Neuropharmacology
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Emerging evidence indicates that gut microbiota interacts with immune and nervous systems in the host and plays a critical role in the pathogenesis of multiple sclerosis (MS) and many psychiatric disorders such as depression and anxiety. The aim of this study was to explore the influence of gut bacterial depletion from early adolescence on adult immunological and neurobehavioral responses in mice with experimental-autoimmune-encephalomyelitis (EAE). We used an animal model of gut microbiota depletion induced by antibiotics from weaning to adulthood to assess clinical signs, cognitive function and depression-and anxiety-related symptoms in non-EAE and EAE-induced mice. ⋯ However, no significant changes were found in non-EAE mice. Non-EAE and EAE mice treated with antibiotics exhibited increased anxiety-related behaviors, whereas depression-related symptoms and increased hippocampal TNF-α and IL-1β were only observed in EAE-induced mice treated with antibiotics. This study supports the view that depletion of gut microbiota by antibiotics from weaning profoundly impacts adult immunological and neurobehavioral responses.
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Orexin has multiple physiological functions including wakefulness, appetite, nicotine intake, and nociception. The cerebral cortex receives abundant orexinergic projections and expresses both orexinergic receptor 1 (OX1R) and 2 (OX2R). However, little is known about orexinergic regulation of GABA-mediated inhibitory synaptic transmission. ⋯ Laser photolysis of caged GABA revealed that orexin A enhanced GABA-mediated currents in PNs. Downstream blockade of Gq/11 protein-coupled OX1Rs by IP3 receptor or protein kinase C (PKC) blockers and BAPTA injection into postsynaptic PNs diminished the orexin A-induced uIPSC enhancement. These results suggest that the orexinergic uIPSC enhancement is mediated via postsynaptic OX1Rs, which potentiate GABAA receptors through PKC activation.
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While evidence indicates that sigma-1 receptors (Sig-1Rs) play an important role in the induction of peripheral neuropathic pain, there is limited understanding of the role that the neurosteroidogenic enzymes, which produce Sig-1R endogenous ligands, play during the development of neuropathic pain. We examined whether sciatic nerve injury upregulates the neurosteroidogenic enzymes, cytochrome P450c17 and 3β-hydroxysteroid dehydrogenase (3β-HSD), which modulate the expression and/or activation of Sig-1Rs leading to the development of peripheral neuropathic pain. Chronic constriction injury (CCI) of the sciatic nerve induced a significant increase in the expression of P450c17, but not 3β-HSD, in the ipsilateral lumbar spinal cord dorsal horn at postoperative day 3. ⋯ Co-administration of the Sig-1R agonist, PRE084 restored the development of mechanical allodynia originally suppressed by the ketoconazole administration. However, ketoconazole-induced inhibition of thermal hyperalgesia was not affected by co-administration of PRE084. Collectively these results demonstrate that early activation of P450c17 modulates the expression and activation of astrocyte Sig-1Rs, ultimately contributing to the development of mechanical allodynia induced by peripheral nerve injury.
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HIV-Associated Neurocognitive disorder (HAND) affects nearly half of infected patients. The HIV envelope protein gp120 is shed by infected cells and is a potent neurotoxin in vitro that reproduces many aspects of HAND when expressed in vivo. Here, we show that HIV gp120 increases the amplitude of a tonic current mediated by γ-aminobutyric acid type-A receptors (GABAARs). ⋯ Subsequent stimulation of IL-1 receptors activates p38 MAPK in neurons leading to the upregulation of α5-containing GABAARs. Increased tonic inhibition impairs neuroplasticity and inhibition of α5-containing GABAARs improves cognitive function in disease models. Thus, gp120-induced upregulation of α5-containing GABAARs presents a novel therapeutic target for HAND.
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Hypothermia, the gold standard after a hypoxic-ischemic insult, is not beneficial in all treated newborns. Cannabidiol is neuroprotective in animal models of newborn hypoxic-ischemic encephalopathy. This study compared the relative efficacies of cannabidiol and hypothermia in newborn hypoxic-ischemic piglets and assessed whether addition of cannabidiol augments hypothermic neuroprotection. ⋯ cannabidiol administration after hypoxia-ischemia in piglets offers some neuroprotective effects but the combination of cannabidiol and hypothermia shows some additive effect leading to more complete neuroprotection than cannabidiol or hypothermia alone.