Different addictive drug exposure induces selective alterations of the Endogenous Opioid System : modulation of transcription and epigenetic mechanisms

Drug addiction manifests clinically as compulsive drug seeking, and cravings that can persist and recur even after extended periods of abstinence. The fundamental principle that unites addictive drugs is that each one enhances synaptic DA by means that dissociate it from normal behavioral control, so that they act to reinforce their own acquisition. Our attention has focused on the study of phenomena associated with the consumption of alcohol and heroin. Alcohol has long been considered an unspecific pharmacological agent, recent molecular pharmacology studies have shown that acts on different primary targets. Through gene expression studies conducted recently it has been shown that the classical opioid receptors are differently involved in the consumption of ethanol and, furthermore, the system nociceptin / NOP, included in the family of endogenous opioid system, and both appear able to play a key role in the initiation of alcohol use in rodents. What emerges is that manipulation of the opioid system, nociceptin, may be useful in the treatment of addictions and there are several evidences that support the use of this strategy. The linkage between gene expression alterations and epigenetic modulation in PDYN and PNOC promoters following alcohol treatment confirm the possible chromatin remodeling mechanism already proposed for alcoholism. In the second part of present study, we also investigated alterations in signaling molecules directly associated with MAPK pathway in a unique collection of postmortem brains from heroin abusers. The interest was focused on understanding the effects that prolonged exposure of heroin can cause in an individual, over the entire MAPK cascade and consequently on the transcription factor ELK1, which is regulated by this pathway. We have shown that the activation of ERK1/2 resulting in Elk-1 phosphorylation in striatal neurons supporting the hypothesis that prolonged exposure to substance abuse causes a dysregulation of MAPK pathway.

Cascading events triggering industrial accidents: quantitative assessment of NaTech and domino scenarios

The so called cascading events, which lead to high-impact low-frequency scenarios are rising concern worldwide. A chain of events result in a major industrial accident with dreadful (and often unpredicted) consequences. Cascading events can be the result of the realization of an external threat, like a terrorist attack a natural disaster or of “domino effect”. During domino events the escalation of a primary accident is driven by the propagation of the primary event to nearby units, causing an overall increment of the accident severity and an increment of the risk associated to an industrial installation. Also natural disasters, like intense flooding, hurricanes, earthquake and lightning are found capable to enhance the risk of an industrial area, triggering loss of containment of hazardous materials and in major accidents. The scientific community usually refers to those accidents as “NaTechs”: natural events triggering industrial accidents. In this document, a state of the art of available approaches to the modelling, assessment, prevention and management of domino and NaTech events is described. On the other hand, the relevant work carried out during past studies still needs to be consolidated and completed, in order to be applicable in a real industrial framework. New methodologies, developed during my research activity, aimed at the quantitative assessment of domino and NaTech accidents are presented. The tools and methods provided within this very study had the aim to assist the progress toward a consolidated and universal methodology for the assessment and prevention of cascading events, contributing to enhance safety and sustainability of the chemical and process industry.