Three photoinitiators induce breast tumor growth in mouse xenografts with MCF-7 breast cancer cells.

Photoinitiators are utilized in the production of a wide range of commonly used products. However, some photoinitiators exert toxic effects. We previously demonstrated the endocrine-disrupting effects of photoinitiators in vitro. The present study investigated the estrogenic activities of three photoinitiators: 1-hydroxycyclohexyl phenyl ketone (1-HCHPK), methyl 2-benzoylbenzoate (MBB), and 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (MTMP), which were subcutaneously injected into mouse xenografts with MCF-7 breast cancer cells. The results obtained showed that 1-HCHPK, MBB, and MTMP promoted breast tumor growth in these xenografts. A pretreatment with the estrogen receptor antagonist tamoxifen blocked the tumor growth-promoting effects of each photoinitiator. Collectively, the present results suggest that the three photoinitiators exhibit estrogenic agonist activities in vivo. Furthermore, as a factor for breast tumor growth, these photoinitiators potentially have estrogenic properties in vivo.

Development of an appropriate simple suspension method for valganciclovir medication.

BACKGROUND: Valganciclovir (VGC) is essential for preventing cytomegalovirus infections after transplants in adult and pediatric patients. In pediatric patients, VGC tablets have to be pulverized so that they can be delivered via nasogastric tubes. The "simple suspension method" is usually used to suspend tablets in hot water in Japan. However, the optimal suspension conditions and metering methods for preparing VGC suspensions using the simple suspension method are unclear. The purpose of this study was to clarify these issues. METHODS: VGC tablets were suspended in water (initial water temperature: 25 °C or 55 °C) using the simple suspension method. The residual rate of VGC after it had been suspended in hot water was determined using HPLC. In addition, the suspended solution was passed through 6, 8, and 12 Fr. gavage tubes. The VGC concentrations of suspensions produced using different preparation methods were also determined using HPLC. RESULTS: Cracking the surfaces of VGC tablets and suspending them in water at an initial temperature of 55 °C was effective at dissolving the tablets. The VGC concentration of the suspension remained stable for at least 80 min. Furthermore, the VGC concentration remained stable for 48 h during cold dark storage. Cracking the surfaces of VGC tablets could be a more effective metering method than preparing powder from VGC tablets. In addition, little VGC remained in 6, 8, or 12 Fr. gavage tubes after VGC solution was passed through them. CONCLUSION: The amount of VGC should be measured carefully when preparing VGC solutions using the simple suspension method.

Effects of Magnesium Oxide on the Serum Duloxetine Concentration and Antidepressant-Like Effects of Duloxetine in Rats.

Duloxetine is a serotonin/noradrenaline reuptake inhibitor that is used as an antidepressant. However, it is known to cause constipation as a side effect. Magnesium compounds, such as magnesium oxide and magnesium hydroxide aqueous solution, are often combined with duloxetine to ameliorate the constipation caused by duloxetine. However, there is concern that these magnesium compounds might alter the effects of duloxetine via physicochemical interactions. In this study, we attempted to clarify the interactions that take place between duloxetine and magnesium oxide using in vivo and in vitro experiments. We evaluated the influence of magnesium oxide on in vitro duloxetine concentrations using HPLC. In addition, we examined the in vivo antidepressant-like effects and serum concentrations of duloxetine in rats. In the in vitro experiment, the duloxetine concentration was significantly decreased by co-treatment with magnesium oxide. In the in vivo experiment, the antidepressant-like effects of duloxetine were not affected by the combined oral administration of magnesium oxide and a duloxetine formulation although the serum duloxetine level was significantly decreased. However, the antidepressant-like effects of a duloxetine reagent were significantly attenuated by the co-administration of magnesium oxide. These results suggest that duloxetine and magnesium oxide directly interact and that such interactions affect the absorption and antidepressant-like effects of duloxetine.

[Training 5th-Year Clinical Pharmacy Students to Collect and Evaluate Information from Original Articles].

　Pharmacists are required to contribute to evidence-based medicine (EBM) by providing drug information, which can be collected from various sources such as books, websites, and original articles. In particular, information from original articles is needed in some situations. For example, original articles by international researchers are used to aid the management of novel in-hospital preparations on which little knowledge is available. We introduced an information evaluation program, the Okayama University Hospital EBM Model, into the clinical training of 5th-year pharmacy students. It aims to enable students to evaluate the validity of novel in-hospital preparations using original articles. This program has improved students' knowledge of EBM, and the satisfaction level of those enrolled was high. In addition, customer satisfaction analysis revealed that the overall degree of student satisfaction was related to their understanding of the necessity for EBM and the difficulty of practical training. In addition, students' achievements were evaluated using rubrics, and that method allowed the achievements of each student to be assessed appropriately. We hope to revise this program with the aim of improving students' understanding of EBM.

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.

In vitro quantitative determination of the concentration of the polymerization agent methyl 2-benzoylbenzoate in intravenous injection solution and the cytotoxic effects of the chemical on normal human peripheral blood mononuclear cells.

In previous studies, we detected the photoinitiators 1-hydroxycyclohexyl phenyl ketone (1-HCHPK) and 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (MTMP) in an intravenous injection solution. Importantly, 1-HCHPK and MTMP have been demonstrated to be cytotoxic to normal human peripheral blood (PB) mononuclear cells (MNC). Cell death (apoptosis) pathways can be classified into two modes, caspase-dependent and -independent pathways. However, it is unclear whether methyl 2-benzoylbenzoate (MBB) induces the caspase-dependent and/or -independent pathway in normal human PBMNC. In the present in vitro study, we examined the levels of MBB in a solution from an intravenous fluid bag and the cytotoxicity of MBB towards normal human PBMNC via the caspase-8-, caspase-9-, or apoptosis-inducing factor (AIF)-mediated apoptosis pathways. We found that extracts from the injection solution had been contaminated with approximately 80 µM of the photoinitiator MBB. In addition, MBB induced apoptosis in the high concentration range in normal human PBMNC in vitro. Moreover, we found that MBB-induced apoptosis occurs via the caspase-9 pathway, but not the AIF pathway. In conclusion, we suggest that MBB has cytotoxic effects on normal human PBMNC in vitro, which are mediated via the caspase-dependent pathway.

[Monitoring of the Blood Concentrations of Antiepileptic Drugs (TDM)].

The incidence of epilepsy is high in infants/children and elderly persons. Patients with epilepsy account for approximately 1% of the population. This chronic cerebral disorder is characterized by repeated epileptic seizures related to excessive excitation of the brain, and it is important to reduce such seizures in life. Therapeutic drug monitoring (TDM) is useful for evaluating the treatment response and checking for adverse effects. When interpreting the results of measurement of the blood concentrations of antiepileptic drugs, the duplication of various factors must be understood. In this article, matters that clinical technologists face in routine work are presented/arranged so that the results of TDM may be adequately interpreted. In 270% of patients with epilepsy, as a nervous disease, seizures may be reduced by administering adequate therapy with antiepileptic drugs; the response rate is high. If measurements deviate from the reference range, clini- cal technologists should utilize their specialized knowledge and adequately evaluate the values obtained, con- tributing to drug therapy. [Review].

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.

[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.

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.

Characteristics of the runway model of intracranial self-stimulation behavior and comparison with other motivated behaviors.

Motivation incorporates several psychological aspects that produce reward-related and learning behaviors. Although reward-related behavior is reported to be mediated by the dopaminergic reward pathway, the involvement of dopaminergic systems in motivated behavior has not been fully clarified. Several experimental methodologies for motivational behavior have been reported, but pharmacological characteristics seem to vary among these methodologies. In this review, we attempt to summarize three main concepts:(1) the relationship of dopamine neuron physiology with motivated behavior, (2) the pharmacological characteristics of the runway intracranial self-stimulation model, and (3) the behavioral distinction of disparate motivated behaviors.

Differential combined effect of COX inhibitors on cell survival suppressed by sorafenib in the HepG2 cell line.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Sorafenib, a molecular-targeted drug, is a multi-target oral anti-neoplastic drug that is used as a first-line treatment for patients with advanced Human HCC. An increase in the expression of the cyclooxygenase-2 (COX-2) protein and sequential production of prostaglandin (PG) E2 were previously shown to significantly enhance carcinogenesis. Although the synergistic and/or additive effects of various COX inhibitors have been demonstrated in HCC, those of a combination of sorafenib and COX inhibitors remain unclear. The aim of the present study was to examine the antitumor effects of a combination of sorafenib and COX inhibitors on HCC HepG2 cells. Various COX inhibitors suppressed HepG2 cell survival, and exhibited a combined effect with sorafenib. However, COX-2 selectivity had little relevance. The co-administration of COX inhibitors and sorafenib increased the frequency of apoptosis. Moreover, the combination of sorafenib and diclofenac significantly increased Bax protein expression levels. The results of the present study indicate that COX inhibitors can be administered in combination with sorafenib for HCC therapy.

The polymerization agent, 2-methyl-4'-(methylthio)-2-morpholinopropiophenone induces caspases-3/7 in human blood mononuclear cells in vitro.

Our previous studies detected the presence of a photoinitiator 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (MTMP) in an intravenous (i.v.) injection bag solution. Importantly, MTMP has demonstrated cytotoxicity for normal human peripheral blood (PB) mononuclear cells (MNC). Cell death pathways have two well-known modes, apoptosis and necrosis. But it has not been clear whether MTMP induced apoptosis or necrosis in normal human PB MNC. In the present in vitro study, we examined normal human PB MNC for the frequencies of apoptosis and necrosis and changes upon exposure to MTMP. We observed time-dependent changes in MNC viability with MTMP. We also assessed the activity of caspases-3/7. The results demonstrated that MTMP induced apoptosis in normal human PB MNC after 24 h. In addition, MTMP induced caspases-3/7 in a time-dependent manner. In conclusion, we suggest that MTMP induces apoptosis in a caspase-dependent pathway in vitro.

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

BACKGROUND: Smoking 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. METHODS: We 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). RESULTS: The 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. CONCLUSION: Our 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.

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.

Quantitation and human monocyte cytotoxicity of the polymerization agent 1-hydroxycyclohexyl phenyl ketone (Irgacure 184) from three brands of aqueous injection solution.

In this study, levels of the photoinitiator 1-hydroxycyclohexyl phenyl ketone (1-HCHPK) in aqueous injection solutions were analyzed by GC-MS. In our previous studies, photoinitiators such as 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (MTMP) were detected in intravenous (i.v.) injection bag solution, and they were found to be cytotoxic to human monocytes. Therefore, we hypothesized that 1-HCHPK might display similarly cytotoxicity. The purpose of this study was to quantitate the amount of contaminants from plastic containers such as those used for peripheral parenteral nutrition and to determine the cytotoxicity of such extracts on human monocytes. The sample extraction procedure for GC-MS analysis involved a liquid-phase extraction. The solvent was evaporated under a stream of nitrogen at 50°C to yield a residue, which was dissolved in n-hexane and injected into a GC-MS. Normal human peripheral blood mononuclear cells (PBMC), isolated from the buffy coat by centrifugation, were suspended in RPMI 1640 medium supplemented with 10% (v/v) heat-inactivated fetal calf serum. In the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assay, cells (1×10(4)) were treated with 1-HCHPK for 24 h or 48 h at 37°C. From the GC-MS analysis, 6.13-8.32 µg/mL of 1-HCHPK was found in 20 mL vials of water for injection solution. In the MTT assay, 1-HCHPK decreased cell viability for both the 24 h and 48 h incubation periods. In conclusion, our findings suggest that 1-HCHPK could promote adverse events in patients. Future studies will clarify the possible health risks of photoinitiator accumulation in human cells.

[Usefulness of group work as a teaching strategy for long-term practical training in the 6-year pharmaceutical education].

At the initiation of long-term practical training in the 6-year pharmaceutical education, there are many issues to be solved. For example, it is necessary for teaching pharmacists, who are in charge of both staffing and teaching pharmacy students, to manage their workload with other staff pharmacists. To overcome this situation and to improve the motivation of teaching pharmacists towards student practical training, we twice held group work (GW) sessions for teaching pharmacists, and then evaluated whether such training was effective for their understanding of the Model Core Curriculum for Practical Training and for promoting a higher level of motivation. During the two-day GW discussions, teaching pharmacists, who work daily in the dispensing area, were separated into two groups to discuss teaching skills. A questionnaire survey was completed by participants before and after each GW session. According to the survey, more than 90% of the pharmacists had a higher motivation level for practical training after the sessions. Particularly in the second GW training, the response rate of "being actively involved" improved from 40% to 70%. Furthermore, "The Educational Evaluation Testing" was conducted, which confirmed the increased participant comprehension. The median scores of the comprehensive exams significantly (p<0.01) improved in twice GW, respectively. Therefore, we conclude that GW sessions are a useful tool for both improving professional knowledge about the Model Core Curriculum and motivating teaching pharmacists involved in the practical training of students. We hope that this exercise will lead to higher student motivation and satisfaction during their practical training.

Cytotoxicity of the polymerization agent, 2-methyl-4'-(methylthio)-2-morpholinopropiophenone on human monocytes.

This is the first study to detect 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (MTMP) from an intravenous injection bag solution by GC-MS. In previous studies, several other photoinitiators were reported to be very cytotoxic. Therefore, we theorized that photoinitiators such as MTMP might also have adverse cellular effects. The purpose of this study was to quantitate the amounts of contaminants from plastic containers such as those used for peripheral parenteral nutrition and to determine the cytotoxicity of such extracts on human monocytes. The sample extraction procedure for GC-MS analysis involved a liquid-phase extraction. The solvent was evaporated under a stream of nitrogen at 50°C. The residue was dissolved in n-hexane and injected into a GC-MS. Normal human peripheral blood mononuclear cells (PBMC), isolated from the buffy coat by centrifugation, were suspended in RPMI 1640 medium supplemented with 10% (v/v) heat-inactivated fetal calf serum. In the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cells (1×10(4)) were treated with MTMP for 24 h or 48 h at 37°C. From the GC-MS analysis, 5.62 ± 1.03 µg/mL of MTMP was found in the BFLUID(®) Injection 500 mL solution. In the MTT assay, MTMP decreased cell viability in a dose-dependent manner for both the 24 h and 48 h incubation periods. Our findings suggest that photoinitiators could promote adverse effects in patients. Future studies will clarify the possible health risks of photoinitiator accumulation in human cells.

[Clinical usefulness of the new Japanese glomerular filtration rate equation for initial and individualized dosage adjustment concentrations of vancomycin].

To clarify whether the new Japanese glomerular filtration rate (eGFR) equation was able to accurately determine the initial and individualized dosage adjustment concentrations of vancomycin (VCM), the predictive performance for VCM concentrations using the eGFR and Cockcroft-Gault (CG) equations was compared. Data were retrospectively collected from clinical records of 90 patients with MRSA infection whose trough and peak VCM concentrations had been determined. The predicted VCM initial and individualized dosage adjustment concentrations were performed with the 2-compartment linear model using pharmacokinetic parameter means and their individual values via Bayesian estimation, respectively. The prediction error (PE) and its absolute value (APE) between the observed and predicted VCM concentrations were calculated as indices of bias and accuracy in predictive performance, respectively. In the initial dosage adjustment of VCM, the PE value, calculated with the eGFR equation in trough and peak VCM concentrations of patients whose BMI were 18.5 kg/m(2) and higher, was significantly smaller than that calculated with the CG equation. In particular, both PE and APE values obtained from the eGFR calculated concentrations from nonelderly patients (younger than 65 years old) were significantly improved compared with those from the CG equation. In the individualized dosage adjustment of VCM, the eGFR equation gave a significantly smaller PE value in nonelderly patients' trough concentrations than the CG equation. These findings provide useful information for adjusting the VCM dosage to achieve optimal therapeutic efficacy in patients with MRSA infection.

Involvement of dopaminergic receptor signaling in the effects of glutamatergic receptor antagonists on conditioned place aversion induced by naloxone in single-dose morphine-treated rats.

A better understanding of the neurochemical mechanisms mediating the aversive consequences of drug withdrawal is important for understanding drug addiction. We previously demonstrated that the inhibitory effect of glutamate receptor antagonists on the conditioned place aversion (CPA) induced by naloxone-precipitated withdrawal after a single morphine exposure could be blocked by dopamine receptor antagonists. Thus, a glutamatergic-dopaminergic interaction may participate in this phenomenon. The current study was undertaken to further characterize this interaction by employing both D(1) (SCH 23390) and D(2) (raclopride and eticlopride) dopamine receptor antagonists. The influence of these antagonists on the attenuation of CPA by MK-801 (NMDA receptor antagonist), GYKI 52466 (AMPA receptor antagonist), and MCPG (metabotropic glutamate receptor antagonist) was determined in rats receiving a single dose of morphine. The dopamine antagonists showed either a significant reversal or a tendency to reverse the effects of MK-801 on CPA. The effect of GYKI 52466 was also attenuated by the blockade of either D(1) or D(2) receptors. The effect of MCPG, however, was only blocked by D(2) antagonists and not by the D(1) antagonist SCH 23390. These results add evidence to the hypothesis that a glutamatergic-dopaminergic interaction may be involved in the CPA induced by naloxone-precipitated withdrawal following a single morphine exposure and suggest that both D(1) and D(2) dopamine receptor signaling mechanisms play a role in mediating the aversive aspects of acute dependence.