Jeong Hwan Oh

Protein kinase G increases AMPA receptor GluR1 phosphorylation at serine 845 after repeated cocaine administration in the rat nucleus accumbens.

The regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluR1 subunit phosphorylation at serine 845 (GluR1-Ser845) by protein kinase G (PKG) activation was investigated in the nucleus accumbens (NAc) after repeated cocaine administration. Intra-NAc injection of the cyclic guanosine monophosphate (cGMP) analog, Rp-8-Br-PET-cGMPS (5 nmol) and the PKG inhibitor, KT5823 (2 nmol), prior to the final drug injection significantly decreased GluR1-Ser845 phosphorylation elevated by repeated systemic injections of cocaine (20mg/kg) once a day for seven consecutive days. The inhibition of PKG also attenuated Ca(2+)-calmodulin-dependent protein kinases II (CaMKII) phosphorylation, however inhibition of CaMKII with KN62 (20 nmol) did not alter the phosphorylation state of GluR1-Ser845. Similarly, inhibition of cGMP or PKG attenuated the repeated cocaine-induced increase in locomotor activity. These findings suggest that the AMPA receptor provides a PKG-sensitive phosphorylation site on GluR1-Ser845 in the NAc after repeated cocaine, thus contributing to behavioral alterations.

Alterations in differentially expressed genes by exposure to a mixture of carcinogenic polycyclic aromatic hydrocarbons in the liver of Oryzias latipes.

The effects of a mixture of carcinogenic polycyclic aromatic hydrocarbons (cPAHs) on transcriptional responses in the liver of medaka, Oryzias latipes, were investigated by identifying differentially expressed genes (DEGs). Five DEGs were identified as cytochrome P450 2P1 (CYP450 2P1), malate dehydrogenase, anti-thrombin III, NADH dehydrogenase subunit 4, and transferrin. These DEGs were quantified by real-time polymerase chain reaction. Only CYP450 2P1 mRNA was found to be upregulated by exposure to cPAHs mixture, suggesting that CYP450 2P1 mRNA can be a potential marker for prediction of the biological effects of a mixture of cPAHs on fish.

Protein kinase G linked to dopamine D3 receptors in the dorsal striatum controls dopamine release, ΔFosB expression and locomotor activity after repeated cocaine administration.

Protein kinase G (PKG) has been implicated in a variety of physiological functions including synaptic plasticity in the brain. This study investigated the involvement of dopamine D3 (D3) receptors in PKG-regulated dopamine release, long-term changes in gene expression and behavioral sensitization after repeated cocaine administration. Repeated systemic injections of cocaine (20mg/kg), once a day for seven consecutive days, increased extracellular dopamine concentrations in the dorsal striatum. Inhibition of neuronal nitric oxide synthase, cGMP or PKG, stimulation of D3 receptors, and simultaneous inhibition of each of them with D3 receptor stimulation decreased the repeated cocaine-induced increase in dopamine concentrations and locomotor activity. Similarly, inhibition of PKG and simultaneous inhibition of PKG with D3 receptor stimulation decreased ΔFosB immunoreactivity elevated by repeated cocaine administration, however stimulation of D3 receptors alone did not. These findings suggest that activation of PKG after repeated cocaine administration is more sensitive to interact with D3 receptors in the dopamine terminals than those in medium spiny neurons. This interaction may result in the development of behavioral sensitization by the upregulation of dopamine releases in the dorsal striatum.

Activation of Protein Kinase G After Repeated Cocaine Administration Is Necessary for the Phosphorylation of α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor GluA1 at Serine 831 in the Rat Nucleus Accumbens

Phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the striatum plays a crucial role in regulating the receptor-coupled signaling cascades leading to behavioral changes associated with psychostimulant exposure. The present study determined if activation of protein kinase G (PKG) contributes to the phosphorylation of AMPA receptor GluA1 subunit at the position of serine 831 (GluA1-S831) in the rat nucleus accumbens (NAc) after repeated cocaine administration. The results demonstrated that repeated intraperitoneal (i.p.) injections of cocaine (20 mg/kg) once a day for seven consecutive days significantly increased the level of phosphorylated (p)GluA1-S831. This increase was decreased by the intra-NAc infusion of either the cyclic guanosine monophosphate (cGMP) analog, Rp-8-Br-PET-cGMPS (5 nmol/1 μL), or the PKG inhibitor, KT5823 (2 nmol/1 μL). Repeated cocaine administration increased PKG binding activity to GluA1. This increase in GluA1-S831 phosphorylation after repeated cocaine administration was decreased by the intra-NAc infusion of the synthetic peptide (Tat-tagged interfering peptide (Tat-GluA1-i)), that interferes with the binding of PKG to GluA1. Intra-NAc infusion of the interfering peptide also reduced the repeated cocaine-induced increase in locomotor activity. These findings suggest that activated PKG, after repeated exposure to cocaine, binds to AMPA receptor GluA1 and is required for the phosphorylation of S831, contributing to behavioral changes.

Repeated Administration of Cigarette Smoke Condensate Increases Glutamate Levels and Behavioral Sensitization

Nicotine, a nicotinic acetylcholine receptor agonist, produces the reinforcing effects of tobacco dependence by potentiating dopaminergic and glutamatergic neurotransmission. Non-nicotine alkaloids in tobacco also contribute to dependence by activating the cholinergic system. However, glutamatergic neurotransmission in the dorsal striatum associated with behavioral changes in response to cigarette smoking has not been investigated. In this study, the authors investigated alterations in glutamate levels in the rat dorsal striatum related to behavioral alterations after repeated administration of cigarette smoke condensate (CSC) using the real-time glutamate biosensing and an open-field behavioral assessment. Repeated administration of CSC including 0.4 mg nicotine (1.0 mL/kg/day, subcutaneous) for 14 days significantly increased extracellular glutamate concentrations more than repeated nicotine administration. In parallel with the hyperactivation of glutamate levels, repeated administration of CSC-evoked prolonged hypersensitization of psychomotor activity, including locomotor and rearing activities. These findings suggest that the CSC-induced psychomotor activities are closely associated with the elevation of glutamate concentrations in the rat dorsal striatum.

Characterization of proteins in the gonad of Limanda yokohamae from Masan Bay, Korea

The putative biological effects of the toxic organic pollutants polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and the dioxin-like polychlorinated biphenyls (DLPCBs) in the sediments of Masan Bay, Korea, on the gonad of Limanda yokohamae were investigated using proteomic and bioinformatic analyses. The results demonstrated that 11 protein spots from the bay site, Duckdong, were statistically different from the reference site Gaduck Island. We identified 20 proteins from the 11 altered protein spots and these were found to be involved in multi-cellular functions as previously demonstrated in a variety of species. The concentrations of toxic equivalents of PCDD/Fs and DLPCBs in the sediments of Masan Bay were approximately twenty six-fold higher than those from Gaduck Island. These findings indicate that the organic contaminants in the sediments of Masan Bay may have contributed to the change in the phenotypes of fish gonads.