Enhanced self-administration of the CB1 receptor agonist WIN55,212-2 in olfactory bulbectomized rats: evaluation of possible serotonergic and dopaminergic underlying mechanisms

Depression has been associated with drug consumption, including heavy or problematic cannabis use. According to an animal model of depression and substance use disorder comorbidity, we combined the olfactory bulbectomy (OBX) model of depression with intravenous drug self-administration procedure to verify whether depressive-like rats displayed altered voluntary intake of the CB1 receptor agonist WIN55,212-2 (WIN, 12.5 μg/kg/infusion). To this aim, olfactory-bulbectomized (OBX) and sham-operated (SHAM) Lister Hooded rats were allowed to self-administer WIN by lever-pressing under a continuous [fixed ratio 1 (FR-1)] schedule of reinforcement in 2 h daily sessions. Data showed that both OBX and SHAM rats developed stable WIN intake; yet, responses in OBX were constantly higher than in SHAM rats soon after the first week of training. In addition, OBX rats took significantly longer to extinguish the drug-seeking behavior after vehicle substitution. Acute pre-treatment with serotonin 5HT1B receptor agonist, CGS-12066B (2.5-10 mg/kg), did not significantly modify WIN intake in OBX and SHAM Lister Hooded rats. Furthermore, acute pre-treatment with CGS-12066B (10 and 15 mg/kg) did not alter responses in parallel groups of OBX and SHAM Sprague Dawley rats self-administering methamphetamine under higher (FR-2) reinforcement schedule with nose-poking as operandum. Finally, dopamine levels in the nucleus accumbens (NAc) of OBX rats did not increase in response to a WIN challenge, as in SHAM rats, indicating a dopaminergic dysfunction in bulbectomized rats. Altogether, our findings suggest that a depressive-like state may alter cannabinoid CB1 receptor agonist-induced brain reward function and that a dopaminergic rather than a 5-HT1B mechanism is likely to underlie enhanced WIN self-administration in OBX rats

Toxicity of aflatoxin B1 towards the vitamin D receptor (VDR)

This research describes an unexpected toxicity of the aflatoxin B1 towards the vitamin D receptors. Rickets is a childhood disease, and calcium deficiency is the aetiological cause in Africa, being primarily associated with nutritional problems; in this research the contribution of aflatoxin B1 exposure during the early months of life is an interesting factor to deepen in order to prevent liver damages or the development of rickets. The results show that the expression of vitamin D receptor in osteosarcoma cell line SAOS-2 is significantly down-modulated by exposure to aflatoxin B1. This seems to suggest that Aflatoxin B1, toxic towards the vitamin D receptor, interferes with the actions of the vitamin D on calcium binding gene expression in the kidney and intestine. Experimental data indicate a 58% and 86% decrease if the cells are exposed to 5 ng/mL and 50 ng/mL of aflatoxin B1, respectively. These results seem to indicate that natural occurrence of the aflatoxin B1 and allelic variant of vitamin D receptor on (F allele) increase the risk of developing rickets of African children

Chronic cannabinoid exposure reduces phencyclidine-induced schizophrenia-like positive symptoms in adult rats

Rationale: Chronic cannabis use can induce psychotic states that resemble schizophrenia. Yet, schizophrenic patients often smoke cannabis as a form of self-medication to counter the aversive symptoms of schizophrenia. We recently demonstrated an ameliorating effect of cannabinoid self-administration (SA) on negative and cognitive schizophrenia-like symptoms induced experimentally by the non-competitive N-methyl-d-aspartate receptor antagonist phencyclidine (PCP). Whether cannabinoid SA alleviates or exacerbates schizophrenia-like positive symptoms is still unclear. Objectives: This follow-up study aimed to evaluate the effect of self-administered cannabinoid on PCP-induced schizotypic positive symptoms in adult rats. Methods: Male rats were trained to self-administer either the cannabinoid CB1 receptor agonist WIN 55,212-2 (WIN; 12.5 μg/kg/infusion) or its vehicle (Veh) intravenously. The effects of acute and chronic intermittent intraperitoneal administration of PCP (2.5 mg/kg) on motor parameters were then tested in Veh-SA and WIN-SA. Results: Cannabinoid SA significantly attenuated the psychotomimetic effects of PCP exposure observed in control rats. Following acute PCP administration, WIN-SA animals displayed more frequent rearing and lower anxiety-like profile than Veh-SA rats. WIN-SA rats also exhibited lower behavioural sensitisation to chronic PCP treatment as demonstrated by reduced hyperlocomotion in response to an acute PCP challenge. In addition, parallel experiments performed in experimenter-administered rats that received WIN at comparable SA doses confirmed the ameliorating effects of cannabinoid exposure on PCP-induced schizotypic behaviours, indicating that motivational effects were not responsible for the ameliorative effects of cannabinoids. Conclusions: Our results indicate that cannabis may exert protective effects on positive schizotypic symptoms in adult animals such as hypermotility and anxiety state

Socioeconomic and environmental determinants of adolescent asthma in urban Latin America: an ecological analysis

The prevalence of asthma is high in urban areas of many Latin-American countries where societies show high levels of inequality and different levels of development. This study aimed to examine the relationship between asthma symptoms prevalence in adolescents living in Latin American urban centers and socioeconomic and environmental determinants measured at the ecological level. Asthma prevalence symptoms were obtained from the International Study of Asthma and Allergies in Childhood (ISAAC) phase III. A hierarchical conceptual framework was defined and the explanatory variables were organized in three levels: distal, intermediate, proximal. Linear regression models weighed by sample size were undertaken between asthma prevalence and the selected variables. Asthma prevalence was positively associated with Gini index, water supply and homicide rate, and inversely associated with the Human Development Index, crowding and adequate sanitation. This study provides evidence of the potential influence of poverty and social inequalities on current wheezing in adolescents in a complex social context like Latin America.A prevalência da asma é alta nas áreas urbanas da América Latina, onde as sociedades exibem altos níveis de desigualdade e diferente grau de desenvolvimento. O objetivo é examinar a relação entre a prevalência de sintomas asmáticos em adolescentes de centros urbanos da América Latina e determinantes socioeconômicos e ambientais medidos no nível ecológico. A prevalência de sintomas asmáticos foi obtida do International Study of Asthma and Allergies in Childhood (ISAAC), fase III. Foi definido um modelo conceitual hierárquico. As variáveis explicativas foram organizadas em três níveis: distal, intermediário, proximal. Ajustaram-se modelos de regressão lineal ponderados pelo tamanho amostral entre prevalência de sintomas asmáticos e variáveis selecionadas. A prevalência da asma foi associada positivamente com índice de Gini, índice de desenvolvimento humano, subministro de água potável, e inversamente com aglomeração e saneamento. Em conclusão, este estudo ecológico fornece evidência da influência da pobreza e da desigualdade social sobre os sintomas asmáticos em adolescentes em um contexto social complexo como o da América Latina

Sex-specific tonic 2-arachidonoylglycerol signaling at inhibitory inputs onto dopamine neurons of Lister Hooded rats

Addiction as a psychiatric disorder involves interaction of inherited predispositions and environmental factors. Similarly to humans, laboratory animals self-administer addictive drugs, whose appetitive properties result from activation and suppression of brain reward and aversive pathways, respectively. The ventral tegmental area (VTA) where dopamine (DA) cells are located is a key component of brain reward circuitry, whereas the rostromedial tegmental nucleus (RMTg) critically regulates aversive behaviors. Reduced responses to either aversive intrinsic components of addictive drugs or to negative consequences of compulsive drug taking might contribute to vulnerability to addiction. In this regard, female Lister Hooded (LH) rats are more vulnerable than male counterparts to cannabinoid self-administration. We, therefore, took advantage of sex differences displayed by LH rats, and studied VTA DA neuronal properties to unveil functional differences. Electrophysiological properties of DA cells were examined performing either single cell extracellular recordings in anesthetized rats or whole-cell patch-clamp recordings in slices. In vivo, DA cell spontaneous activity was similar, though sex differences were observed in RMTg-induced inhibition of DA neurons. In vitro, DA cells showed similar intrinsic and synaptic properties. However, females displayed larger depolarization-induced suppression of inhibition (DSI) than male LH rats. DSI, an endocannabinoid-mediated form of short term plasticity, was mediated by 2-arachidonoylglycerol (2-AG) activating type 1-cannabinoid (CB1) receptors. We found that sex-dependent differences in DSI magnitude were not ascribed to CB1 number and/or function, but rather to a tonic 2-AG signaling. We suggest that sex specific tonic 2-AG signaling might contribute to regulate responses to aversive intrinsic properties to cannabinoids, thus resulting in faster acquisition/initiation of cannabinoid taking and, eventually, in progression to addiction

Targeting Policies for Multidimensional Poverty and Social Fragility Relief Among Migrants in Italy, Using F-FOD Analysis

In this paper, we apply the novel Fuzzy First-Order Dominance (F-FOD) methodology to rank migrant subpopulations in Lombardy (Italy), in terms of multidimensional poverty and social fragility, for the year 2014, with the purpose to possibly provide useful support to policy-makers, in targeting relief interventions from poverty and discomfort. The F-FOD methodology allows for the direct comparison of different distributions of poverty and fragility, assessed by means of suitable ordinal multi-indicator systems, so extending to this more complex setting, the usual univariate first-order dominance criterion. It also provides complimentary “incomparability” scores, to assess to what extent the final rankings are reliable or instead forcing. It turns out that the levels of poverty and fragility of migrant subpopulations are quite different and, in particular, that the time since migrations has a key impact, on the identification of most critical cases, which typically involve recently migrated people. Evidence also emerges that the temporal poverty/fragility trajectories of migrants, distinguished by country of origin, follow different paths, suggesting how policy interventions must be properly, and differently, tuned to be effective

The promise of liquid biopsy to predict response to immunotherapy in metastatic melanoma

Metastatic melanoma is the deadliest form of skin cancer whose incidence has been rising dramatically over the last few decades. Nowadays, the most successful approach in treating advanced melanoma is immunotherapy which encompasses the use of immune checkpoint blockers able to unleash the immune system’s activity against tumor cells. Immunotherapy has dramatically changed clinical practice by contributing to increasing long term overall survival. Despite these striking therapeutic effects, the clinical benefits are strongly mitigated by innate or acquired resistance. In this context, it is of utmost importance to develop methods capable of predicting patient response to immunotherapy. To this purpose, one major step forward may be provided by measuring non-invasive biomarkers in human fluids, namely Liquid Biopsies (LBs). Several LB approaches have been developed over the last few years thanks to technological breakthroughs that have allowed to evaluate circulating components also when they are present in low abundance. The elements of this so-called “circulome” mostly encompass: tumor DNA, tumor and immune cells, soluble factors and non-coding RNAs. Here, we review the current knowledge of these molecules as predictors of response to immunotherapy in metastatic melanoma and predict that LB will soon enter into routine practice in order to guide clinical decisions for cancer immunotherapy

A cembranoid from tobacco prevents the expression of nicotineinduced withdrawal behavior in planarian worms

Using an adaptation of published behavioral protocols, we determined that acute exposure to the cholinergic compounds nicotine and carbamylcholine decreased planarian motility in a concentration-dependent manner. A tobacco cembranoid (1S,2E,4R,6R,7E,11E)-cembra-2,7,11- triene-4,6-diol (4R-cembranoid), also decreased planarian motility. Experiments in the presence of 1 μM 4R-cembranoid did increase the IC50 for nicotine- but not carbamylcholine-induced decrease in planarian motility. When planarians were exposed for 24 h to either nicotine or carbamylcholine at concentrations near their respective IC50 values and then transferred to plain media, nicotineexposed, but not carbamylcholine- or cembranoid-exposed worms displayed withdrawal-like distress behaviors. In experiments where planarians were pre-exposed to 100 μM nicotine for 24 h in the presence of 1 μM 4R-cembranoid, the withdrawal-like effects were significantly reduced. These results indicate that the 4R-cembranoid might have valuable applications for tobacco abuse research. This experimental approach using planarians is useful for the initial screening of compounds relevant to drug abuse and dependence