Neuroscience
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Our previous study demonstrated that chronic prenatal methamphetamine (MA) exposure and a single dose of MA in adulthood decrease focally induced epileptiform activity in adult male rats. As seizures are known to be dependent on sex and female estrous cycle, the goal of the present study was to examine the combined effect of prenatal MA exposure (5mg/kg) and the MA challenge dose (1mg/kg) in adulthood on electroencephalography (EEG) recordings and consequences of brain stimulation in freely moving adult female rats with respect to the estrous cycle. Overall, 12 groups of adult female rats were tested: prenatally MA-exposed, prenatally saline-exposed and rats without prenatal injections, each of these groups was either postnatally challenged with MA or with saline injection (MA-MA, MA-S; S-MA, S-S; C-MA, C-S) and further divided according to the stage of the estrous cycle to metestrus/diestrus (M/D) or proestrus/estrus (P/E). ⋯ The challenge dose of MA also decreased the seizure threshold. Moreover, prenatal as well as adult MA administration decreased the number and occurrence of WDS, respectively. Thus, the present study demonstrates that the effect of prenatal MA exposure and challenge dose of the same drug on focally induced epileptiform activity in adult female rats depends on the estrous cycle.
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Noradrenaline acting via β-adrenoceptors (β-ARs) in the CNS plays an important role in learning/memory and cognitive functions. β-ARs have been shown to be expressed in cortical pyramidal and subcortical principal cells. However, little is known about β-AR expression in different subtypes of GABAergic neurons. ⋯ SST-ir interneurons are more likely to express β2-AR compared with the other subtypes of interneurons. The present results are of significance for understanding the role of β-ARs in prefrontal cortical functions.
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Clinical studies have shown that agonist-antagonist opioid analgesics that produce their analgesic effect via action on the kappa-opioid receptor, produce a delayed-onset anti-analgesia in men but not women, an effect blocked by co-administration of a low dose of naloxone. We now report the same time-dependent anti-analgesia and its underlying mechanism in an animal model. Using the Randall-Selitto paw-withdrawal assay in male rats, we found that nalbuphine, pentazocine, and butorphanol each produced analgesia during the first hour followed by anti-analgesia starting at ∼90min after administration in males but not females, closely mimicking its clinical effects. ⋯ The selective NOP receptor antagonists, JTC801, and J-113397, but not the sigma receptor antagonist, BD 1047, antagonized nalbuphine anti-analgesia. Furthermore, the NOP receptor agonist NNC 63-0532 produced anti-analgesia with the same delay in onset observed with the three agonist-antagonists, but without producing preceding analgesia and this anti-analgesia was also blocked by naloxone. These results strongly support the suggestion that clinically used agonist-antagonists act at the NOP receptor to produce anti-analgesia.
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β-Amyloid (Aβ) accumulation has been proved to be responsible for the pathogenesis of Alzheimer's disease (AD). However, it is not yet clear what makes Aβ accumulate and become toxic in the AD brains. Our previous studies demonstrated that glycated Aβ (Aβ-AGE) could be formed, and it exacerbated the authentic Aβ-mediated neurotoxicity in vitro, but we did not show the role of Aβ-AGE in vivo and the underlying mechanism. ⋯ We also observed the overexpression of receptor for advanced glycation endproducts receptor for AGEs (RAGE) and the activation of downstream molecular (GSK3, NF-κB, p38) in RAGE-mediated pathways. On the other hand, simultaneous application of RAGE antibody or GSK3 inhibitor LiCl reversed the cognitive decline amplified by Aβ-AGE. Our data revealed that in vivo the Aβ-AGE is more toxic than Aβ, and Aβ-AGE could lead to the aggravation of AD-like pathology though the RAGE pathway, suggesting that Aβ-AGE and RAGE may be new therapeutic targets for AD.
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Pro-inflammatory cytokines induced by inflammation and iron accumulation in the substantia nigra (SN) have been implicated in the pathogenesis of Parkinson's disease (PD). In the present study, we aimed to investigate the relationship between inflammation and iron accumulation in a lipopolysaccharide (LPS)-induced Parkinsonian rat model. The activation of glial cells and elevated levels of pro-inflammatory cytokines were observed in the SN of LPS models, accompanied by iron deposits in the same region. ⋯ The expression of heme oxygenase-1 (HO-1) was also upregulated in vivo and in vitro. These results suggested that pro-inflammatory cytokines might induce Fpn downregulation, which leads to iron accumulation and dopaminergic neurons' degeneration in PD. HO-1 may also contribute to the iron accumulation in neurons, but its mechanism needs to be further investigated.