Polycystic ovarian syndrome (PCOS) is one of the most common human ovarian pathologies affecting women of reproductive age. Despite extensive investigation, the etiology of PCOS remains poorly understood. Experimentally, a PCO-like syndrome can be induced in rodents by a single dose of the long-acting estrogen, estradiol valerate (EV). We have used this model to examine the possibility that PCOS is associated with derangement of the sympathetic control of the ovary. The release of newly incorporated norepinephrine (NE) from ovarian nerve terminals in response to transmural stimulation of the gland increased significantly before the formation of cysts (30 days after EV injection) and remained elevated at the time when cysts form (60 days). The increase in evoked NE release was accompanied by an augmented NE content and enhanced incorporation of [3H]NE into ovarian tissue; both of these changes had been initiated by 30 days after EV treatment and became unambiguous at the time of cyst formation. The overall increase in ovarian sympathetic outflow suggested by these alterations in catecholamine homeostasis was accompanied by a thecal cell-interstitial tissue selective down-regulation of beta-adrenergic receptors; the beta-adrenergic receptor concentration in these sympathetically innervated ovarian compartments was significantly lower in PCO than during the estrous phase of the estrous cycle, a time at which the beta-adrenergic receptor concentration reaches its lowest levels in normal cycling ovaries. Tyrosine hydroxylase activity was found to increase only when expressed per mg ovary, but not in absolute terms (i.e. per total ovary), suggesting regulation of enzyme activity by the enhanced catecholamine content. The results demonstrate that an activation of the sympathetic neurons innervating the ovary precedes the development of cysts in EV-induced PCOS and raise the possibility that a derangement of sympathetic inputs to the ovary contributes to the etiology of PCOS.

Backround While the molecular entity responsible for the rewarding effects of virtually all drugs of abuse is known; that for ethanol remains uncertain. Some lines of evidence suggest that the rewarding effects of alcohol are mediated not by ethanol per se but by acetaldehyde generated by catalase in the brain. However, the lack of specific inhibitors of catalase has not allowed strong conclusions to be drawn about its role on the rewarding properties of ethanol. The present studies determined the effect on voluntary alcohol consumption of two gene vectors; one designed to inhibit catalase synthesis and one designed to synthesize alcohol dehydrogenase, to respectively inhibit or increase brain acetaldehyde synthesis. Methods The lentiviral vectors, which incorporate the genes they carry into the cell genome, were: (i) one encoding a shRNA anticatalase synthesis and (ii) one encoding alcohol dehydrogenase (rADH1). These were stereotaxically microinjected into the brain ventral tegmental area (VTA) of Wistar-derived rats bred for generations for their high alcohol preference (UChB), which were allowed access to an ethanol solution and water. Results Microinjection into the VTA of the lentiviral vector encoding the anticatalase shRNA virtually abolished (-94% p<0.001) the voluntary consumption of alcohol by the rats. Conversely, injection into the VTA of the lentiviral vector coding for alcohol dehydrogenase greatly stimulated (2-3 fold p<0.001) their voluntary ethanol consumption. Conclusions The study strongly suggests that to generate reward and reinforcement, ethanol must be metabolized into acetaldehyde in the brain. Data suggest novel targets for interventions aimed at reducing chronic alcohol intake.

Perinatal asphyxia occurs still with great incidence whenever delivery is prolonged, despite improvements in perinatal care. After asphyxia, infants can suffer from short- to long-term neurological sequelae, their severity depend upon the extent of the insult, the metabolic imbalance during the re-oxygenation period and the developmental state of the affected regions. Significant progresses in understanding of perinatal asphyxia pathophysiology have achieved. However, predictive diagnostics and personalised therapeutic interventions are still under initial development. Now the emphasis is on early non-invasive diagnosis approach, as well as, in identifying new therapeutic targets to improve individual outcomes. In this review we discuss (i) specific biomarkers for early prediction of perinatal asphyxia outcome; (ii) short and long term sequelae; (iii) neurocircuitries involved; (iv) molecular pathways; (v) neuroinflammation systems; (vi) endogenous brain rescue systems, including activation of sentinel proteins and neurogenesis; and (vii) therapeutic targets for preventing or mitigating the effects produced by asphyxia.

Asphyxia during delivery produces long-term deficits in brain development, including hippocampus. We investigated hippocampal plasticity after perinatal asphyxia, measuring postnatal apoptosis and neurogenesis. Asphyxia was performed by immersing rat fetuses with uterine horns removed from ready-to-deliver rats into a water bath for 20 min. Caesarean-delivered pups were used as controls. The animals were euthanized 1 week or 1 month after birth. Apoptotic nuclear morphology and DNA breaks were assessed by Hoechst and TUNEL assays. Neurogenesis was estimated by bromodeoxyuridine/MAP-2 immunocytochemistry, and the levels and expression of proteins related to apoptosis and cell proliferation were measured by Western blots and in situ hybridization, respectively. There was an increase of apoptosis in CA1, CA3, and dentate gyrus (DG) and cell proliferation and neurogenesis in CA1, DG, and hilus regions of hippocampus 1 week after asphyxia. The increase of apoptosis in CA3 and cell proliferation in the suprapyramidal band of DG was still observed 1 month following asphyxia. There was an increase of BAD, BCL-2, ERK2, and bFGF levels in whole hippocampus and bFGF expression in CA1 and CA2 and hilus at P7 and P30. There was a concomitant decrease of phosphorylated-BAD (Ser112) levels. The increase of BAD levels supports the idea of delayed cell death after perinatal asphyxia, whereas the increases of BCL-2, ERK2, and bFGF levels suggest the activation of neuroprotective and repair pathways. In conclusion, perinatal asphyxia induces short- and long-term regionally specific plastic changes, including delayed cell death and neurogenesis, involving pro- and antiapoptotic as well as mitogenic proteins, favoring hippocampal functional recovery.

The main purpose of this study was to characterize the initial neurotransmission cascade elicited by methamphetamine, analysing simultaneously with in vivo microdialysis monoamine, amino acid and neuropeptide release in substantia nigra and neostriatum of the rat. The main effect of a single systemic dose of methamphetamine (15 mg/kg, subcutaneously) was an increase in dopamine levels, both in substantia nigra ( 10-fold) and neostriatum ( 40-fold), accompanied by a significant, but lesser, increase in dynorphin B ( two-fold, in both regions), and a decrease in monoamine metabolites. A similar effect was also observed after local administration of methamphetamine (100 lM) via the microdialysis probes, but restricted to the treated region. In other experiments, rats were repeatedly treated with methamphetamine or saline, with the last dose administered 12 h before microdialysis. Dopamine K + -stimulated release was decreased following repeated methamphetamine administration compared with that following saline, both in the substantia nigra (by 65%) and neostriatum (by 20%). In contrast, the effect of K + -depolarization on glutamate, aspartate and GABA levels was increased following repeated administration of methamphetamine. In conclusion, apart from an impairment of monoamine neurotransmission, repeated methamphetamine produces changes in amino acid homeostasis, probably leading to NMDA-receptor overstimulation.