Dottorato in FARMACOLOGIA E TOSSICOLOGIA

Titolo della tesi: RESILIENCE AND SUSCEPTIBILITY TO STRESS-RELATED DISORDERS: INSIGHTS FROM ANIMAL MODELS

Stressful experiences can produce both accurate or generalized memories, reflecting an interindividual differences in response to stress. Psychostimulants outcomes on memory enhancement are known from many years, but literature data also show their memory generalization effects. However, the mechanisms through which psychostimulants affect memory quality is still poor investigated. In Chapter 1 we explored the memory generalization effects induced by amphetamine and a new psychostimulant: the 3,4-methylenedioxypyrovalerone (MDPV), also called “bath salt”. Both psychostimulants share a similar, yet not identical mechanism of action, augmenting noradrenaline and dopamine levels in the synaptic cleft. Thus, in a second experiment we aimed at evaluating the different involvement of the noradrenergic and dopaminergic system in the effects on memory enhancement, and on memory generalization. Treatment with the anesthetic ketamine, a renowned drug of abuse, in trauma patients during emergency care aggravated early post-traumatic stress reaction which is highly predictive of PTSD development and severity. Based on the evidence that ketamine induces a robust central and peripheral adrenergic/noradrenergic potentiation and that activation of this system is essential for the formation of memory for stressful events, in Chapter 2 we explored the possibility that the strong sympathomimetic action of ketamine might underlie its memory enhancing effects. Given that PTSD is a chronic psychiatric disease, it is of critical importance to evaluate whether animal model of PTSD resemble the chronicity nature of this pathology. The single prolonged stress paradigm has been extensively shown to induce behavioral and endocrine effects resembling the hallmark symptoms observed in PTSD patients and, similarly to PTSD, the manifestation of these effects is time-dependent and requires a 1-2 weeks incubation period. Although women have a two-fold greater risk to develop PTSD, most preclinical studies have been carried out in males. In Chapter 3 we aimed at investigating whether SPS induced persistent PTSD-like behavioral alterations in rats long after trauma exposure and whether these effects are sex-dependent. Another important aspect of PTSD is the susceptibility to develop this pathology. Animal models are a useful tool to investigate this issue. However, in the sparse studies considering the individual variability in response to trauma, only the anxiety symptoms are used to discern between different PTSD-like phenotypes, without considering the cognitive aspects of PTSD. In Chapter 4 we aimed at the development of an animal model of PTSD, with translational value, able to predict the susceptibility and the resilience phenotype considering both the cognitive and emotional alterations long after trauma. For this purpose, we outstretched our previously validated animal model in order to identify susceptible and resilient rats in terms of over- consolidation, impaired extinction and social behavior alterations. Nowadays there are different hypotheses to explain the interindividual variability in response to stress. Different studies used the “two hit” stress model to investigate whether exposure to two different stressors at different ages may increase (or decrease) the risk to develop psychopathologies after experiencing the second stressor. However, how a social stress similar to bullying in humans experienced at adolescence may affect the reaction to additional stressor later in life are less investigated. Adolescence is a period of impressive brain maturation in which the structure of the brain is ever-changing. Thus, maintaining a correct balance between mediators that sustain synaptic plasticity is of utmost importance. In Chapter 5 we evaluated whether the exposure to social defeat stress, a highly validated animal model of bullying in rodents, at adolescence and/or single prolonged stress experienced at adulthood affect the later development of emotional and cognitive alterations and whether the behavioral alterations are linked to any modification of hippocampal brain derived neurotrophic factor (BDNF) expression and plasma corticosterone levels. While adolescent bullying occurs in a small subset of population, a more common social stressor is represented by the deprivation of social interactions with conspecifics which is able to induce profound behavioral changes in rodents. Social isolation stress paradigm is commonly used to reproduce schizophrenia in rodents and it is conducted chronically from weaning to adulthood. However, long-term effects induced by a briefer period of social isolation stress during adolescence, which is a critical window for brain development, are not investigated. Moreover, it is known that in mammals, females have greater risk to develop stress-related disorders than males. In Chapter 6 we firstly evaluated whether repeated brief periods of SIS may alter emotionality and cognitive functions in adult male rats. Secondly, we examined whether brief and repeated social isolation stress during at adolescence and/or single prolonged stress at adulthood affect the later development of alteration on emotionality and cognition. Further, we aimed at evaluating whether such effects are sex-dependent.