Neuropharmacology
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Randomized Controlled Trial
Online effects of transcranial direct current stimulation on prefrontal metabolites in gambling disorder.
Gambling disorder is characterized by persistent maladaptive gambling behaviors and is now considered among substance-related and addictive disorders. There is still unmet therapeutic need for these clinical populations, however recent advances indicate that interventions targeting the Glutamatergic/GABAergic system hold promise in reducing symptoms in substance-related and addictive disorders, including gambling disorder. There is some data indicating that transcranial direct current stimulation may hold clinical benefits in substance use disorders and modulate levels of brain metabolites including glutamate and GABA. ⋯ There were no significant changes between stimulation conditions in prefrontal glutamate + glutamine and N-acetyl Aspartate, or in striatal metabolite levels. Results also indicated positive correlations between metabolite levels during active, but not sham, stimulation and levels of risk taking, impulsivity and craving. Our findings suggest that transcranial direct current stimulation can modulate GABA levels in patients with gambling disorder which may represent an interesting future therapeutic avenue.
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Chemotherapy-Induced Peripheral Neuropathy (CIPN) is the most frequent adverse effect of pharmacological cancer treatments. The occurrence of neuropathy prevents the administration of fully-effective drug regimen, affects negatively the quality of life of patients, and may lead to therapy discontinuation. CIPN is currently treated with anticonvulsants, antidepressants, opioids and non-opioid analgesics, all of which are flawed by insufficient anti-hyperalgesic efficacy or addictive potential. ⋯ Biochemically, we observed a downregulation of HCN2 expression and an upregulation of the HCN regulatory beta-subunit MirP1. Finally, we report the efficacy of the selective HCN1 inhibitor MEL57A in reducing hyperalgesia and allodynia in oxaliplatin-treated rats without cardiac effects. In conclusion, this study strengthens the evidence for a disease-specific role of HCN1 in CIPN, and proposes HCN1-selective inhibitors as new-generation pain medications with the desired efficacy and safety profile.
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Alzheimer's disease (AD) is a progressively neurodegenerative disease with typical hallmarks of amyloid β (Aβ) plaque accumulation, neurofibrillary tangle (NFT) formation and neuronal death extension. Aggressive Aβ accumulation promotes senile plaque formation and perturbs endoplasmic reticulum (ER) function to trigger the unfolded protein response (UPR) leading to neuronal apoptosis. The stress-dependent activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) increases the phosphorylation of eukaryotic translation initiation factor-2α (eIF2α) to promote the preferential synthesis of β-site APP cleavage enzyme 1 (BACE1) and Aβ generation in turn. ⋯ DDPU reduced Aβ production mainly by inhibiting the PERK/eIF2α signaling-mediated BACE1 translation and stimulated Aβ clearance by promoting autophagy as a PI3K inhibitor through PI3K/AKT/mTOR signaling pathway, while exhibited neuroprotective effect involving attenuation of ER stress. DDPU might be the first reported ginsenoside derivative with dual effects on both autophagy promotion and ER stress amelioration. Our results have highlighted the potential of DDPU in the treatment of AD.
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Low-dose ketamine is a rapid-acting antidepressant, to which female rodents are more sensitive as compared to males. However, the mechanism mediating this sex difference in ketamine sensitivity remains elusive. ⋯ Our results indicate that females' enhanced sensitivity to ketamine during Pro is likely mediated through estradiol acting on ERα and ERβ, leading to greater activation of synaptic plasticity-related kinases within the PFC and HPC.
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The novel potent analgesic cebranopadol is an agonist at nociceptin/orphanin FQ peptide (NOP) and classical opioid receptors, with the highest in-vitro activity at NOP and mu-opioid peptide (MOP) receptors, and somewhat lower activity at kappa-opioid peptide (KOP) and delta-opioid peptide (DOP) receptors. We addressed the question of which of these pharmacological activities contribute to the stimulus properties of cebranopadol using a rat drug discrimination procedure. First, cebranopadol was tested in generalization tests against a morphine cue, including receptor-specific antagonism. ⋯ Conversely, generalization of cebranopadol was reduced by naloxone and J-113397, but not by a DOP or a KOP receptor antagonist. These results suggest a contribution of MOP receptor activity and a relative lack of contribution of DOP and KOP receptor activity to cebranopadol's stimulus properties. The findings regarding the contribution of NOP receptor activity were equivocal, but interestingly, the morphine-like stimulus property of cebranopadol appears to be reduced by its intrinsic NOP receptor activity.