Characterization of the Roman lines/strains of rats as a genetic model of psychiatric disorders: a behavioral and brain dialysis study

State of the art Depressive disorders are fairly prevalent in the general population, with a higher rate in women compared to men, are disabling, since they can significantly impair psychosocial functioning, and are typically associated with high mortality due mainly to the high rate of suicides but also to the negative impact that depression has on the course of co-occurring illnesses. In addition, pharmacological and psychological antidepressant therapies in use have a limited efficacy and/or are associated with side effects that reduce the compliance in many patients. Although the etiology and pathogenesis of depression are poorly understood, it is most likely that the combination of genetics, early life adverse events, and ongoing stress may ultimately determine the individual vulnerability to stress-related disorders, such as depression. Therefore, the development and characterization of animal models of vulnerability and resistance to the effects of stress, including early life stress, is a major challenge for depression research. One such model is represented by the Roman high- (RHA) and low-avoidance (RLA) lines/strains of rats, which are psychogenetically selected for, respectively, rapid versus extremely poor acquisition of active avoidance in a shuttle box. A large body of evidence indicates that a major reason for their divergent performance in this test is their different reactivity to stressful stimuli, that is, their coping style. Thus, when exposed to aversive stimuli, RLA rats display a reactive coping strategy, associated with a strong activation of the HPA axis; moreover, they display robust depressive-like behaviors in the forced swim test (FST) that are normalized by the subacute administration of antidepressants. In contrast, compared with their RLA counterparts, RHA rats display a proactive coping strategy in the face of aversive conditions, associated with higher baseline levels of impulsivity, a more robust sensation/novelty seeking profile, a marked preference for, and intake of, natural and drug rewards along with a greater responsiveness of the mesolimbic dopaminergic system.Aims The behavioral and neurochemical traits that distinguish the two lines/strains suggest that RLA rats may represent a model of vulnerability to stress-induced depression, whereas RHA rats may model resistance to stress-induced depression-like behaviour. To test this hypothesis, in the first study we evaluated the performance of RLA and RHA rats in the FST in response to chronic antidepressant treatments, since clinical evidence indicates that several weeks of treatment with antidepressant drugs are required to achieve an adequate therapeutic response. Furthermore, one of the cardinal symptoms of depression observed in many patients is anhedonia, which is defined as the loss of interest in once enjoyable activities, including sexual activity. Accordingly, depressive episodes are frequently associated with sexual dysfunctions. In consideration of this clinical evidence, and given the well-established role of dopamine in sexual behavior, the second study was aimed at characterizing the sexual behavior of RHA and RLA rats and its correlation with the functional state of their mesolimbic dopaminergic system. In keeping with the long-term consequences on mental health elicited by early-life adverse events, it has been observed that post weaning social isolation in rodents may lead to a later increment in the prevalence of anxiety/fear related behaviors. Thus, in the third study we evaluated the impact of post weaning isolation on the anxiety-related behaviors of inbred RHA and RLA rats in the Elevated Zero Maze, and in motility cages used to asssess locomotor activity in a new environment. Results In study I we demonstrated that chronic treatments with low doses of antidepressants, that were ineffective when given subacutely, were able to decrease immobility and also to increase climbing (desipramine) or swimming (fluoxetine) in RLA rats. Conversely, neither subacute nor chronic antidepressant treatments affected the behavior of RHA rats in the FST. iii In addition, the results of study II showed that, compared with their RLA counterparts, RHA rats displayed higher levels of sexual motivation and a better copulatory performance, associated with a greater release of DA in the AcbSh. These line-related differences were attenuated but not abolished by sexual experience. Moreover, RLA rats were more responsive than their RHA counterparts to both, the facilitatory effect of apomorphine and the inhibitory effect of haloperidol on sexual behavior. Finally, in study III we found that the isolation-rearing procedure significantly increased the level of anxiety of RHA-I rats in the EZM, as reflected by a smaller number of entries and a shorter time spent in the open space, associated with decreased head dipping, increased latency to enter in the open space, and reduced novelty-induced locomotor activation, whereas it failed to produce significant changes in the behavior of RLA-I rats. Conclusions The results of these studies show that the Roman lines/strains of rats may represent a valid experimental approach to investigate the neural substrates and molecular mechanisms involved in the individual vulnerability and resistance to stress-induced depression, with the aim of identifying both, potential biomarkers for an early diagnosis of depression and potential molecular targets for novel antidepressant treatments. Moreover, the Roman lines/strains may be used to study the neurophysiology of the appetitive and consummatory aspects of sexual behaviour, in order to better understand the mechanisms underlying the psychological and pathological causes of sexual dysfunctions. Finally, the Roman rats may provide a useful model to identify the mechanisms whereby early-life adverse events interact with the genetic make up to induce psychiatric disorders in adulthood.