Yoichi Kawasaki

Effect of glutamate receptor antagonists on place aversion induced by naloxone in single-dose morphine-treated rats

1 The neurobiological mechanism underlying the negative motivational component of withdrawal from acute opiate dependence is far from understood. 2 Our objectives were to determine whether the glutamatergic system is involved in the motivational component of morphine withdrawal in acutely dependent rats and such an involvement is associated with dopaminergic neurotransmission. 3 We examined the effects of various kinds of glutamate receptor antagonists on conditioned place aversion (CPA) induced by naloxone‐precipitated withdrawal from a single morphine exposure 24 h before. Furthermore, the influence of pretreatment with the dopamine receptor antagonist haloperidol on those effects of glutamate receptor antagonists was also investigated. 4 CPA was attenuated in a dose‐dependent manner by all glutamate receptor antagonists examined including the NMDA receptor antagonists (+)‐5‐methyl‐10,11‐dihydro‐5H‐dibenzo[a,d]cyclo‐hepten‐5,10‐imine maleate (MK‐801) and phencyclidine hydrochloride (PCP), AMPA receptor antagonist 1‐(4‐aminophenyl)4‐methyl‐7,8‐methylenedioxy‐5H‐2,3‐benzodiazepine hydrochloride (GYKI 52466), and metabotropic receptor antagonists (±)‐2‐amino‐3‐phosphonopropionic acid (AP‐3) and (±)‐α‐methyl‐4‐carboxyphenylglycine (MCPG). The effects of MK‐801, GYKI 52466 and MCPG were blocked by haloperidol. 5 These results suggest that the glutamatergic system involving multiple classes of receptors plays a role in the motivational component of withdrawal from acute morphine dependence, and the function of the glutamatergic system would be closely associated with dopaminergic neurotransmission.

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.

The glutamate release inhibitor riluzole attenuates the formation of conditioned place aversion induced by naloxone in rats undergoing a single morphine exposure

Acute morphine exposure has been hypothesized to produce long-lasting central changes that contribute to the withdrawal aversion. We have most recently demonstrated that those changes may involve the glutamatergic system, including multiple classes of receptors. The present study was undertaken to further determine the involvement of the glutamatergic system by examining the effect of riluzole, a glutamate release inhibitor, on the motivational component of withdrawal from acute morphine dependence. The role of the amygdala in the action of riluzole was also assessed. We investigated the effects of riluzole on the conditioned place aversion (CPA) induced by naloxone-precipitated withdrawal from a single morphine exposure 24 h before, and on c-Fos expression within the amygdala during the withdrawal period in rats. Riluzole (2, 4, 8 mg/kg) dose-dependently attenuated the CPA without producing place conditioning itself. This result provided further evidence that glutamatergic mechanisms may be recruited in adaptational changes following acute morphine exposure and play a role in withdrawal aversion. In addition, riluzole appeared to produce nonspecific effects on c-Fos expression by itself, without specifically modifying c-Fos expression following naloxone-precipitated withdrawal in any region of the amygdala examined, suggesting that the amygdala may not serve as a specific site of action for riluzole.

Effect of glutamate receptor antagonists microinjected into the nucleus accumbens on place aversion induced by naloxone in single-dose, morphine-treated rats

It is well established that acute morphine withdrawal can be observed following opioid receptor antagonism in rodents. Glutamate receptor antagonists can attenuate the conditioning place aversion (CPA) induced by naloxone in single-dose, morphine-treated rats. Anatomically, the nucleus accumbens appears to be involved in opiate dependence. In the present study, we examined the effects of various glutamate receptor antagonists in the nucleus accumbens on naloxone-induced CPA in rats. MK-801 (an NMDA receptor antagonist), GYKI52466 (an AMPA receptor antagonist), and MCPG (a metabotropic glutamate receptor antagonist) significantly attenuated naloxone-induced CPA following microinjection into the accumbens. In contrast, none of the agents showed place conditioning ability on their own in either morphine-exposed or naïve rats. The present study suggests that glutamate receptors in the nucleus accumbens play a key role in the motivational component of withdrawal during acute morphine dependence.

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.

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.

Cetuximab-induced skin reactions are suppressed by cigarette smoking in patients with advanced colorectal cancer

BackgroundSmoking is widely accepted as the most important risk factor for cancer in the modern world. Several constituents of cigarette smoke are known to interact with drug-metabolizing enzymes, potentially affecting the outcomes of drug treatment. Cetuximab (Erbitux®; Merck Serono) is indicated for the treatment of colorectal cancer with respect to restoring chemosensitivity to irinotecan in irinotecan-resistant patients. The purpose of this study was to determine whether cigarette smoking adversely affects the actions of cetuximab in the treatment of colorectal cancer.MethodsWe studied 56 patients with colorectal cancer who were treated with cetuximab in our hospital during the time period from 2009 through 2010. We compared the adverse reaction rates of 16 patients who smoked (smokers) with those of 38 patients who did not smoke (non-smokers, including 16 patients who never smoked and 22 patients who were former smokers).ResultsThe incidence of skin reactions after cetuximab treatment was lower in the smokers than in the non-smokers. In addition, the incidence of anorexia was higher in the smokers than in the non-smokers. Within the group of non-smokers, no statistically significant differences were observed between the never smokers and the former smokers with regard to adverse reactions.ConclusionOur findings suggest that cigarette smoking during anticancer treatment with cetuximab-based regimens reduces the skin reaction, which leads to a reduction in the benefit of the treatment; therefore, patients should quit smoking, at least while receiving cetuximab-based treatment.

UV-irradiated 2-methyl-4′-(methylthio)-2-morpholinopropiophenone-containing injection solution produced frameshift mutations in the Ames mutagenicity assay

In previous studies, we detected the photoinitiators 1-hydroxycyclohexyl phenyl ketone (1-HCHPK), methyl 2-benzoylbenzoate (MBB), and 2-methyl-4′-(methylthio)-2-morpholinopropiophenone (MTMP) in intravenous injection solutions. In addition, we reported that 1-HCHPK, MBB, and MTMP exhibited cytotoxicity towards normal human peripheral blood mononuclear cells. A previous in vitro study reported that a free-radical photoinitiator introduced covalently bound purine residues into DNA. However, little is known about the in vitro mutagenicity of 1-HCHPK, MBB, and MTMP. In the present in vitro study, we evaluated the mutagenicity of 1-HCHPK, MBB, and MTMP using the Ames test. We found that untreated 1-HCHPK, MBB, and MTMP were not mutagenic in S. typhimurium strain TA97, TA98, TA100, TA102, or TA1535, regardless of the presence/absence of S9 activation. However, ultraviolet (UV) light-irradiated MTMP exhibited mutagenicity in S. typhimurium strain TA97 in the absence of S9 activation. In conclusion, we suggest that exposure to UV-irradiated MTMP, including in intravenous injection solutions, can result in frameshift mutations.

Development of injection containers for patient and medical staff

Recently, there has been a transition from glass to plastic injection containers in Japan. In our previous study, we suggested that plastic containers had less impurity contamination than glass containers. However, the use of some plasticizers has been limited because of their endocrine disrupting effects. Therefore, contamination has been a concern due to chemicals in injection solution packed with plastic containers. Indeed, in our recent study, photoinitiators were detected in an injection solution coming from plastic containers. Photoinitiators mainly exist in ink. We therefore speculated that ink originating from a photoinitiator directly printing on plastic containers had migrated into the injection solutions. In a clinical setting, plastic containers are very tractable because they are lightweight and less breakable. On the other hand, from a safety view point, these containers may be hazardous because of permeation by steam, ambient air or photoinitiators. In the present symposium, we will discuss the risk of photoinitiators leaking into injection solution packed with plastic containers, and countermeasures to avoid this risk.