Xueqin Zhang

BACKGROUND: Environmental pollutant exposure may play certain roles in the pathogenesis and progression of diabetes mellitus including gestational diabetes mellitus (GDM). We hypothesize that heavy metal exposure may trigger GDM during pregnancy. The objective of this study was to investigate the possible associations between selected heavy metal exposure and GDM risk. METHODS: This investigation is a retrospective case-control study nested within a cohort of 1359 pregnant women. These participants were recruited in Xiamen Maternity and Child Care Hospital, China, during June to July, 2012. All their newborns' meconium samples were collected. By reviewing the antenatal care records, 166 GDM mothers were screened out from the 1359 participants; 137 of 166 GDM mothers offered their newborns' meconium samples for the metal analysis. Those 137 mothers were set as the case group. Similarly, 294 healthy mothers without any gestational complication were initially screened out from the rest 1193 non-GDM mothers. 190 of the 294 healthy mothers offered their newborns' meconium samples for the metal analysis. Those 190 mothers were set as the control group. Arsenic (As), mercury (Hg), lead (Pb), cadmium (Cd), and chromium (Cr) levels in these case-control meconium samples were measured by inductively coupled plasma mass spectrometry. The possible association between the metal levels and maternal GDM risk of studied subjects was assessed by binary logistic regression. RESULTS: GDM prevalence of 12.21% was observed in the investigated 1359 participants. The concentrations of As, Hg, Cr and Cd in studied cases were significantly higher (p < 0.05) than those of controls. After adjustments for maternal age, pre-pregnant body mass index, gravidity, parity, hepatitis B virus infection, and newborn sex, As, Cd and Cr were found to be positively associated with GDM prevalence in dose-dependent manners. Among them, As was detected in all samples and its levels associated the maternal GDM with the adjusted odds ratios of 3.28 [95% CI 1.24, 8.71], 3.35 [95% CI 1.28, 8.75] and 5.25 [95% CI 1.99, 13.86] for the 2(nd), 3(rd) and 4(th) quartiles, respectively. CONCLUSIONS: The present work implies that exposure to some of the selected metals (noticeably As) may contribute to maternal GDM risk during pregnancy.

Accumulating evidence indicates that the hippocampal dentate gyrus (DG), a critical brain region contributing to learning and memory, is involved in the addiction and relapse to abused drugs. Emerging studies also suggest the role of orexin signaling in the rewarding behavior induced by repeated exposure to opiates. In the present study, we investigated the dynamic adaptation of orexin signaling in the DG and its functional significance in the acquisition, expression, maintenance of and relapse to rewarding behavior induced by morphine. Repeated place conditioning with morphine significantly increased the orexin A content released from the lateral hypothalamic area projecting neurons into the DG. Local infusions of orexin A into the DG sensitized the acquisition of and relapse to the conditioned place preference induced by morphine. The application of the orexin receptor type 1 (OXR1) antagonist SB334867 significantly abolished the acquisition, expression and maintenance of the conditioned place preference induced by repeated exposure to morphine. Furthermore, the significant increase of the phosphorylation of AKT in the DG was associated with preference for the morphine-paired chamber in rats, which was reversed by the local administration of an OXR1 antagonist. Thus, these findings suggested that the dynamic upregulation of orexin A signaling, via the AKT pathway in the DG, may promote the acquisition and maintenance of opioid-induced craving behaviors and may increase sensitivity to the rewarding effect of subsequent opioids.

Abstract Addiction‐related behaviors, such as conditioned place preference (CPP), require animals to remember an association between environmental cue and drug treatment, and exposure to environmental cue is one of the key contributing factors to relapse. However, how central neural circuit participates in the formation of CPP induced by stimulus of morphine‐paired environment remains unknown. In the present study, we found that reexposure to morphine‐paired environment significantly increased the activity of hippocampal CA3 neurons, increased the excitability of GABAergic neurons and expression of glutamic acid decarboxylase 65/67 in the caudal lateral septum (LSc) and decreased the activity of GABAergic neurons and GAD65/67 expression in ventral tegmental area (VTA), leading to activation (disinhibition) of dopaminergic neurons. Inactivation of CA3 neurons attenuated GABAergic neurons activity and decreased the upregulation of GAD65/67 in LSc, prevented the dopaminergic neurons activation,and GAD65/67 downregulation in VTA and ameliorated the CPP behavior following exposure to morphine‐paired context. Blockade of NMDA receptor in LSc also prevented the upregulation of GAD65/67 in LSc and formation of CPP induced by stimulus of morphine‐paired environment. Suppression of GAD activity in LSc also remarkably attenuated the dopaminergic neurons activation and the GAD65/67 downregulation in VTA and prevented the formation of CPP induced by reexposure to morphine‐associated context. Collectively, these results, for the first time, illustrated the involvement of neural circuitry of CA3‐LSc‐VTA, through integration of the contexts and reward information, participated in the reinstatement of CPP induced by exposure to morphine‐associated context, which advanced our understanding on neurobiological basis for the context‐associated memory and rewarding behavior.