST, and also increased struggling behavior in the mouse TST. These effects of URB597 in the FST and TST were sustained after 4 days of repeated dosing. In each of these tests, the antidepressant-like activity of AM404 or URB597 was prevented by preadministration of a selective CB1 receptor antagonist. Given that symptoms of anxiety are often present during depression, it is noteworthy that anandamide deactivation inhibitors also appear to have anxiolytic-like effects. Administration of URB597 decreased isolation-induced ultrasonic vocalizations in rat pups, and increased the time spent in the open arms of the elevated zero and plus mazes. Similarly, AM404 dose-dependently reduced isolation-induced ultrasonic vocalizations in rat pups,vertical grow rack and increased the time spent in the open arms of the elevated plus maze or in the open field during the defensive withdrawal test. However, it appears that the effects of inhibition of anandamide deactivation on stress-coping behaviors are sensitive to environmental conditions. In a recent report, Naidu and colleagues failed to find a reduction of immobility in the TST or an increase in the percentage of time spent in the open arms in the elevated plus maze in FAAH−/− mice or in wild type mice treated with URB597 when conducted under normal laboratory lighting. However, when they adopted lighting conditions similar to those used by Patel and Hillard in the elevated plus maze , or Gobbi and colleagues in the TST , they did observe anxiolytic and antidepressant-like effects of FAAH deletion or inhibition. The reported sensitivity of the anxiolytic- and antidepressant-like effects of URB597 to the lighting conditions is consistent with recent findings in our lab, which show that the anxiolytic-like effect of URB597 in the elevated plus maze varies with experimental context. It is important to note that both the tail suspension and forced swim tests are only assays for antidepressant-like drug activity, not models of depression. In the reports cited above, the experiments were performed in undiseased animals, demonstrating an enhancement of active stress-coping behavior by URB597 or AM404 in a manner similar to standard antidepressant drugs during normal physiological conditions, but under specific environmental contexts. The ability of inhibitors of anandamide degradation to regulate stress-related behaviors under pathophysiological conditions should be more indicative of their efficacy in the treatment of depression. In the CMS model, administration of URB597 for 5 weeks at a dose of 0.3 mg kg−1 reversed chronic stress-induced reductions in sucrose consumption and in body weight gain. In this same study, treatment with URB597 also opposed the increases in CB1 mRNA expression in the prefrontal cortex and midbrain that were observed after 10 weeks of CMS. The magnitude and time course for the antidepressant-like effect of URB597 in this study was comparable to that seen in the treatment of depression with the known antidepressant compound, imipramine. These findings are important because they demonstrate, for the first time, the ability of an anandamide deactivation inhibitor to reverse behavioral symptoms observed in a model of depression with high construct and face validity.
It is important to note though, that alterations in 2-AG are observed both in depressed humans and in animal models of depression, and the significance of these changes are unclear. FAAH inhibitors have proven to be valuable tools for investigating the role of anandamide in mood disorders, and DGL and MGL inhibitors will no doubt further elucidate the interaction between endogenous cannabinoid signaling and stress-related behaviors. For example, the MGL inhibitor, URB602, when injected locally into the dorsolateral periaqueductal grey of the midbrain, produced an enhancement of stress-induced analgesia, demonstrating a role for 2-AG in a specific stress-coping response. Inhibition of MGL has also identified 2-AG asa mediator of synaptic plasticity in the hippocampus, a structure likely involved in the effects of chronic stress and antidepressant treatment on behavior. Unfortunately, URB602 has low potency and cannot be administered systemically to study the effects of global in vivo modulation of 2-AG on stress-coping behavior. As inhibitors of DGL and MGL are developed and tested in behavioral models of emotional reactivity, we will have a better understanding of the functions of both endocannabinoid signaling molecules, perhaps each with distinct roles in stress-coping and mood disorders. This is the first population-based study of HCV screening among US Medicaid patients with and without schizo phrenia. As hypothesized, we found that HCV screening varied over time, across states, and by patient demographic and comorbid characteristics. However, contrary to our hypothesis, screening was higher for patients with schizo phrenia compared to controls. We also found that despite 1998 CDC guidelines to target high-risk populations for annual screening,over 95% of Medicaid patients with schizophrenia who were eligible for screening were not screened for HCV within any clinical setting in 2012. Among patients with schizophrenia, states in the northeast had the highest HCV screening rates and increases in screening from 2002 to 2012. Large state level rises in HCV screening were potentially due to various integration of care initiatives implemented state wide, warranting further examination that is beyond the scope of our exploratory study. For example, by 2012, several northeastern states had active initiatives to reduce Medicaid fragmentation and were among the highest in Medicaid spending per enrollee.There were also state wide integration initiatives aimed to decrease hepatitis transmission. For instance, New York State launched the 2004 Viral Hepatitis Strategic Plan modeled after the HIV/AIDS prevention and care continuum.Similarly in 2008, the Massachusetts’ Office of HIV/AIDS was created to integrate strategies for HIV prevention with HCV programs.Also, Connecticut stakeholders partnered with the CDC to develop the Viral Hepatitis Prevention Plan that was released in 2004.Despite these efforts however, CMS reports that chronic HCV prevalence for Medicaid only enrollees in 2012 was still higher than the national average in Connecticut and New York , but not Massachusetts.It is conceivable that a nationwide comprehensive integrated prevention program could have wide ranging positive impacts on HCV screening and prevention efforts; however, the low rate of HCV screening found during the current study period suggests that national CDC guidelines were insufficient when compared to state-level efforts. In addition to new CDC recommendations for universal HCV screening in adults, expanding statewide HIV prevention policies to include HCV might mitigate traditional clinical challenges in HCV screening among this vulnerable population.