Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors

Delta-9-tetrahydrocannabinol (THC), the main psychoactive compound of marijuana, induces numerous undesirable effects, including memory impairments, anxiety, and dependence. Conversely, THC also has potentially therapeutic effects, including analgesia, muscle relaxation, and neuroprotection. However, the mechanisms that dissociate these responses are still not known. Using mice lacking the serotonin receptor 5-HT2A, we revealed that the analgesic and amnesic effects of THC are independent of each other: while amnesia induced by THC disappears in the mutant mice, THC can still promote analgesia in these animals. In subsequent molecular studies, we showed that in specific brain regions involved in memory formation, the receptors for THC and the 5-HT2A receptors work together by physically interacting with each other. Experimentally interfering with this interaction prevented the memory deficits induced by THC, but not its analgesic properties. Our results highlight a novel mechanism by which the beneficial analgesic properties of THC can be dissociated from its cognitive side effects

Antidepressant-like and anxiolytic-like effects following activation of the mu-delta opioid receptor heteromer in the nucleus accumbens

Treatment-resistant major depressive disorder remains inadequately treated with currently available antidepressants. Opioid receptors (ORs) are involved in the pathophysiology of depression yet remain an untapped therapeutic intervention. The μ-δ OR heteromer represents a unique signaling complex with distinct properties compared with μ- and δ-OR homomers; however, its role in depression has not been characterized. As there are no ligands exclusively targeting the μ-δ heteromer, we devised a strategy to selectively antagonize the function of the μ-δOR complex using a specific interfering peptide derived from the δOR distal carboxyl tail, a sequence implicated in μ-δOR heteromerization. In vitro studies using a minigene expressing this peptide demonstrated a loss of the unique pharmacological and trafficking properties of δ-agonists at the μ-δ heteromer, with no effect on μ- or δ-OR homomers, and a dissociation of the μ-δOR complex. Intra-accumbens administration of the TAT-conjugated interfering peptide abolished the antidepressant-like and anxiolytic-like actions of the δ-agonist UFP-512 (H-Dmt-Tic-NH-CH(CH2-COOH)-Bid) measured in the forced swim test, novelty-induced hypophagia and elevated plus maze paradigms in rats. UFP-512's antidepressant-like and anxiolytic-like actions were abolished by pretreatment with either μOR or δOR antagonists. Overall, these findings demonstrate that the μ-δ heteromer may be a potential suitable therapeutic target for treatment-resistant depression and anxiety disorders

Bayesian Prediction of Fault-Proneness of Agile-Developed Object-Oriented System

15th International Conference on Enterprise Information Systems, ICEIS 2013, France, 4-7 July 2013Logistic regression (LR) and naïve Bayes (NB) extensively used for prediction of fault-proneness assume linear addition and independence that often cannot hold in practice. Hence, we propose a Bayesian network (BN) model with incorporation of data mining techniques as an integrative approach. Compared with LR and NB, BN provides a flexible modeling framework, thus avoiding the corresponding assumptions. Using the static metrics such as Chidamber and Kemerer’s (C-K) suite and complexity as predictors, the differences in performance between LR, NB and BN models were examined for fault-proneness prediction at the class level in continual releases (five versions) of Rhino, an open-source implementation of JavaScript, developed using the agile process. By cross validation and independent test of continual versions, we conclude that the proposed BN can achieve a better prediction than LR and NB for the agile software due to its flexible modeling framework and incorporation of multiple sophisticated learning algorithms.Department of Computin

Double Fluorescent Knock-In Mice to Investigate Endogenous Mu-Delta Opioid Heteromer Subcellular Distribution

International audienceThe heteromerization of mu (MOP) and delta (DOP) opioid receptors has been extensively studied in heterologous systems. These studies demonstrated significant functional interaction of MOP and DOP evidenced by new pharmacological properties and intracellular signaling in transfected cells co-expressing the receptors. Due to the lack of appropriate tools for receptor visualization, such as specific antibodies, the pharmacological and functional properties of MOP-DOP heteromers in cells naturally expressing these receptors remain poorly understood. To address endogenous MOP-DOP heteromer trafficking and signaling in vivo and in primary neuronal cultures, we generated a double knock-in mouse line expressing functional fluorescent versions of DOP and MOP receptors. This mouse model has successfully been used to map the neuroanatomic distribution of the receptors and to identify brain regions in which the MOP-DOP heteromers are expressed. Here, we describe a method to quantitatively and automatically analyze changes in the subcellular distribution of MOP-DOP heteromers in primary hippocampal culture from this mouse model. This approach provides a unique tool to address specificities of endogenous MOP-DOP heteromer trafficking

Tuned-Affinity Bivalent Ligands for the Characterization of Opioid Receptor Heteromers

[Image: see text] Opioid receptors, including the μ- and δ-opioid receptors (MOR and DOR), are important targets for the treatment of pain. Although there is mounting evidence that these receptors form heteromers, the functional role of the MOR/DOR heteromer remains unresolved. We have designed and synthesized bivalent ligands as tools to elucidate the functional role of the MOR/DOR heteromer. Our ligands (L2 and L4) are comprised of a compound with low affinity at the DOR tethered to a compound with high affinity at the MOR, with the goal of producing ligands with “tuned affinity” at MOR/DOR heteromers as compared to DOR homomers. Here, we show that both L2 and L4 demonstrate enhanced affinity at MOR/DOR heteromers as compared to DOR homomers, thereby providing unique pharmacological tools to dissect the role of the MOR/DOR heteromer in pain