Neuroscience
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Modulation of L-type Ca(2+)-channel function by dopamine is a major determinant of the rate of action potential firing by striatal medium spiny neurons (MSNs). However, the role of these channels in modulating GABA release by nerve terminals in the basal ganglia is unknown. We found that depolarization induced [(3)H]GABA release in both the substantia nigra reticulata and the external globus pallidus, was depressed by about 50% by either the selective L-channel dihydropiridine blocker nifedipine or the P/Q channel blocker ω-agatoxin TK. ⋯ In the globus pallidus nifedipine blocked the effects of D2 and A2A receptor coactivation as well as the effects of activating adenylyl cyclase with forskolin. ω-agatoxin TK did not interfere with the action of these modulatory agents. The L-type Ca(2+)-channel agonist BAYK 8644 stimulated GABA release in both substantia nigra reticulata and globus pallidus. Because dihydropiridine sensitivity is a key criteria to identify L-type Ca(2+)-channel activity, our results imply that these channels are determinant of GABA release modulation by dopamine in striatonigral, striatopallidal and pallidonigral terminals.
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We investigated in this study the pharmacological properties of AC-3933 [5-(3-methoxyphenyl)-3-(5-methyl-1, 2, 4-oxadiazol-3-yl)-1, 6-naphthyridin-2(1H)-one], a novel benzodiazepine receptor (BzR) partial inverse agonist. AC-3933 potently inhibited [(3)H]-flumazenil binding to rat whole brain membrane with a Ki value of 5.15 ± 0.39 nM and a γ-aminobutyric acid (GABA) ratio of 0.84 ± 0.03. AC-3933 exhibited almost no affinity for the other receptors, transporters and ion channels used in this study. ⋯ AC-3933 (0.1-10 μM) significantly enhanced KCl-evoked acetylcholine (ACh) release from rat hippocampal slices in a concentration dependent manner. Moreover, in vivo brain microdialysis showed that intragastric administration of AC-3933 at the dose of 10 mg/kg significantly increased extracellular ACh level in the hippocampus of freely moving rats (AUC0-2 h of ACh level; 288.3% of baseline). These results indicate that AC-3933, a potent and selective BzR inverse agonist with low intrinsic activity, might be useful in the treatment of cognitive disorders associated with degeneration of the cholinergic system.
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This study investigates the role of phonology in reading logographic Chinese. Specifically, whether phonological information is obligatorily activated in reading Chinese two-character compounds was examined using the masked-priming paradigm with ERP recordings. Twenty-two native Cantonese Chinese speakers participated in a lexical decision experiment. ⋯ In addition, attenuation in ERP amplitudes was found in the Semantic-related condition in the window of 250-500ms (N400). However, no significant results (neither behavioral nor ERP) were found in the Syllable-related condition. These results suggest that phonological activation is not mandatory and the role of phonology is minimal at best in reading Chinese two-character compounds.
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The mood stabilizing drug lithium is the most commonly used treatment for bipolar disorder. Previous studies have shown that chronic treatment with lithium produces a protective effect against oxidative stress. Nuclear factor E2-related factor 2 (Nrf2) is a gene transcription factor that binds to the electrophile response element (EpRE) and triggers expression of various genes with antioxidant properties. ⋯ Electrophorectic gel shift analysis further showed that chronic treatment with lithium increased Nrf-2 - EpRE binding activity. We also found that knocking down Nrf2 with its short hairpin RNA inhibited lithium-increased expression of Nrf2 and suppressed the protective effect of lithium against hydrogen peroxide (H2O2)-reduced cell viability and H2O2-increased DNA fragmentation. Because Nrf2 can induce expression of various genes that play important roles in cytoprotection, the current findings suggest that Nrf2 may mediate the neuroprotective effect of lithium against oxidative stress.
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In the striatum, the dendritic tree of the two main populations of projection neurons, called "medium spiny neurons (MSNs)", are covered with spines that receive glutamatergic inputs from the cerebral cortex and thalamus. In Parkinson's disease (PD), striatal MSNs undergo an important loss of dendritic spines, whereas aberrant overgrowth of striatal spines occurs following chronic cocaine exposure. This review examines the possibility that opposite dopamine dysregulation is one of the key factors that underlies these structural changes. ⋯ Recent studies have suggested that opposite calcium-mediated regulation of the transcription factor myocyte enhancer factor 2 (MEF2) function induces these structural defects. In conclusion, there is strong evidence that dopamine is a major, but not the sole, regulator of striatal spine pathology in PD and addiction to psychostimulants. Further studies of the role of glutamate and other genes associated with spine plasticity in mediating these effects are warranted.