Glycoproteins of Capsosiphon fulvescens modulate synaptic clustering of PSD95 and prevent social isolation-induced cognitive decline in aged male rats.

Social isolation and loneliness inducing cognitive decline are serious health problems in the elderly. Although the hydrophilic glycoproteins of Capsosiphon fulvescens (Cf-hGP) prevent aging-induced cognitive impairment, its effects on social isolation-induced cognitive dysfunction are unclear. This study investigated the efficacy of Cf-hGP against cognitive dysfunction in aged rats and delineated its underlying mechanisms. The oral administration of Cf-hGP (15 mg/kg/d, 4 weeks) reversed the social isolation-induced decreases in phosphorylation of extracellular signal­regulated protein kinase 1/2 (ERK1/2), postsynaptic density protein 95, and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor subunit 1 and increased expression of metabotropic glutamate receptor 5 in the synaptosome of the dorsal hippocampus. Furthermore, Cf-hGP prevented social isolation-induced spatial memory impairment, and its effects were attenuated by inhibition of ERK1/2 or deglycosylation of Cf-hGP. Cf-hGP-induced clustering of ERK1/2-mediated postsynaptic density protein 95 in the dorsal hippocampus improves memory formation in socially isolated aged rats, and protein glycosylation contributes to enhancing the Cf-hGP effect.

Interaction of JNK and mGluR5 in the regulation of psychomotor behaviours after repeated cocaine administration.

Activation of protein kinases after cocaine administration controls psychomotor behaviours by interacting with metabotropic receptors in the brain. This study identified how c-Jun N-terminal kinase (JNK) interacts with metabotropic glutamate receptor 5 (mGluR5) in vitro and in the caudate and putamen (CPu). The potential role of this interaction in the regulation of psychomotor behaviour was also evaluated after administration of cocaine. Active JNK phosphorylates a threonine residue at position 1055 in the carboxyl terminus (CT) of mGluR5 in vitro. The binding of active JNK to the D-motif within CT2 is necessary for that phosphorylation. Interaction of phosphorylated JNK and mGluR5 occurs in the CPu. Unilateral interference of the interaction decreases the repeated cocaine-induced increases in locomotor activity and conditioned place preference. These findings suggest that activation of JNK has the capability to interact with mGluR5 in the CPu. Phosphorylation of mGluR5 following the JNK-mGluR5 interaction may be responsible for the potentiation of behavioural sensitisation and cocaine-wanting behaviour in response to cocaine administration.

Repeated nicotine exposure increases the intracellular interaction between ERK-mGluR5 in the nucleus accumbens more in adult than adolescent rats.

Intracellular interactions between protein kinases and metabotropic receptors in the striatum regulate behavioral changes in response to drug exposure. We investigated the difference in the degree of interaction between extracellular signal-regulated kinase (ERK) and metabotropic glutamate receptor subtype 5 (mGluR5) in the nucleus accumbens (NAc) after repeated exposure to nicotine in adult and adolescent rats. The results showed that repeated exposure to nicotine (0.5 mg/kg/day, s.c.) for seven consecutive days increased ERK phosphorylation more in adults than in adolescents. Furthermore, membrane expression of mGluR5 in gamma-aminobutyric acid (GABA) medium spiny neurons was higher in adults than adolescents as a result of repeated exposure to nicotine. Blockade of mGluR5 with MPEP (0.5 nmol/side) decreased the repeated nicotine-induced increase in ERK phosphorylation. Either blockade of mGluR5 or inhibition of ERK with SL327 (150 nmol/side) decreased the repeated nicotine-induced increase in the level of inositol-1,4,5-triphosphate (IP3 ), a key transducer associated with mGluR5-coupled signaling cascades. Similarly, interference of binding between activated ERK and mGluR5 by the blocking peptide, Tat-mGluR5-i (2 nmol/side), decreased the repeated nicotine-induced increases in IP3 and locomotor activity in adults. These findings suggest that the intracellular interaction between ERK and mGluR5 in the NAc is stronger in adult than in adolescent rats, which enhances the understanding of age-associated behavioral changes that occur after repeated exposure to nicotine.

Capsosiphon fulvescens Glycoproteins Enhance Probiotics-Induced Cognitive Improvement in Aged Rats.

Aging-induced cognitive dysfunction can be regulated by probiotics through bidirectional communication with the brain. This study aimed to investigate whether Capsosiphon fulvescens glycoproteins (Cf-hGP) enhanced probiotic-induced improvement of memory in aged rats and the underlying mechanism in the dorsal hippocampus. Cf-hGP were isolated using lectin resin. Cf-hGP (15 mg/kg/day) and/or Lactobacillus plantarum (L. plantarum) (109 CFU/rat/day) were orally administered once a day for 4 weeks. Co-treatment with Cf-hGP and L. plantarum synergistically improved spatial memory in aged rats, which was overturned by functional blocks of brain-derived neurotrophic factor (BDNF) signaling. Increases in BDNF expression and nuclear factor erythroid 2-related factor 2 (Nrf2) phosphorylation were accompanied by mono- and/or co-administration in the dorsal hippocampus, while c-Jun N-terminal kinase (JNK) phosphorylation and glucose-regulated protein 78 expression were decreased. These synergistic effects were downregulated by blocks of BDNF/Nrf2-mediated signaling. In particular, co-treatment, not mono-treatment, reduced phosphorylation of eukaryotic elongation factor 2 (eEF2) regulated by eEF2 kinase and protein phosphatase 2A. Additionally, co-treatment downregulated the interaction between eEF2 kinase and JNK. These data demonstrated that cognitive impairment in aged rats was synergistically diminished by co-treatment with Cf-hGP and L. plantarum through BDNF-mediated regulation of Nrf2 and eEF2 signaling pathways in the dorsal hippocampus.

Synthesis of Metal Boride Nanoparticles Using Triple Thermal Plasma Jet System.

Titanium, nickel, and tungsten boride nanoparticles were synthesized in the triple thermal plasma jet system. The coalesced high-enthalpy thermal plasma jet not only generates extensive high temperature regions but also allows the starting materials to penetrate into the center of high temperature regions effectively. The synthesis process of metal boride was investigated according to the nucleation temperature of three metals and boron. In the case of titanium and nickel borides synthesis, metals nucleation temperatures are lower than boron. The crystallinity of synthesized titanium boride nanoparticles was higher than nickel boride nanoparticles, since not only the nucleation temperature of titanium is higher than nickel but also the Gibbs free energy of all titanium boride was lower than whole nickel boride. However, the nucleation temperature of tungsten is higher than boron where nanoparticle synthesis process differed from former synthesis processes. It had influence on the crystal growth time in the high temperature regions where tungsten boride crystal structure was strongly prepared than nickel boride nanoparticles.

Synthesis of Tungsten Carbide Nanomaterials in Triple DC Thermal Plasma Jet System.

The tungsten carbide nanomaterials were synthesized in the triple DC thermal plasma jet system using refractory tungsten, and carbon sources such as multi wall carbon nanotube (MWCNT), amorphous carbon and methane. The starting materials were evaporated in the high temperature region of triple plasma jet, then condensed particles were prepared in nanoscale under 100 nm. The effect of carbon sources was investigated on a view of crystal phase structure and morphology. W2C crystal nanoparticles were mainly synthesized and WC and WC1-x phase nanoparticles were observed additionally with all carbon sources. From MWCNT starting material, tungsten carbide attached MWCNT composite were produced with spherical tungsten carbide nanoparticles. In case of amorphous carbon, spherical and rod-shaped tungsten carbide was synthesized. Only spherical tungsten carbide nanoparticles were synthesized by methane. In addition, it was revealed that the main crystal structure was changed from W2C to WC1-x by increasing W/CH4 composition ratio.

Hydrophilic Glycoproteins of an Edible Green Alga Capsosiphon fulvescens Prevent Aging-Induced Spatial Memory Impairment by Suppressing GSK-3ß-Mediated ER Stress in Dorsal Hippocampus.

Endoplasmic reticulum (ER) stress is involved in various neurodegenerative disorders. We previously found that Capsosiphon fulvescens (C. fulvescens) crude proteins enhance spatial memory by increasing the expression of brain-derived neurotrophic factor (BDNF) in rat dorsal hippocampus. The present study investigated whether the chronic oral administration of hydrophilic C. fulvescens glycoproteins (Cf-hGP) reduces aging-induced cognitive dysfunction by regulating ER stress in the dorsal hippocampus. The oral administration of Cf-hGP (15 mg/kg/day) for four weeks attenuated the aging-induced increase in ER stress response protein glucose-regulated protein 78 (GRP78) in the synaptosome of the dorsal hippocampus; this was attenuated by the function-blocking anti-BDNF antibody (1 µg/µL) and a matrix metallopeptidase 9 inhibitor 1 (5 µM). Aging-induced GRP78 expression was associated with glycogen synthase kinase-3 beta (GSK-3ß) (Tyr216)-mediated c-Jun N-terminal kinase phosphorylation, which was downregulated upon Cf-hGP administration. The Cf-hGP-induced increase in GSK-3ß (Ser9) phosphorylation was downregulated by inhibiting tyrosine receptor kinase B and extracellular signal-regulated kinase (ERK)1/2 with cyclotraxin-B (200 nM) and SL327 (10 µM), respectively. Cf-hGP administration or the inhibition of ER stress with salubrinal (1 mg/kg, i.p.) significantly decreased aging-induced spatial memory impairment. These findings suggest that the activation of the synaptosomal BDNF-ERK1/2 signaling in the dorsal hippocampus by Cf-hGP attenuates age-dependent ER stress-induced cognitive dysfunction.

Fucosterol from an Edible Brown Alga Ecklonia stolonifera Prevents Soluble Amyloid Beta-Induced Cognitive Dysfunction in Aging Rats.

Fucosterol from edible brown seaweeds has various biological activities, including anti-inflammatory, anti-adipogenic, antiphotoaging, anti-acetylcholinesterase, and anti-beta-secretase 1 activities. However, little is known about its effects on soluble amyloid beta peptide (sAß)-induced endoplasmic reticulum (ER) stress and cognitive impairment. Fucosterol was isolated from the edible brown seaweed Ecklonia stolonifera, and its neuroprotective effects were analyzed in primary hippocampal neurons and in aging rats. Fucosterol attenuated sAß1-42-induced decrease in the viability of hippocampal neurons and downregulated sAß1-42-induced increase in glucose-regulated protein 78 (GRP78) expression in hippocampal neurons via activation of tyrosine receptor kinase B-mediated ERK1/2 signaling. Fucosterol co-infusion attenuated sAß1-42-induced cognitive impairment in aging rats via downregulation of GRP78 expression and upregulation of mature brain-derived neurotrophic factor expression in the dentate gyrus. Fucosterol might be beneficial for the management of cognitive dysfunction via suppression of aging-induced ER stress.

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.

Association between preoperative high sensitive troponin I levels and cardiovascular events after hip fracture surgery in the elderly.

OBJECTIVE: Cardiovascular complications contribute to postoperative morbidity and mortality in elderly hip fracture patients. Limited data are available regarding which preoperative risk factors predict cardiovascular course following hip fracture surgery (HFS). We used high sensitive troponin I (hs-TnI) assays and clinical parameters to identify preoperative risk factors associated with major adverse cardiac events (MACE) in elderly hip fracture patients. METHOD: From August 2014 to November 2016, 575 patients with hip fracture were enrolled in a retrospective, single-center registry. A total of 262 of these patients underwent HFS and hs-TnI assays. MACE was defined as postoperative all-cause deaths, heart failure (HF), new-onset atrial fibrillation (AF), myocardial infarction (MI) and cardiovascular re-hospitalization that occurred within 90 days postoperative. RESULTS: Of 262 HFS patients, MACE developed following HFS in 65 (24.8%). Patients with MACE were older and had higher rates of renal insufficiency, coronary artery disease, prior HF, low left ventricular ejection fraction and use of beta blockers; higher levels of hs-TnI and N-terminal pro-brain natriuretic peptide (NT-proBNP) and higher revised cardiac risk index. A preoperative hs-TnI ≥ 6.5 ng/L was associated with high risk of postoperative HF, new-onset AF and MACE. In multivariable analysis, preoperative independent predictors for MACE were age > 80 years [adjusted hazard ratio (HR): 1.79, 95% confident interval (CI): 1.03-3.13, P = 0.04], left ventricular ejection fraction (LVEF) < 50% (adjusted HR: 3.17, 95% CI: 1.47-6.82, P < 0.01) and hs-TnI > 6.5 ng/L (adjusted HR: 3.75, 95% CI: 2.09-6.17, P < 0.01). CONCLUSION: In elderly patients with hip fracture who undergo HFS, a preoperative assessment of hs-TnI may help the risk refinement of cardiovascular complications.

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.

Phycoerythrin-Derived Tryptic Peptide of a Red Alga Pyropia yezoensis Attenuates Glutamate-Induced ER Stress and Neuronal Senescence in Primary Rat Hippocampal Neurons.

SCOPE: Glutamate excitotoxicity has been observed in association with neurodegenerative disorders. This study aimed to investigate whether a phycoerythrin-derived tryptic peptide of Pyropia yezoensis (PYP) reduces glutamate-induced excitotoxicity and neuronal senescence in primary rat hippocampal neurons. METHODS AND RESULTS: Glutamate exposure (100 µm) decreased cell viability and increased expression of endoplasmic reticulum (ER) stress response protein glucose-regulated protein 78 (GRP78) starting at 60 min following glutamate exposure, which was prevented by pretreating the neurons with PYP (1 µg mL-1 ). The glutamate-induced increase in GRP78 expression was downregulated by blocking N-methyl-d-aspartate (NMDA) receptor with MK801 (10 µm) and inhibiting c-Jun N-terminal kinase (JNK) phosphorylation with SP600125 (10 µm). Moreover, phosphorylation of JNK was decreased by blockade of NMDA receptor. The PYP pretreatment downregulated glutamate-induced increase in GRP78 expression and JNK phosphorylation, and this effect was abolished by inhibiting tropomyosin-related kinase B (TrkB) receptor, phosphatidylinositiol 3-kinase, and extracellular signal-regulated kinase (ERK)1/2 using cyclotraxin B (200 nm), LY294002 (20 µm), and SL327 (10 µm), respectively. In addition, PYP downregulated increase in GRP78 expression, senescence-associated ß-galactosidase activity, and neurite degeneration in aging hippocampal neurons. CONCLUSION: These findings indicate that activation of TrkB receptor-mediated ERK1/2 by PYP attenuates glutamate-induced ER stress, which may improve the survival of hippocampal neurons with age.

Sewable soft shields for the γ-ray radiation.

Soft shields are required to protect the human body during a radioactive accident. However, the modulus of most soft shields, such as HDPE and epoxy, is high, thereby making it difficult to process them in wearable forms like gloves and clothes. We synthesized a soft shield based on a hydrogel that is very compliant, stretchable, and biocompatible. The shields were fabricated by integrating γ-ray-shield particles into hydrogels with an interpenetrating network. The soft shields containing 3.33 M of PbO2 exhibited a high attenuation coefficient (0.284 cm-1) and were stretched to 400% without a rupture. Furthermore, the fabricated soft shield can be sewn without a fabric support due to its high energy-dispersion ability. A wearable arm shield for the γ-ray radiation was demonstrated using a direct sewing of the soft-shield materials.

Phycoerythrin Peptide from Pyropia yezoensis Alleviates Endoplasmic Reticulum Stress Caused by Perfluorooctane Sulfonate-Induced Calcium Dysregulation.

Perfluorooctane sulfonate (PFOS), a stable fluorosurfactant, causes endoplasmic reticulum (ER) stress in the brain. This study was designed to investigate whether a phycoerythrin-derived peptide of Pyropia yezoensis (PYP) reduces PFOS-induced ER stress associated with calcium dysregulation. The protective effects of PYP were determined by cell viability, immunoblotting for ER stress response protein glucose-regulated protein 78 (GRP78) and calcium-dependent protein kinases in rat frontal cortical neurons. PFOS-induced decrease in cell viability was attenuated by PYP pretreatment (1 µg/mL) for 24 h, which was downregulated by inhibiting tropomyosin-receptor kinase B (TrkB). PYP pretreatment downregulated the increase in intracellular calcium levels and phosphorylation of calcium/calmodulin-dependent protein kinase II and c-Jun N-terminal kinase which are associated with a PFOS-induced increase in GRP78. The PFOS-induced increase in GRP78 was downregulated via activation of TrkB receptor-linked extracellular signal-regulated kinases 1/2 (ERK1/2) by PYP pretreatment. Moreover, PYP microinjections (1 µg/kg, 0.54 nmol) attenuated the GRP78 expression in rat prefrontal cortex caused by PFOS (10 mg/kg) exposure for 2 weeks. These findings demonstrate that PYP enhances frontal cortical neuron viability via activation of TrkB receptor-ERK1/2 signaling and attenuation of ER stress in rat prefrontal cortex against PFOS exposure, suggesting that PYP might prevent neuronal dysfunctions caused by PFOS-induced ER stress.

Behavioral changes after nicotine challenge are associated with α7 nicotinic acetylcholine receptor-stimulated glutamate release in the rat dorsal striatum.

Neurochemical alterations associated with behavioral responses induced by re-exposure to nicotine have not been sufficiently characterized in the dorsal striatum. Herein, we report on changes in glutamate concentrations in the rat dorsal striatum associated with behavioral alterations after nicotine challenge. Nicotine challenge (0.4 mg/kg/day, subcutaneous) significantly increased extracellular glutamate concentrations up to the level observed with repeated nicotine administration. This increase occurred in parallel with an increase in behavioral changes in locomotor and rearing activities. In contrast, acute nicotine administration and nicotine withdrawal on days 1 and 6 did not alter glutamate levels or behavioral changes. Blockade of α7 nicotinic acetylcholine receptors (nAChRs) significantly decreased the nicotine challenge-induced increases in extracellular glutamate concentrations and locomotor and rearing activities. These findings suggest that behavioral changes in locomotor and rearing activities after re-exposure to nicotine are closely associated with hyperactivation of the glutamate response by stimulating α7 nAChRs in the rat dorsal striatum.

Negative regulation of ERK1/2 by PI3K is required for the protective effects of Pyropia yezoensis peptide against perfluorooctane sulfonate-induced endoplasmic reticulum stress.

Perfluorooctane sulfonate (PFOS) is a stable fluorosurfactant, which causes adverse effects in various organisms. The present study was designed to investigate the effects of Pyropia yezoensis peptide (PYP), a peptide comprised of 11 residues (ALEGGKSSGGG), on PFOS-induced endoplasmic reticulum (ER) stress in Chang cells. PFOS exposure (400 µM) for 24 h significantly decreased cell viability, which was upregulated by 250­1,000 pg/ml PYP treatment. Exposure to PFOS also significantly increased expression of the ER stress response protein, glucose-regulated protein 78 (GRP78), and phosphorylation of extracellular signal­regulated kinase 1/2 (ERK1/2). These elevations were significantly decreased by PYP (250 pg/ml), and, in particular, the PFOS­induced GRP78 upregulation was decreased following treatment with 10 µM SL327, an ERK­kinase inhibitor. However, PYP­induced decreases in GRP78 expression and ERK1/2 phosphorylation were upregulated following treatment with LY294002 (20 µM), a phosphatidylinositol­3 kinase (PI3K) inhibitor. PFOS-induced apoptosis was also significantly attenuated by PYP (250 pg/ml) treatment, and the PYP­induced reduction in apoptosis was abolished by inhibition of PI3K. These findings indicate that negative regulation of ERK1/2 by PI3K is essential for the protective effects of PYP against PFOS-induced cell death, suggesting that PYP may be a candidate for therapeutic use.

Dopamine D4 receptors linked to protein kinase G are required for changes in dopamine release followed by locomotor activity after repeated cocaine administration.

We previously found that the dopamine D2-type receptors (D2 and D3 receptors), coupled to protein kinase G (PKG), upregulate locomotor activity after repeated cocaine administration. In this study, D4 receptors, another type of D2 receptor also coupled to PKG, were examined to determine their requirement in the regulation of locomotor activity after repeated cocaine administration. The results demonstrated that repeated injections of cocaine (20 mg/kg), given once a day for seven consecutive days, significantly increased extracellular dopamine concentrations. Intra-caudate infusion of the D4 receptor agonist, PD168077 (10 nmol), and the PKG inhibitor, KT5823 (2 nmol), significantly decreased the repeated cocaine-induced increase in dopamine levels and locomotor activity. However, intra-caudate infusion of KT5823, but not PD168077, decreased ∆FosB immunoreactivity elevated by repeated cocaine administration. These findings suggest that D4 receptors linked to PKG could be a key modulator for dopamine release required for changes in locomotor activity caused by repeated cocaine exposure.

Analysis of the contribution of wind drift factor to oil slick movement under strong tidal condition: Hebei Spirit oil spill case.

The purpose of this study is to investigate the effects of the wind drift factor under strong tidal conditions in the western coastal area of Korea on the movement of oil slicks caused by the Hebei Spirit oil spill accident in 2007. The movement of oil slicks was computed using a simple simulation model based on the empirical formula as a function of surface current, wind speed, and the wind drift factor. For the simulation, the Environmental Fluid Dynamics Code (EFDC) model and Automatic Weather System (AWS) were used to generate tidal and wind fields respectively. Simulation results were then compared with 5 sets of spaceborne optical and synthetic aperture radar (SAR) data. From the present study, it was found that highest matching rate between the simulation results and satellite imagery was obtained with different values of the wind drift factor, and to first order, this factor was linearly proportional to the wind speed. Based on the results, a new modified empirical formula was proposed for forecasting the movement of oil slicks on the coastal area.

Protein kinase G regulates dopamine release, ΔFosB expression, and locomotor activity after repeated cocaine administration: involvement of dopamine D2 receptors.

Protein kinase G (PKG) activation has been implicated in the regulation of synaptic plasticity in the brain. This study was conducted to determine the involvement of PKG-associated dopamine D2 (D2) receptors in the regulation of dopamine release, ΔFosB expression and locomotor activity in response to repeated cocaine exposure. Repeated systemic injections of cocaine (20 mg/kg), once a day for seven consecutive days, increased cyclic guanosine monophosphate (cGMP) and extracellular dopamine concentrations in the dorsal striatum. Inhibition of neuronal nitric oxide synthase (nNOS), cGMP or PKG and stimulation of D2 receptors decreased the repeated cocaine-induced increase in dopamine concentrations. Similar results were obtained by the combining nNOS, cGMP or PKG inhibition with stimulation of D2 receptors. Parallel to these data, PKG inhibition, D2 receptor stimulation, and combining PKG inhibition with stimulation of D2 receptors decreased the repeated cocaine-induced increases in ΔFosB expression and locomotor activity. These findings suggest that control of D2 receptors by PKG activation after repeated cocaine is responsible for upregulating dopamine release and sustained long-term changes in gene expression in the dopamine terminals and gamma-aminobutyric acid neurons of the dorsal striatum, respectively. This upregulation may contribute to behavioral changes in response to repeated exposure to cocaine.

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.