In the present study, we evaluate the effect of acute restraint stress (15 min) of male Wistar rats on social interaction measurements and c-Fos immunoreactivity (c-Fos-ir) expression, a marker of neuronal activity, in areas involved with the modulation of acute physical restraint in rats, i.e., the paraventricular nucleus of the hypothalamus (PVN), median raphe nucleus (MnR), medial prefrontal cortex (mPFC), cingulate prefrontal cortex (cPFC), nucleus accumbens (NaC), hippocampus (CA3), lateral septum (LS) and medial amygdala (MeA). We considered the hypothesis that restraint stress exposure could promote social withdrawal induced by the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis, and increase c-Fos expression in these limbic forebrain areas investigated. In addition, we investigated whether pretreatment with the atypical antipsychotic clozapine (5 mg/kg; I.P.) could attenuate or block the effects of restraint on these responses. We found that restraint stress induced social withdrawal, and increased c-Fos-ir in these areas, demonstrating that a single 15 min session of physical restraint of rats effectively activated the HPA axis, representing an effective tool for the investigation of neuronal activity in brain regions sensitive to stress. Conversely, pretreatment with clozapine, prevented social withdrawal and reduced c-Fos expression. We suggest that treatment with clozapine exerted a preventive effect in the social interaction deficit, at least in part, by blocking the effect of restraint stress in brain regions that are known to regulate the HPA-axis, including the cerebral cortex, hippocampus, hypothalamus, septum and amygdala. Further experiments will be done to confirm this hypothesis.

Manganese (Mn) is one of the most common chemical elements on Earth and an essential micronutrient in animal organism. However, in supraphysiological levels and long-term exposures, it is a potential toxicant. Although nervous system is the most studied in relation to Mn toxicity, other tissues can have their function impaired by Mn in high doses. The present study investigated the possible adverse effects of subchronic exposure to supraphysiologic level of Mn (5 mg/kg or 15 mg/kg, intraperitoneally) on reproductive, neurobehavioral, renal and hepatic parameters of male rats. For the first time, the vulnerability of these parameters to Mn was concomitantly investigated. While our results demonstrate that Mn treatments were not sufficient to produce a marked effect of neurotoxic, hepatotoxic or renal toxicity in adult rats, we found typical indicators of reproductive toxicity such as histopathological changes (major in testes and epididymis) and impaired sperm concentration and quality. Mn, under these experimental conditions, seems to exert reproductive toxicity by different testicular mechanisms, i.e. direct and indirect action on germ cells. On the other hand, exposure to Mn did not change the pattern of cognitive and emotional behaviors and the histological organization of kidneys of experimental rats. The liver showed a weight increasement and hidropic degeneration, probable due to the detoxification overload. In summary, for the first time it was demonstrated that adult male reproductive system was more sensitive to Mn toxicity than nervous, hepatic and renal systems, although nervous system is known as the main target tissue of this metal.

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