Pharmacology & toxicology最新文献_第5页

Evidence for a trigger function of valproic acid in xenobiotic-induced hepatotoxicity. 丙戊酸在外源性肝毒性中触发功能的证据。

Pharmacology & toxicology Pub Date : 2000-08-01 DOI: 10.1034/j.1600-0773.2000.d01-50.x

S Klee, S Johanssen, F R Ungemach

{"title":"Evidence for a trigger function of valproic acid in xenobiotic-induced hepatotoxicity.","authors":"S Klee, S Johanssen, F R Ungemach","doi":"10.1034/j.1600-0773.2000.d01-50.x","DOIUrl":"https://doi.org/10.1034/j.1600-0773.2000.d01-50.x","url":null,"abstract":"The influence of the antiepileptic drug, valproic acid (2-n-propylpentanoic acid), on the hepatocellular capacity, to cope with an extrinsic oxidative stress was investigated. Freshly isolated rat hepatocytes exposed to therapeutic concentrations of valproic acid (0.25-1.0 mmol/l) were less resistant than controls, as evidenced by a significant cytotoxic response after challenge of the cells with a non-toxic dose of allyl alcohol (2-propen-1-ol). Valproic acid alone was not toxic to hepatocytes even at ten times higher concentrations (10 mmol/l), suggesting that cell damage was not a mere additive effect. Incubation with valproic acid plus allyl alcohol induced an irreversible depletion of hepatocellular glutathione, in contrast to allyl alcohol alone which induced a transient loss. Hepatocytes treated with valproic acid plus allyl alcohol were protected by N-acetylcysteine, a precursor of glutathione. These findings indicate that valproic acid affects hepatocellular defence mechanisms and suggest that a predisposition of hepatocytes to oxidative stress may play a role in the fatal hepatotoxicity of valproic acid in epileptic patients.","PeriodicalId":19876,"journal":{"name":"Pharmacology & toxicology","volume":"87 2","pages":"89-95"},"PeriodicalIF":0.0,"publicationDate":"2000-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21823260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 18

Age-dependent induction of aberrant crypt foci in rat colon by 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine and azoxymethane. 2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶和偶氮甲烷对大鼠结肠异常隐窝灶的年龄依赖性诱导。

Pharmacology & toxicology Pub Date : 2000-08-01 DOI: 10.1034/j.1600-0773.2000.d01-46.x

J E Paulsen, R C Fulland, J Alexander

{"title":"Age-dependent induction of aberrant crypt foci in rat colon by 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine and azoxymethane.","authors":"J E Paulsen, R C Fulland, J Alexander","doi":"10.1034/j.1600-0773.2000.d01-46.x","DOIUrl":"https://doi.org/10.1034/j.1600-0773.2000.d01-46.x","url":null,"abstract":"Pups and adult rats received seven oral exposures (three time weekly) of the food mutagen PhIP (50 mg/kg), or two subcutaneous exposures (once weekly) of the experimental carcinogen azoxymethane (3.75 mg/kg). Aberrant crypt foci (ACF) were scored 8 weeks after the first exposure. In addition, lactating dams with suckling pups were orally exposed to 50 mg/kg of PhIP, three times weekly for three weeks. Direct PhIP exposure of pups induced 2.2 times more ACF than similar exposure of adult rats (2.0+/-0.0 versus 0.9+/-0.8, P<0.05). The growth of ACF, expressed as crypt multiplicity AC/ACF, was 3.5 times larger in neonatally exposed rats than in rats exposed in adulthood (8.0+/-7.3 versus 2.3+/-1.6, P<0.05). PhIP exposure via breast milk induced ACF in 3 of 25 animals. However, the difference versus controls, which had no ACF, did not reach statistical significance. Contrary to PhIP, azoxymethane induced more ACF in adult rats than in pups (2.8+/-1.9 versus 4.8+/-1.7, P<0.05). Similarly to PhIP however, azoxymethane induced 3.2 times larger ACF (AC/ACF) in pups than in adult rats (11.9+/-8.4 versus 3.7+/-1.9, P<0.001). Whereas no PhIP-induced ACF (0/15) were observed in the lymphoid follicles, approximately 60% of the azoxymethane-induced ACF (32/56) were located in these structures. This difference was statistically significant (P<0.001). The density of azoxymethane-induced ACF was 80 times larger in the lymphoid follicles than in the surrounding mucosa (P<0.01). Based on the assumption that the formation of ACF with high multiplicity is predicative for the tumour development we conclude that neonatal rats are more susceptible to PhIP and azoxymethane than adult rats.","PeriodicalId":19876,"journal":{"name":"Pharmacology & toxicology","volume":"87 2","pages":"69-73"},"PeriodicalIF":0.0,"publicationDate":"2000-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21823354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 6

Is the 5-HT2C receptor a therapeutic target in cerebral ischaemia? 5-HT2C受体是脑缺血的治疗靶点吗?

Pharmacology & toxicology Pub Date : 2000-08-01 DOI: 10.1034/j.1600-0773.2000.d01-47.x

L Torup, N H Diemer

引用次数: 1

Studies on the prevention of nigericin action in neuroblastoma X glioma hybrid (NG108-15) cells. 尼日利亚菌素对神经母细胞瘤X胶质瘤杂交(NG108-15)细胞预防作用的研究。

Pharmacology & toxicology Pub Date : 2000-08-01 DOI: 10.1034/j.1600-0773.2000.d01-45.x

J A Doebler

{"title":"Studies on the prevention of nigericin action in neuroblastoma X glioma hybrid (NG108-15) cells.","authors":"J A Doebler","doi":"10.1034/j.1600-0773.2000.d01-45.x","DOIUrl":"https://doi.org/10.1034/j.1600-0773.2000.d01-45.x","url":null,"abstract":"Electrophysiological analysis of neuroblastoma X glioma hybrid (NG108-15) cells was used as an in vitro neuronal model system to evaluate antagonists of the K+-selective carboxylic ionophore, nigericin. Changes in membrane electrical characteristics induced by nigericin with and without the simultaneous administration of antagonists were measured using intracellular microelectrode techniques. Bath application of nigericin (3 microM) produced a severe hyperpolarization and blocked the generation of action potentials in response to electrical stimulation. Simultaneous administration of nigericin plus the Na+-K+ pump inhibitor ouabain or drugs known to influence Ca++ signaling in cells, i.e., quinidine, compound R24571, verapamil or haloperidol, was able to significantly attenuate the hyperpolarization. All antagonists acted in a concentration-dependent manner. However, nigericin plus maximally effective concentrations of ouabain (1 microM), verapamil (3 microM) and haloperidol (3 and 10 microM) resulted in moderate-to-severe depolarization by the end of 24 min. superfusions, suggesting that the concentrations of antagonists were excessive and that NG108-15 cell damage had occurred. In addition, none of the compounds studied was able to effectively prevent nigericin-induced blockade of action potentials. Thus, none of these antagonists appears suitable for transition to in vivo antidotal protection studies.","PeriodicalId":19876,"journal":{"name":"Pharmacology & toxicology","volume":"87 2","pages":"63-8"},"PeriodicalIF":0.0,"publicationDate":"2000-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21823353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Selegiline metabolism and cytochrome P450 enzymes: in vitro study in human liver microsomes. 塞来吉兰代谢和细胞色素P450酶:人肝微粒体的体外研究。

Pharmacology & toxicology Pub Date : 2000-05-01 DOI: 10.1034/j.1600-0773.2000.d01-38.x

P Taavitsainen, M Anttila, L Nyman, H Karnani, J S Salonen, O Pelkonen

{"title":"Selegiline metabolism and cytochrome P450 enzymes: in vitro study in human liver microsomes.","authors":"P Taavitsainen, M Anttila, L Nyman, H Karnani, J S Salonen, O Pelkonen","doi":"10.1034/j.1600-0773.2000.d01-38.x","DOIUrl":"https://doi.org/10.1034/j.1600-0773.2000.d01-38.x","url":null,"abstract":"Although being a drug therapeutically used for a long time, the enzymatic metabolism of selegiline has not been adequately studied. In the current work we have studied the cytochrome P450 (CYP)-catalyzed oxidative metabolism of selegiline to desmethylselegiline and 1-methamphetamine and the effects of selegiline, desmethylselegiline and 1-methamphetamine on hepatic CYP enzymes in human liver microsomes in vitro. The apparent Km values for desmethylselegiline and 1-methamphetamine formation were on an average 149 microM and 293 microM, and the apparent Vmax values, 243 pmol/min./mg and 1351 pmol/min./mg, respectively. Furafylline and ketoconazole, the known reference inhibitors for CYP1A2 and CYP3A4, respectively, inhibited the formation of desmethylselegiline with Ki value of 1.7 microM and 15 microM. Ketoconazole inhibited also the formation of 1-methamphetamine with Ki of 18 microM. Fluvoxamine, an inhibitor of CYP1A2, CYP2C19 and CYP3A4, inhibited the formation of desmethylselegiline and 1-methamphetamine with Ki values of 9 and 25 microM, respectively. On the basis of these results we suggest that CYP1A2 and CYP3A4 contribute to the formation of desmethylselegiline and that CYP3A4 participates in the formation of 1-methamphetamine. In studies with CYP-specific model activities, both selegiline and desmethylselegiline inhibited the CYP2C19-mediated S-mephenytoin 4'-hydroxylation with average IC50 values of 21 microM and 26 microM, respectively. The Ki for selegiline was determined to be around 7 microM. Selegiline inhibited CYP1A2-mediated ethoxyresorufin O-deethylation with a Ki value of 76 microM. Inhibitory potencies of selegiline, desmethylselegiline and 1-methamphetamine towards other CYP-model activities were much lower. On this basis, selegiline and desmethylselegiline were shown to have a relatively high affinity for CYP2C19, but no evidence about selegiline metabolism by CYP2C19 was obtained.","PeriodicalId":19876,"journal":{"name":"Pharmacology & toxicology","volume":"86 5","pages":"215-21"},"PeriodicalIF":0.0,"publicationDate":"2000-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21704994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 24

Dose-dependent protection by lipoic acid against cisplatin-induced nephrotoxicity in rats: antioxidant defense system. 硫辛酸对顺铂所致大鼠肾毒性的剂量依赖性保护作用:抗氧化防御系统。

Pharmacology & toxicology Pub Date : 2000-05-01 DOI: 10.1034/j.1600-0773.2000.d01-41.x

S M Somani, K Husain, C Whitworth, G L Trammell, M Malafa, L P Rybak

{"title":"Dose-dependent protection by lipoic acid against cisplatin-induced nephrotoxicity in rats: antioxidant defense system.","authors":"S M Somani, K Husain, C Whitworth, G L Trammell, M Malafa, L P Rybak","doi":"10.1034/j.1600-0773.2000.d01-41.x","DOIUrl":"https://doi.org/10.1034/j.1600-0773.2000.d01-41.x","url":null,"abstract":"This study was designed to investigate the role of graded doses of lipoic acid pretreatment against cisplatin-induced nephrotoxicity. Male Wistar rats were divided into six groups and treated as follows: 1) vehicle (saline) control; 2) cisplatin (16 mg/kg, intraperitoneally); 3) lipoic acid (100 mg/kg, intraperitoneally); 4) cisplatin plus lipoic acid (25 mg/kg); 5) cisplatin plus lipoic acid (50 mg/kg) and 6) cisplatin plus lipoic acid (100 mg/kg). Rats were sacrificed three days after treatment, and plasma as well as kidneys were isolated and analyzed. Plasma creatinine increased (677% of control) following cisplatin administration alone which was decreased by lipoic acid in a dose-dependent manner. Cisplatin-treated rats showed a depletion of renal glutathione (GSH), increased oxidized GSH and decreased GSH/GSH oxidized ratio (62%, 166% and 62% of control), respectively which were restored with lipoic acid pretreatment. Renal superoxide dismutase, catalase, glutathione peroxidase (GSH peroxidase) and glutathione reductase activities decreased (62%, 75%, 62% and 80% of control), respectively, and malondialdehyde content increased (204% of control) following cisplatin administration, which were restored with increasing doses of lipoic acid. The renal platinum concentration increased following cisplatin administration, which was possibly decreased by chelation with lipoic acid. The data suggest that the graded doses of lipoic acid effectively prevented a decrease in renal antioxidant defense system and prevented an increase in lipid peroxidation, platinum content and plasma creatinine concentrations in a dose-dependent manner.","PeriodicalId":19876,"journal":{"name":"Pharmacology & toxicology","volume":"86 5","pages":"234-41"},"PeriodicalIF":0.0,"publicationDate":"2000-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21704997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 184

Antioxidative and prooxidative action of stilbene derivatives. 二苯乙烯衍生物的抗氧化和促氧化作用。

Pharmacology & toxicology Pub Date : 2000-05-01 DOI: 10.1034/j.1600-0773.2000.d01-36.x

T Miura, S Muraoka, N Ikeda, M Watanabe, Y Fujimoto

{"title":"Antioxidative and prooxidative action of stilbene derivatives.","authors":"T Miura, S Muraoka, N Ikeda, M Watanabe, Y Fujimoto","doi":"10.1034/j.1600-0773.2000.d01-36.x","DOIUrl":"https://doi.org/10.1034/j.1600-0773.2000.d01-36.x","url":null,"abstract":"The effects of stilbene derivatives, including resveratrol, diethylstilboestrol and stilbene, as antioxidants or prooxidants were examined. Resveratrol and diethylstilboestrol, but not stilbene, strongly inhibited NADPH- and adenosine 5'-diphosphate (ADP)-Fe3+-dependent lipid peroxidation at the initial and propagation stages. In addition, phenolic stilbenes also inhibited ultraviolet light-induced lipid peroxidation. Resveratrol and diethylstilboestrol efficiently scavenged 2,2'-azobis-(2-amidinopropane)-dihydrochloride peroxyl radicals. However, 2,2'-diphenyl-p-picrylhydrazyl radicals were trapped only by resveratrol, but not by diethylstilboestrol. These results suggest that the inhibitory effect of phenolic stilbenes on lipid peroxidation was due to their scavenging ability of lipid peroxyl and/or carbon-cantered radicals. Resveratrol efficiently reduced ADP-Fe3+, but not EDTA-Fe3+. Stilbenes and diethylstilboestrol did not reduce either ADP-Fe3+ or EDTA-Fe3+. The strand breaks of DNA were stimulated during the interaction of resveratrol with ADP-Fe3+ in the presence of H2O2. These results suggest that phenolic stilbenes act as antioxidants of membrane lipids and that resveratrol has a prooxidative effect DNA damage during interaction with ADP-Fe3+ in the presence of H2O2.","PeriodicalId":19876,"journal":{"name":"Pharmacology & toxicology","volume":"86 5","pages":"203-8"},"PeriodicalIF":0.0,"publicationDate":"2000-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21705649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 75

Hydrolytic and metabolic characteristics of the esters of 1-(3'-hydroxypropyl)-2-methyl-3-hydroxypyridin-4-one (CP41), potentially useful iron chelators. 潜在有用的铁螯合剂1-(3′-羟丙基)-2-甲基-3-羟吡啶-4-酮(CP41)酯的水解和代谢特性

Pharmacology & toxicology Pub Date : 2000-05-01 DOI: 10.1034/j.1600-0773.2000.d01-40.x

D Y Liu, Z D Liu, S L Lu, R C Hider

{"title":"Hydrolytic and metabolic characteristics of the esters of 1-(3'-hydroxypropyl)-2-methyl-3-hydroxypyridin-4-one (CP41), potentially useful iron chelators.","authors":"D Y Liu, Z D Liu, S L Lu, R C Hider","doi":"10.1034/j.1600-0773.2000.d01-40.x","DOIUrl":"https://doi.org/10.1034/j.1600-0773.2000.d01-40.x","url":null,"abstract":"1-(3'-Hydroxypropyl)-2-methyl-3-hydroxypyridin-4-one (CP41) has been extensively investigated as an orally effective iron chelator. In order to improve the pharmacokinetic and metabolic properties of CP41, eleven aromatic esters have been synthesised and tested as potential prodrugs. In the present study, the hydrolytic rates of these CP41 esters in phosphate buffer (pH2.0 and pH 7.4), rat blood and rat liver homogenate have been determined and found to cover a wide range. Generally, they possessed relatively slow hydrolytic rates in phosphate buffer (0-50 nmol/ml/hr at pH 2.0 and 0-140 nmol/ml/hr at pH 7.4). The hydrolytic rates in rat blood fell in the range of 9-5766 nmol/ml blood/hr and in rat liver homogenate 1-800 micromol/g liver tissue/hr. All esters possess a higher lipophilicity than that of the parent compound CP41. Although no apparent relationship was observed between the lipophilicities and hydrolytic rates, the esters with relatively higher hydrolytic rates in liver homogenate tend to possess higher iron scavenging efficacies. Further investigation of the metabolism of selected CP41 esters indicates that metabolism is a key factor influencing the efficacy of CP41 esters, as some esters can be metabolically inactivated in the liver in preference to undergoing ester hydrolysis. Ester design, combined with a knowledge of the prodrug metabolism, is a useful strategy for the production of 3-hydroxypyridin-4-ones with enhanced iron scavenging efficacy.","PeriodicalId":19876,"journal":{"name":"Pharmacology & toxicology","volume":"86 5","pages":"228-33"},"PeriodicalIF":0.0,"publicationDate":"2000-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21704996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 6

Ultrastructural evidence of the protective effect of Na+/H+ exchange inhibition on the in vitro damage induced by ischaemia reperfusion in the interventricular septum of the rabbit heart. 抑制Na+/H+交换对兔心脏室间隔缺血再灌注损伤保护作用的超微结构证据。

Pharmacology & toxicology Pub Date : 2000-05-01 DOI: 10.1034/j.1600-0773.2000.d01-39.x

P Salinas, P Gil-Loyzaga, S Barrigon

{"title":"Ultrastructural evidence of the protective effect of Na+/H+ exchange inhibition on the in vitro damage induced by ischaemia reperfusion in the interventricular septum of the rabbit heart.","authors":"P Salinas, P Gil-Loyzaga, S Barrigon","doi":"10.1034/j.1600-0773.2000.d01-39.x","DOIUrl":"https://doi.org/10.1034/j.1600-0773.2000.d01-39.x","url":null,"abstract":"We investigated the effects of the Na+/H+ antiporter inhibitor, dimethylamiloride, on myocardial injury after 1 h global ischaemia and 30 min. reperfusion in the isolated arterially perfused interventricular septum of the rabbit heart. After ischaemia and reperfusion challenge, dimethylamiloride significantly increased the recovery of developed tension in a dose-dependent manner, and significantly decreased the maximal increase in resting tension. Ultrastructural analysis of myocytes submitted to the experimental in vitro model supported functional maintenance of physiologically-like conditions. Where myocardial portions were submitted to ischaemic conditions and reperfusion, myocyte cell damage reached usual characteristics of infarct-like induced lesions. Intracellular oedema, severe disruption of myofibrils with loss of muscle striation and both swelling and fragmentation of mitochondria were the main characteristics observed. Dimethylamiloride treatment clearly modifies ultrastructural findings towards the normalization of cell shape and structure, only a slight-middle intracellular oedema and contraction bands were found. On the basis of the present results, we suggest that the protective effects exhibited by dimethylamiloride on the ischaemic myocardium are compatible with its Na+/H+ antiporter inhibition properties, they diminish Na+ accumulation and then either Ca2+ overload or non-exocytotic noradrenaline release during the ischaemia and reperfusion challenge.","PeriodicalId":19876,"journal":{"name":"Pharmacology & toxicology","volume":"86 5","pages":"222-7"},"PeriodicalIF":0.0,"publicationDate":"2000-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21704995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Lesioning of locus coeruleus projections by DSP-4 neurotoxin treatment: effect on amphetamine-induced hyperlocomotion and dopamine D2 receptor binding in rats. sp -4神经毒素对大鼠蓝斑突起的损伤:对安非他明诱导的过度运动和多巴胺D2受体结合的影响。

Pharmacology & toxicology Pub Date : 2000-05-01 DOI: 10.1034/j.1600-0773.2000.d01-35.x

J Harro, A Meriküla, M Lepiku, A R Modiri, A Rinken, L Oreland

{"title":"Lesioning of locus coeruleus projections by DSP-4 neurotoxin treatment: effect on amphetamine-induced hyperlocomotion and dopamine D2 receptor binding in rats.","authors":"J Harro, A Meriküla, M Lepiku, A R Modiri, A Rinken, L Oreland","doi":"10.1034/j.1600-0773.2000.d01-35.x","DOIUrl":"https://doi.org/10.1034/j.1600-0773.2000.d01-35.x","url":null,"abstract":"DSP-4 is a neurotoxin highly selective for the noradrenergic nerve terminals of the locus coeruleus projections. Data on the effect of DSP-4 treatment on amphetamine-induced hyperlocomotion are contradictory. In this study, DSP-4 (50 mg/kg) caused reduction of noradrenaline levels by 70% in the cerebral cortex and by 79% in the cerebellum. This treatment resulted in upregulation of dopamine D2 receptors in the striatum as evidenced by [3H]-raclopride binding. In an open field test, DSP-4 reduced locomotor activity. D-Amphetamine (1.5 mg/kg) caused a similar increase in locomotor activity in control and DSP-4-pretreated animals not familiar to the apparatus. However, when the rats were habituated to the test apparatus, the effect of amphetamine on horizontal activity was significantly larger in the DSP-4-pretreated animals. These data suggest that supersensitivity of D2 receptors develops after locus coeruleus denervation, but that the enhanced efficacy of amphetamine in DSP-4-treated rats is masked by neophobia.","PeriodicalId":19876,"journal":{"name":"Pharmacology & toxicology","volume":"86 5","pages":"197-202"},"PeriodicalIF":0.0,"publicationDate":"2000-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21705648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 41