Satoru Esumi

Effect of GBR12909 on affective behavior: Distinguishing motivational behavior from antidepressant-like and addiction-like behavior using the runway model of intracranial self-stimulation

RATIONALE It was recently demonstrated that the priming stimulation effect (PSE) in the runway model of intracranial self-stimulation (ICSS) can be used as a model system to study the motivational effects of drugs. However, the characteristics of this novel experimental model have not been fully clarified. OBJECTIVE To elucidate the involvement of dopamine uptake inhibition in motivated behavior and the difference in experimental characteristics between closely related experimental models, we investigated the effects of the dopamine uptake inhibitor GBR12909 in the runway ICSS model, in the forced swimming test (FST), and on conditioned place preference (CPP). In addition, the role of dopamine receptor signaling in the runway model was evaluated using dopamine receptor agonists and antagonists. RESULTS GBR12909 dose-dependently increased running speed on the runway and decreased immobility time in the FST without affecting the time spent in the drug-associated compartment in CPP tests. The effect of GBR12909 in the runway model was inhibited by pre-treatment with the dopamine receptor antagonists haloperidol and raclopride. The dopamine receptor agonists SKF38393 and quinpirole dose-dependently decreased running speed. CONCLUSIONS These results demonstrate that GBR12909 displays motivation-enhancing and antidepressant-like effects without place conditioning effects. In addition, the mechanisms of PSE enhancement in the runway ICSS model are different from those underlying closely associated experimental models and are mediated by increases in dopamine signaling.

Photoinitiators enhanced 1,2-dichloropropane-induced cytotoxicity in human normal embryonic lung fibroblasts cells in vitro

Dichloromethane (DCM) and 1,2-dichloropsropane (DCP) have various uses, including being solvents for paint removers. Photoinitiators are also used in a wide range of commercial applications such as printing. These chemicals have been shown to induce cytotoxic effects. In the present study, we evaluated the combined effects of DCM or DCP from paint removers and photoinitiators used in printing on normal human embryonic lung fibroblasts with the aim of preventing occupational injuries. We showed that DCP, 2,2-dimethoxy-2-phenylacetophenone (2,2-DMPAP), 2-ethylhexyl-4-(dimethylamino) benzoate (2-EHDAB), 1-hydroxycyclohexyl phenyl ketone (1-HCHPK), and methyl 2-benzoylbenzoate (MBB) induced cytotoxicity, whereas DCM and 2-isopropylthioxanthone (2-ITX) did not. In addition, 2-methyl-4′-(methylthio)-2-morpholinopropiophenone (MTMP) caused a slight increase in cytotoxicity. The combination of DCP and the four photoinitiators (2,2-DMPAP, 2-EHDAB, MBB, and MTMP) significantly induced cytotoxicity and also led to apoptosis. In conclusion, the combination of DCP and photoinitiators may increase the risk of respiratory diseases.

Differential effects of nomifensine and imipramine on motivated behavior in the runway model of intracranial self-stimulation

A motivational deficit (the loss of pleasure or interest in previously rewarding stimuli) is one of the core symptoms of major depression, and valid models evaluating the motivational effects of drugs are needed. It was recently demonstrated that the priming stimulation effect in the runway model of intracranial self-stimulation (ICSS) can be used as a model system to study the motivational effects of drugs. However, the characteristics of this novel experimental model have not been fully clarified. In this study, we investigated the effects of nomifensine and imipramine in the runway ICSS model, forced swim tests, and locomotor activity tests to differentiate motivation from affective-like states. Nomifensine dose-dependently increased running speed on the runway and decreased immobility time in the forced swim test. In contrast, imipramine decreased running speed on the runway although it also decreased immobility time in the forced swim test. In addition, the motivation-enhancing effect of nomifensine in the runway model was completely inhibited by pretreatment with the dopamine receptor antagonist haloperidol, although nomifensine-induced increases in locomotion were not affected by haloperidol. These results demonstrate that nomifensine displays motivation-enhancing and antidepressant-like effects. In addition, the motivational effects of nomifensine in the runway ICSS model are primarily mediated by dopamine receptors and enhancements of motivated behavior do not simply reflect hyperlocomotion.

Intracranial self-stimulation-reward induces neurite extension in PC12m3 cells and activation of the p38 MAPK pathway

Factors that trigger emotional expression may be divided into two patterns according to the type of motivation, acquiring reward (pleasure) and avoiding aversion (punishment). Repeated exposure to certain external stimuli accompanied by aberrant motivation may produce psychiatric diseases such as bipolar disorder and addiction via dysregulation of the central nervous system. However, neurobiological underpinnings of such diseases have not been clarified, especially at the neuronal level. In the present study, plasma from rats undergoing intracranial self-stimulation (ICSS) produced neurite outgrowth in PC12-variant cells (PC12m3). Stimulated PC12m3 cells also exhibited heightened activity of the p38 MAPK pathway. These findings indicate that reward states lead to not only morphological changes but also increases in p38 MAPK activity at the neuronal level in the central nervous system.

Photoinitiator-Initiated Estrogenic Activity in Human Breast Cancer Cell Line MCF-7

A recent in vitro study reported that the photoinitiator 2-isopropylthioxanthone (2-ITX) is an endocrine-disrupting compound (EDC). However, it is not clear whether other photoinitiators such as 1-hydroxycyclohexyl phenyl ketone (1-HCHPK) and 2-methyl-4′-(methylthio)-2-morpholinopropiophenone (MTMP) produce endocrine-disrupting effects. The purpose of this study was thus to assess the association between estrogenic activity and exposure to photoinitiators. For estimation of the proliferative effect of the photoinitiators, the E-screen assay was used. Six photoinitiators, 2,2-dimethoxy-2-phenylacetophenone (2,2-DMPAP), 2-ethylhexyl 4-(dimethylamino)benzoate (2-EHDAB), 1-HCHPK, 2-ITX, methyl-2-benzoylbenzoate (MBB), and MTMP, significantly increased number of MCF-7 cells, an estrogen-sensitive human breast cancer cell line. In addition, pretreatment with estrogen receptor (ER) antagonists such as clomiphene, tamoxifen, or fulvestrant, significantly reversed the proliferative effect of each photoinitiator. Data demonstrated that the six photoinitiators produced endocrine-disrupting effects and that these photoinitiators interacted with ER as agonists. Evidence indicates that the six photoinitiators demonstrated estrogenic activity via ER as agonists.

Administration of kampo medicine through a tube at an advanced critical care center

n emergency and critical care medical centers, tube administration is employed for patients who have difficulty swallowing oral drugs owing to decreased consciousness or mechanical ventilation. However, tube clogging due to drug injection is a concern. We compared the crushing method with the simple suspension method for the passage of amlodipine, an antihypertensive drug, in combination with rikkunshito, which has been used to treat upper gastrointestinal disorders such as functional dyspepsia and gastroesophageal reflux in emergency and critical care medical centers, to ascertain the effect of Kampo products on the passage of other drugs during tube administration. When the crushing method was employed, poorly water-soluble solid products were formed, while a uniformly dispersed suspension was obtained using the simple suspension method. In addition, the passage rate of amlodipine through the tube was 64% and 93% in the crushing and simple suspension methods, respectively, thereby indicating that the simple suspension method provided more favorable than the crushing method. The results of this study suggested that the passage rate of amlodipine for patients who received Kampo products concurrently was higher when the simple suspension method was used, and an appropriate drug amount might well be able to administered to patients using this method. J. Med. Invest. 65:32-36, February, 2018.

Intracranial self-stimulation and immobilization had different effects on neurite extension and the p38 MAPK pathway in PC12m3 cells

Aim: In mammals, rewarding and aversive states are motivational drivers of behavioral expression. However, it is unclear whether such states affect neuronal functions at the level of individual neurons. In the present study, the neuronal effects of rewarding and aversive states were investigated in using PC12 mutant cells (PC12m3 cells) with low sensitivity to nerve growth factor. Main methods: The intracranial self‐stimulation (ICSS) and immobilization (IMM) methods were used to create rewarding and aversive states, respectively, in rats. Furthermore, experiments involving voluntary running on a wheel and forced running on a rotating rod were used to evaluate the effects of behavioral excitement on neurons. Then, the effects of plasma samples collected from the animals on neurite extension were examined microscopically, and p38 mitogen‐activated protein kinase (MAPK) activity was assessed using Western blotting. Key findings: Plasma samples from the ICSS and IMM rats facilitated neurite outgrowth to different degrees. However, their effects were not influenced by behavioral excitement. Furthermore, the plasma from the ICSS rats also induced upregulated p38 MAPK activity, whereas that from the IMM rats produced the same or slightly lower levels of MAPK activity to the control plasma. Significance: These findings indicate that rewarding and aversive states might cause morphological changes, such as neurite extension. As for the effects of these states on p38 MAPK activity, the former state might directly increase p38 MAPK activity, but the latter state might have no effect or cause a slight reduction in p38 MAPK activity. Graphical abstract Figure. No caption available.