Inhibition of monoacylglycerol lipase reduces nicotine withdrawal

Background and Purpose

Abrupt discontinuation of nicotine, the main psychoactive component in tobacco, induces a withdrawal syndrome in nicotine-dependent animals, consisting of somatic and affective signs, avoidance of which contributes to drug maintenance. While blockade of fatty acid amide hydrolase, the primary catabolic enzyme of the endocannabinoid arachidonoylethanolamine (anandamide), exacerbates withdrawal responses in nicotine-dependent mice, the role of monoacylglycerol lipase (MAGL), the main hydrolytic enzyme of a second endocannabinoid 2-arachidonylglycerol (2-AG), in nicotine withdrawal remains unexplored.

Experimental Approach

To evaluate the role of MAGL enzyme inhibition in nicotine withdrawal, we initially performed a genetic correlation approach using the BXD recombinant inbred mouse panel. We then assessed nicotine withdrawal intensity in the mouse after treatment with the selective MAGL inhibitor, JZL184, and after genetic deletion of the enzyme. Lastly, we assessed the association between genotypes and smoking withdrawal phenotypes in two human data sets.

Key Results

BXD mice displayed significant positive correlations between basal MAGL mRNA expression and nicotine withdrawal responses, consistent with the idea that increased 2-AG brain levels may attenuate withdrawal responses. Strikingly, the MAGL inhibitor, JZL184, dose-dependently reduced somatic and aversive withdrawal signs, which was blocked by rimonabant, indicating a CB₁ receptor-dependent mechanism. MAGL-knockout mice also showed attenuated nicotine withdrawal. Lastly, genetic analyses in humans revealed associations of the MAGL gene with smoking withdrawal in humans.

Conclusions and Implications

Overall, our findings suggest that MAGL inhibition maybe a promising target for treatment of nicotine dependence.     

Tuberculosis despite latent infection screening and treatment in patients receiving TNF inhibitor therapy

Clinical Rheumatology - Although latent tuberculosis infection (LTBI) treatment is given before anti-tumor necrosis factor (TNF) treatment, tuberculosis (TB) still develops in these patients and...     

激素敏感脂酶基因高度表达对泡沫细胞形成的作用

中国仓鼠卵细胞在给予β－ＶＬＤＬ后，细胞内蓄积胆固醇酯，形成泡沫样细胞。以腺病毒基因转移方法书激素敏感脂酶基因转染到中国仓鼠卵细胞中，得到了来自激素敏感脂酶的胆固醇酯水解活性高度表达，此时，β－ＶＬＤＬ导致的胆固醇酯蓄积作用被阻断，提示增加胆固醇酯水解可以防止泡沫细胞形成。     

Mood and metabolic consequences of sleep deprivation as a potential endophenotype’ in bipolar disorder

It has been commonly recognized that circadian rhythm and sleep/wake cycle are causally involved in bipolar disorder. There has been a paucity of systematic research considering the relations between sleep and mood states in bipolar disorder. The current study examines the possible influences of sleep deprivation on mood states and endocrine functions among first-degree relatives of patients with bipolar disorder and healthy controls. Blood samples were taken at two time points in the consecutive mornings at predeprivation and postdeprivation periods. Participants simultaneously completed the Profiles of Mood States at two time points after giving blood samples. Plasma T3 and TSH levels increased after total sleep deprivation in both groups. Sleep deprivation induced TSH levels were reversely associated with depression–dejection among healthy controls. A paradoxical effect was detected for only the first-degree relatives of the patients that changes in plasma cortisol levels negatively linked to depression–dejection and anger–hostility scores after total sleep deprivation. Plasma DHEA levels became correlated with vigor-activity scores after sleep deprivation among first-degree relatives of bipolar patients. On the contrary, significant associations of depression–dejection, anger–hostility, and confusion–bewilderment with the baseline plasma DHEA levels became statistically trivial in the postdeprivation period. Findings suggested that first-degree relatives of patients with bipolar disorder had completely distinct characteristics with respect to sleep deprivation induced responses in terms of associations between endocrine functions and mood states as compared to individuals whose relatives had no psychiatric problems. Considering the relationships between endocrine functions and mood states among relatives of the patients, it appears like sleep deprivation changes the receptor sensitivity which probably plays a pivotal role on mood outcomes among the first-degree relatives of patients with bipolar disorder.     

Roles of PINK1, mTORC2, and mitochondria in preserving brain tumor-forming stem cells in a noncanonical Notch signaling pathway

The self-renewal versus differentiation choice of Drosophila and mammalian neural stem cells (NSCs) requires Notch (N) signaling. How N regulates NSC behavior is not well understood. Here we show that canonical N signaling cooperates with a noncanonical N signaling pathway to mediate N-directed NSC regulation. In the noncanonical pathway, N interacts with PTEN-induced kinase 1 (PINK1) to influence mitochondrial function, activating mechanistic target of rapamycin complex 2 (mTORC2)/AKT signaling. Importantly, attenuating noncanonical N signaling preferentially impaired the maintenance of Drosophila and human cancer stem cell-like tumor-forming cells. Our results emphasize the importance of mitochondria to N and NSC biology, with important implications for diseases associated with aberrant N signaling.     

JuSpace: A tool for spatial correlation analyses of magnetic resonance imaging data with nuclear imaging derived neurotransmitter maps

Recent studies have shown that drug‐induced spatial alteration patterns in resting state functional activity as measured using magnetic resonance imaging (rsfMRI) are associated with the distribution of specific receptor systems targeted by respective compounds. Based on this approach, we introduce a toolbox (JuSpace) allowing for cross‐modal correlation of MRI‐based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, and GABAergic (gamma‐aminobutric acid) neurotransmission. We apply JuSpace to two datasets covering Parkinson''s disease patients (PD) and risperidone‐induced changes in rsfMRI and cerebral blood flow (CBF). Consistently with the predominant neurodegeneration of dopaminergic and serotonergic system in PD, we find significant spatial associations between rsfMRI activity alterations in PD and dopaminergic (D2) and serotonergic systems (5‐HT1b). Risperidone induced CBF alterations were correlated with its main targets in serotonergic and dopaminergic systems. JuSpace provides a biologically meaningful framework for linking neuroimaging to underlying neurotransmitter information.     

Neuroanatomical associations of the Edinburgh cognitive and Behavioural ALS screen (ECAS)

Brain Imaging and Behavior - Cognitive impairment is now recognized in a subset of patients with amyotrophic lateral sclerosis (ALS). The objective of the study was to identify group differences...     

Primary dural lymphoma: A novel concept of heterogeneous disease

Spinal primary dural lymphoma (PDL) is uncommon with a total of 37 previous well‐documented cases reported, including one diagnosed in the authors' institution. More recently we encountered an additional case of spinal PDL that, similarly to our previous case, was grade 1–2 follicular B‐cell PDL. Our two cases were diagnosed over a 3‐year interval in a 72‐year‐old female and a 74‐year‐old male, respectively. An exhaustive literature review on PDL was performed consequently to reveal that: (i) spinal and cerebral sites of involvement by PDL are constantly mutually exclusive; and (ii) unlike cerebral PDL, which is usually of marginal zone B‐cell type, only two of the 38 cases of spinal PDL were diagnosed as such, diffuse large B‐cell lymphoma being the most commonly encountered type in the spine. This divergence infers that, in contrast to the prevailing concept that PDL is a unique disease group, PDL appears to be rather heterogeneous with a difference in predilection of lymphoma type for the anatomical site of dural involvement. Such a site‐specific lymphoma‐type predilection phenomenon, well‐recognized in other organ systems, has not been acknowledged in PDL. This report brings new insights into PDL, and may contribute to a better understanding of nervous system pathophysiology and lymphoma classification.