Alterazioni indotte dall'isolamento sociale sulla regolazione a feedback negativo dell'asse ipotalamo-ipofisi-surrene

Rearing of rodents from weaning to adulthood in isolation induces various behavioral and neurochemical alterations in comparison with group-housed controls, suggesting that socially isolated rodents represent an animal model of neuropsychiatric disorder. Social isolation results in a decrease in plasma adrenocorticotropin (ACTH) and corticosterone levels and in a decrease in the brain and plasma concentrations of neuroactive steroids that act as positive modulators at GABAA receptors. Moreover, social deprivation is accompanied by an enhanced neurosteroidogenesis in response to acute stressful stimuli and it increases the sensitivity of the pituitary to corticotropin-releasing factor (CRF). Furthermore, the corticosterone level after dexamethasone injection was significantly greater in isolated animals than in the group-housed rats. These results suggest that social isolation induces changes in responsiveness and impaired negative feedback regulation of the hypothalamic–pituitary–adrenal (HPA) axis. The aim of this research was to study mechanisms that might contribute to the different HPA reactivity to acute stress. We evaluated plasma corticosterone, hypothalamic level of CRF and of endocannabinoid 2-AG, hypothalamic endocannabinoid receptors (CB1 receptors) and hippocampal and hypothalamic glucocorticoid receptors (GR), in at different time point after acute heterotypic stress (foot-shock, 5 min). Moreover we have investigated GR function by blockade these receptors with mifepristone (a non-selective GR antagonist) in control group-housed animals and we have measured the expression of hypothalamic α4 and δ GABAA receptor subunits in basal condition and allopregnanolone (AP) levels after stress exposure. Socially isolated rats exposed to foot-shock stress showed a marked increased in plasma corticosterone levels which were still significantly high 7 hours later, while in group-housed animals plasma corticosterone levels return to baseline 60 mins after stress exposure. Similar pattern was found in plasma AP where socially isolated rats showed a significant increase at 30 mins and still high 90 mins after acute stress exposure. In the hypothalamus of socially isolated rats a significant increase in the levels of CRF was found at 15 min, 30 and 60 min after the end of the stress, while in control animals no change in CRF levels was detected at any time point measured. Moreover, social isolation induced a decrease of hypothalamic 2-AG, that play a key role in the regulation of negative feedback of HPA axis. Social deprivation results in a increase of expression of hypothalamic CB1 and of both hippocampal and hypothalamic GR than control group, probably as a result by lower corticosterone and 2-AG levels in these animals. After acute stress exposure, in socially isolated rats both CB1 and GR expression did not show any change or was reduced during time course, while in control animals progressively increased with the time. We have hypothesized that this dysregulation of GR expression induced by social isolation may be important in disruption of HPA axis activity and in failure of glucocorticoid negative feedback resulting in prolonged response to acute stress. To study GR function, in control group-housed animals, we have measured plasma corticosterone concentration after mifepristone administration. Mifeprisone treatment resulted in a decrease of basal corticosterone levels and an increase of steroidogenic effect of stress at 30 and 90 min; these effects were similar to that observed in non-treated isolated rats. Moreover, social isolation decreased the expression of both basal hypothalamic α4 and δ GABAA receptor subunits and reduced basal hypothalamic concentration of AP, suggesting a reduction of GABAergic transmission in this area. According to previous data (Serra et al., 2000), foot-shock stress exposure induced an increase of AP levels in socially isolated rats, probably to offset the reduction GABAA-mediated signaling. These data demonstrate that HPA axis hyperresponsiveness to acute heterotypic stress in socially isolated rats may be due to a dysregulation of GR function. Further experiments are in progress in order to clarify the role of endocannabinoid and GABAergic system in the impairment of glucocorticoid negative feedback induced by social isolation.