格尔德霉素体内外抑制单纯疱疹病毒1型的复制

格尔德霉素 ( GA)是一种抗生素 ,它的作用靶点是热休克蛋白 Hsp90 N末端的 ATP/ ADP结合位点。在我们对抗病毒的抗生素筛选中 ,发现格尔德霉素显著抗单纯疱疹病毒 1型 ( HSV- 1)。体外在 Vero细胞内 GA显著抑制 HSV- 1的复制 ,IC50 为0 .0 93μmol/ L,GA对 Vero细胞的毒性 CC50 为 35 0 μmol/ L,治疗指数可达 376 3。HSV- 1腹腔 ( ip)感染 1h后腹腔 ( ip)注射 GA( 0 .0 93～ 0 .37mg/ kg)可以将存活率增加到 6 7%～ 10 0 % ,皮下 ( sc)给药 ( 0 .37mg/ kg)的存活率为 4 3.8% ,都明显高于生理盐水对照组 ( ipP<0 .0 0 1,sc P<0 .0 5 )。GA对小白鼠的急性 L D50 为 15 .5 mg/ kg( ip)。格尔德霉素不影响病毒的吸附、穿入。由于 GA在体内外都能抑制单纯疱疹病毒 1型 ,GA可以成为新的抗单纯疱疹病毒感染的药物     

阿克拉霉素B的抗肿瘤作用及急性毒性的研究

阿克拉霉素B(ACM-B)是加利利链霉菌思文变种产生的一种蒽环类抗肿瘤抗生素,本文报告其对小白鼠S180的抑瘤作用、急性毒性和对金地鼠心电图的影响的研究结果。 在等毒性剂量下腹腔注射ACM-B对小白鼠S180的抑瘤率与阿克拉霉素A(ACM-A)、亚德里亚霉素(ADM)均无显著差别,ACM-B灌胃给药的抑瘤效果与腹腔和静脉注射相同。ACM-B小白鼠急性LD_(50)为14.26mg/kg(iv),13.08mg/kg(ip),15.05mg./kg(sc),32.47mg/kg(po);大白鼠LD_(50)为16.46mg/kg(ip);小白鼠连续给药10天LD_(60)为3.03mg/kg(ip)。静脉注射ADM6.25mg/kg一次后,7只金地鼠的ECG全部出现显著的毒性变化,但静脉注射ACM-B和ACM-A75mg/kg一次后,3只金地鼠的ECG均无明显异常改变,可见ACM-B和ACM-A的心脏毒性为ADM的1/20。     

新铂类化合物奥沙利铂抗肿瘤作用研究

选用小鼠肉瘤 180 ( S- 180 )和小鼠淋巴细胞白血病 L12 10 为病理模型 ,分别观察 ip或 iv L - OHP对荷瘤小鼠瘤重抑制率、生命延长率及 30 d存活率的影响。结果表明 iv L- OHP2 .5mg/ kg,5mg/ kg,10 mg/ kg对 S- 180有较强的抗瘤活性 ,平均瘤重与对照组相比有显著差异 ,抑瘤率小于等剂量的顺铂 ( DDP) :ip 3个剂量组对L12 10 延命率 ,30 d存活率及 iv对 L12 10 延命率均大于等剂量的 DDP。Bliss法算得 LD50 ( ip)为 17.86mg/ kg( iv)为14.63mg/ kg。     

高血压性脑出血与血浆同型半胱氨酸、内皮素1和一氧化氮的关系

目的 探讨血浆同型半胱氨酸(Hcy)、内皮素1(ET-1)和一氧化氮(NO)水平与高血压及其合并脑出血的关系.方法 检测62例单纯高血压患者(A组)、45例单纯脑出血患者(B组)、60例高血压性脑出血患者(C组)和40名健康体检者(D组)血浆Hcy、ET-1和NO的水平.结果 A、B、C和D组的血浆Hcy分别为(17.6±6.6) μmol/L、(18.2±7.2)μmol/L、(21.9±6.7)μmol/L和(10.8±4.6)μmol/L;ET-1分别为(100.7±11.8)μg/L、(101.2±12.1)μg/L、(120.8±15.9)μg/L和(44.7±10.6)μg/L;NO分别为(57.2±11.7) mg/L、(58.6±11.2)m g/L、(41.8±13.2) mg/L和(120.8±12.6)mg/L.与D组比较,A、B和C组Hcy和ET-1水平升高,NO水平降低(P＜0.05);C组Hcy和ET-1水平高于A、B组,NO水平低于A、B组(P＜0.05).脑出血量与血浆Hcy和ET-1水平呈正相关,而与NO水平呈负相关(P＜0.05).结论 高血压性脑出血患者存在内皮细胞损害和内皮功能障碍.     

喜树碱前体多相脂体的药理学研究

本文报道了对喜树碱前体(A-CPT)及喜树碱前体多相脂质体(A-CPT-pl)的药理学研究结果。结果表明,A-CPT腹腔注射给药(ip)及经口腔给药(PO),寇氏法求得小鼠的LD50分别为159.3mg/kg及33.7mg/kg,较喜树碱钠盐(CTP-Na)的毒性降低,按最大允许给药容量(0.5ml/10g)ip或PO A-CPT-pl 50mg/kg,在观察期间未见死亡。抑瘤试验结果表明,A-CPT-pl对S180及HepS的抑制率可达74%及82%,可使荷EAC小鼠的生命延长126%;A-CPT对S180及HepS的抑制率可达52%及53%,可使荷EAc小鼠的生命延长54%。肿瘤相伴免疫试验结果表明,每日ip,A-CPT-pl 0.5mg/kg,连续9天,对小鼠肿瘤相伴免疫没有明显影响。     

干扰素联合阿昔洛韦治疗单纯疱疹病毒脑炎临床效果观察

目的 观察干扰素联合阿昔洛韦治疗单纯疱疹病毒脑炎临床效果.方法 治疗组患儿采用干扰素50～100万U肌内注射,1次/d,联合阿昔洛韦每次10 mg/kg,3次/静脉滴注治疗,对照组阿昔洛韦每次10 mg/kg,3次/d静脉滴注治疗.每天观察记录患儿症状、体征等.结果 治疗组总有效率为95.56%,对照组为78.57%,差异有统计学意义(P<0.05).结论 干扰素联合阿昔洛韦治疗单纯疱疹病毒脑炎临床效果,值得临床推广应用     

朱砂七总蒽醌体外抗单纯疱疹病毒的研究

目的研究朱砂七总蒽醌(ZSQ)体外对单纯疱疹病毒的抑制作用。方法运用单纯疱疹病毒I型(HSV-Ⅰ)和Ⅱ型(HSV-Ⅱ),以非洲绿猴肾细胞(Vero细胞)为宿主细胞,通过观察感染病毒后的细胞变性反应(CPE)和MTI比色法,检测ZSQ对单纯疱疹病毒的抑制作用。结果与病毒对照组相比,朱砂七总蒽醌各质量浓度组均能有效地保护感染HSV-I和HSV-Ⅱ病毒的Vero细胞,抑制单纯疱疹病毒的复制,使病毒导致的细胞病变减弱。ZSQ抗HSV-I病毒作用IC50为0.004 7g.L-1,抗病毒有效率达90.83%,治疗指数(TI)为16.62;总蒽醌抗HSV-Ⅱ病毒作用IC50为0.006 7g.L-1,抗病毒有效率达90.06%,治疗指数(TI)为11.66。结论 ZSQ在体外显示出明显的保护宿主细胞、抵抗单纯疱疹病毒感染的活性。     

α-苦瓜素及α-苦瓜素-PEG体外抗HSV-1的研究

目的研究苦瓜籽核糖体失活蛋白α-苦瓜素(α-MMC)体外抗单纯疱疹病毒(HSV-1)的活性及其聚乙二醇修饰物(α-MMC-PEG)保留这一活性的程度。方法采用MTT法测定α-MMC和α-MMC-PEG对Vero细胞的体外毒性;通过对所培养的上清液中HSV-1囊膜糖蛋白抗原的测定、细胞和病毒的预处理试验,研究了α-MMC和α-MMC-PEG体外抗HSV-1的活性。结果α-MMC和α-MMC-PEG对HSV-1囊膜糖蛋白抗原分泌的抑制作用均呈剂量依赖性,IC50分别为0.67、2.94μmol.L-1;相同剂量下,α-MMC-PEG可保留60%天然α-MMC的抑制活性。3.3μmol.L-1的α-MMC和α-MMC-PEG直接作用病毒后使Vero细胞的存活率分别提高了22%、17%。结论α-MMC经PEG修饰后可保留较高的抗HSV-1活性,修饰前后都对HSV-1有一定的直接灭活作用。     

热休克蛋白90抑制剂格尔德霉素对白色念珠菌耐药性的影响

目的探讨热休克蛋白90(HSP90)抑制剂格尔德霉素(GA)对白色念珠菌体外诱导耐药菌株耐药性的影响,以期证实HSP90抑制剂的体外抗真菌作用。方法用HSP90抑制剂GA处理对特比萘芬片具有稳定耐药性的白色念珠菌体外诱导耐药菌株AC2013112-R,参照美国国家临床试验室标准化委员会(NCCLS)推荐的M27VA药敏试验方案的微量稀释法,应用氧化还原指示剂Alamarblue通过比色判定最低抑菌浓度(MIC)值,分别检测格尔德霉素处理前后白色念珠菌ATCC90028-R菌株对特比萘芬的体外敏感性。结果经过格尔德霉素处理后,对特比萘芬片具有稳定耐药性的白色念珠菌体外诱导耐药菌株AC2013112-R的对特比萘芬的MIC值从≥512μg/mL降低为64μg/mL。结论 HSP90的抑制剂GA具有体外抗念珠菌活性,这种抑菌作用可能与GA的药理作用及白色念珠菌菌株产生耐药性的方式有关。     

姜黄素与Hsp90相互作用以及对Hsp90ATPase 活性的影响

目的 研究姜黄素(curcumin)与Hsp90的结合作用,及其对Hsp90-ATPase 活性抑制作用.方法 采用荧光光谱实验,选取280 nm为激发波长,290~510 nm的波长范围内进行荧光光谱扫描,研究不同浓度curcumin与Hsp90的相互作用.采用孔雀绿磷钼酸铵-无机磷检测法,研究curcumin对Hsp90-ATPase活性抑制.结果 curcumin解离常数为(21.608±1.752) μmol·L-1,格尔德霉素(GA)为(17.372±1.200) μmol·L-1.当ATP为1 mmol·L-1时,GA作用于Hsp90的IC50值为0.38 μmol·L-1,curcumin的IC50值为3.75 μmol·L-1也有较强的Hsp90-ATPase抑制活性.结论 经过荧光光谱分析,可以确定curcumin与Hsp90的结合机制,且curcumin能抑制Hsp90-ATPase活性.     

Antitumor activity of spergualin, a novel antitumor antibiotic

Spergualin (SGL), a novel antitumor antibiotic, exhibited strong antitumor activity against transplantable leukemias in mice: L1210, L1210(IMC), P388, P815, C1498, EL-4 and RL male 1. It also exhibited antitumor activity against M5076 fibrosarcoma, AH66 and AH66F rat hepatomas, but not against Meth-A fibrosarcoma, B16 melanoma, Lewis lung carcinoma (LL) and C26 colon adenocarcinoma. The antitumor activity of SGL was administration-schedule dependent. The strongest activity against L1210 was obtained by ip continuous infusion for 7 days or daily ip administration for 9 days. Single ip injection of SGL at 100 mg/kg to mice caused convulsion and death within 15 minutes after injection. Such acute toxicity was not observed by continuous infusion. SGL showed its strongest activity at subtoxic dose against sensitive tumors except for L1210(IMC). Mice implanted ip with L1210(IMC) were cured by treatment with SGL at 3.13 mg/kg/day for 9 days, but died from the tumor at 50 mg/kg/day X 9. The cured mice rejected a second inoculation of up to 10(6) tumor cells. The tumor cells isolated from mice after treatment with the high dose showed resistance to SGL in vivo. Mice implanted sc with L1210(IMC) were also cured by 9 daily ip administrations of SGL at 12.5 mg/kg/day, but solid tumor was observed at the implantation site until 3 days after the final injection of SGL in some cured mice. These results suggest that the therapeutic effect of SGL has a relatively high specificity for leukemias and that the immunological effect is involved in the antitumor activity.     

Effect of sertindole on raised mesolimbic dopaminergic activity in the rat

The effect of sertindole in models of mesolimbic dopamine excess in the rat was evaluated. Sertindole (0.0057–0.011 μmol/kg = 2.5–5 μg/kg, sc) and haloperidol (0.13–0.27 μmol/kg = 50–100 μg/kg, ip) inhibited the hyperactivity caused by the acute intra-accumbens injection of amphetamine (20 μg). The administration of sertindole (0.0057–2.8 μmol/kg = 2.5 μg–1.25 mg/kg, sc daily), haloperidol (0.027–0.40 μmol/kg = 10–150 μg/kg, ip bd) or clozapine (15–31 μmol/kg = 5–10 mg/kg, ip, bd) during a 13-day period of dopamine infusion (25 μg/24 h) into the nucleus accumbens reduced the dopamine-induced hyperactivity response to control levels, except at the highest dose which reduced activity to below control levels. Locomotor activity remained at control levels after discontinuing the dopamine/sertindole treatment regimen, whereas discontinuation of the dopamine/haloperidol treatment regimen resulted in rebound hyperactivity. Sertindole (0.0057 μmol/kg = 2.5 μg/kg, sc) given either once daily or once every 2 days prevented the development of hyperactivity in the intra-accumbens dopamine infusion model. One injection given every 4 days failed to modify the response to a dopamine infusion. Sertindole (0.0057 μmol/kg = 2.5 μg/kg, sc daily) inhibited hyperactivity caused by unilateral infusion of dopamine (50 μg/24 h, 13 days) into the left amygdala of rats having right hemispheric dominance (as measured in a turn preference test). In contrast to haloperidol, sertindole failed to initiate circling behaviour following unilateral, intrastriatal injection. In conclusion, sertindole, like haloperidol and clozapine, can reduce raised mesolimbic dopaminergic activity in the rat. Sertindole differs from haloperidol by its ability to return the hyperactivity response to control levels. © 1994 Wiley-Liss, Inc.     

Reversal of morphine-induced memory impairment in mice by withdrawal in Morris water maze: possible involvement of cholinergic system

The effects of morphine and morphine withdrawal on memory performance were examined in mice by using Morris water maze task. Morphine-induced memory impairment at the doses of 5 and 10 mg/kg recovered after repeated administration. Oxotremorine, a muscarinic receptor agonist, at the dose of 0.1 mg/kg ip, and physostigmine, a cholinesterase inhibitor, at the dose of 0.1 mg/kg ip, significantly antagonized morphine (10 mg/kg sc)-induced memory impairment in mice. Furthermore, repeated naloxone (0.5 mg/kg ip) attenuated scopolamine (0.2 mg/kg ip)-induced memory impairment. By using escalating doses of morphine for 13 days, morphine-induced memory impairment was continuously maintained. When withdrawal was precipitated by naloxone (5 mg/kg ip), or administration of oxotremorine (0.1 and 0.2 mg/kg ip) or physostigmine (0.05 and 0.1 mg/kg ip), the impairment was completely reversed. These results suggest that morphine-induced memory impairment could be partially due to the inhibition of the central cholinergic activity.     

Antagonism of barium chloride lethality by atropine and naloxone analysis by a multivariate logistic model.

Intracerebroventricular administration of BaCl₂ was found to produce severe, fatal convulsions in male Swiss-Webster mice with an LD50 (95% C.L.) at 10 min postadministration of 0.597 (0.395–0.901) μmol/mouse. Antagonism of BaCl₂-induced convulsions and lethality was obtained with pretreatment of atropine (1 to 5 mg/kg, ip) or naloxone (1 to 5 mg/kg, sc). A multivariate logistic model was used to examine the effect of atropine and naloxone on BaCl₂ lethality. Atropine was found to be significantly more efficacious than naloxone in antagonizing BaCl₂ lethality.     

Nitroprusside intoxication: protection of alpha-ketoglutarate and thiosulphate.

Protection against the lethal effects of sodium nitroprusside (SNP) was observed in mice after treatment with alpha-ketoglutarate (AKG), either alone or in combination with sodium thiosulphate (STS). The LD50 of SNP was 12.0 (11.0-13.0) mg/kg in mice. Ip injection of AFG (500 mg/kg twice in 20 min) increased the LD50 1.7-fold in mice. STS (1 g/kg, ip) alone increased the LD50 5.5-fold. Furthermore, combined administration of AKG and STS increased the LD50 6.9-fold. SNP elicited increased cyanide levels in blood of mice in a dose-dependent manner. SNP (10 mg/kg, sc) administration gave rise to blood cyanide levels of 73.2 +/- 3.0 microM, 30 min after treatment. Ip injection of AKG significantly decreased blood cyanide levels by 30% in mice 30 min after treatment with 10 mg SNP/kg. A single injection of STS (1 g/kg) or a combination of AKG and STS reduced in blood cyanide levels by 88 or 98%, respectively, in mice after treatment with 10 mg SNP/kg. In addition, the increase in blood cyanide levels induced by injection of 50 mg SNP/kg was markedly inhibited by a combination of AKG and STS or (to a lesser extent) by STS alone. These results suggest that the combined administration of AKG and STS, by preventing the increase in blood cyanide levels induced by SNP, may afford protection against the toxic effects of SNP.     

Induction of metallothionein after lead administration by three injection routes in mice

The amount of induced hepatic metallothionein (MT) and the alterations of calcium (Ca) and lead (Pb) concentrations in plasma, liver, kidney, and spleen were compared in male mice after iv, ip, and sc injections of lead acetate at a dose of 30 mg Pb/kg body wt. The amount of hepatic MT at 1 day was in the order of ip greater than iv greater than sc injection approximately 0, despite the hepatic Pb concentration in the order of iv greater than ip greater than sc injection. Heat-stable Pb-binding MT was not detected following any injection route. After the iv injection, a transitory hypercalcemia with hyperphosphatemia was observed. As for the tissue Pb concentration after the iv and ip injections, liver and spleen showed a high concentration, while kidney concentration was relatively low. The high tissue Pb was accompanied by an increase of tissue Ca in most cases. Only 10 to 15% of the total Pb accumulated in the liver at 1 day was recovered from the supernatant fraction after ultracentrifugation. The increase of hepatic Ca was ascribed to that in the sediment fraction. After the sc injection, the tissue Pb concentration was very low and no alterations were observed in tissue Ca concentrations.     

On the mechanism of tolerance to morphine-induced Straub tail reaction in mice

The effect of 5-HT and opioid receptor antagonists on morphine-induced Straub tail was studied in mice. Straub tail behavior was induced by subcutaneous administration of different doses (20, 30, and 40 mg/kg) of morphine hydrochloride to mice. The effect of morphine was dose-dependent. Maximum response was obtained with 40 mg/kg of the drug. The response induced by morphine (20 and 40 mg/kg) was decreased by different doses of intraperitoneal injection of naloxone (1 and 2 mg/kg) or methysergide, mianserin, and ritanserin (1 and 2 mg/kg). The effect of morphine (40 mg/kg) was also reduced by intracerebroventricular injection of naloxone (0.4-0.8 microg/animal) or mianserin (2 and 4 microg/animal). Different groups of mice received one daily dose (50 mg/kg sc) of morphine sulfate for 3 days to develop tolerance to morphine. The Straub tail reaction induced by morphine hydrochloride (40 mg/kg) was tested on the fourth day. Naloxone injection (1 and 2 mg/kg ip) on Day 3 (1 h after morphine sulfate injection) or on Day 4 (1 h before test dose of morphine hydrochloride), decreased tolerance induced to morphine. Methysergide, mianserin, or ritanserin (intraperitoneal) on Days 2 and 3 (1 h after morphine sulfate injection) or on Day 4 (1 h before test dose of morphine hydrochloride), also decreased tolerance induced to morphine. Intracerebroventricular injection of either naloxone or mianserin also reduced tolerance to morphine. It is concluded that 5-HT(2) and opioid receptor mechanisms are involved in morphine-induced Straub tail reaction and tolerance induced to morphine also may be mediated through these receptors.     

去氧乌头碱的抗炎、镇痛和解热作用

本文报告了新近以伏毛铁棒锤中提得的去氧乌头碱(DAC)的抗炎、镇痛和解热作用实验结果,并与已报道过的3-乙酰乌头碱(3AAC)进行比较。DAC0.8mg/kg (ip)显著抑制巴豆油所致小鼠耳廓肿;0.2mg/kg(ip或sc)显著抑制角叉菜胶或甲醛所致大鼠足爪肿、组胺所致大鼠皮肤渗出及醋酸所致小鼠腹腔渗出。于大鼠角叉菜胶足爪肿模型,测得DAC(ip)的抗炎治疗指数(6.38)略高于3AAC(5.92)。醋酸扭体法测得DAC抑制小鼠扭体反应50％的剂量为0.22±0.06mg/kg(sc);热板法测得DAC的小鼠镇痛ED_(50)为0.41±0.10mg/kg(ip),其镇痛治疗指数(6.37)高于3AAC(4.60)。DAC0.24mg/kg(ip)对伤寒副伤寒混合菌苗所致家兔发热有显著解热作用。     

Comparative toxicity and tissue distribution of antimony potassium tartrate in rats and mice dosed by drinking water or intraperitoneal injection

Antimony potassium tartrate (APT) is a complex salt that until recently was used worldwide as an antischistosomal drug. Treatment was efficacious only if APT was administered intravenously to humans at a near lethal total dose of 36 mg/kg. Because unconfirmed epidemiologic studies suggested there might be an association between APT treatment and bladder cancer, we initiated prechronic toxicity studies with the drug to select a route of administration and doses in the event that chronic studies of APT were needed. The toxicity and concentration of tissue antimony levels were compared in 14-d studies with F344 rats and B6C3F1 mice administered APT in the drinking water or by ip injection to determine the most appropriate route for longer term studies. Drinking water doses estimated by water consumption were 0, 16, 28, 59, 94 and 168 mg/kg in rats and 0, 59, 98, 174, 273, and 407 mg/kg in mice. APT was poorly absorbed and relatively nontoxic orally, whereas ip administration of the drug caused mortality, body weight decrements, and lesions in the liver and kidney at doses about one order of magnitude below those in drinking water. Because of these data and the dose-related accumulation of antimony in the target organs, an ip dose regimen was selected for subsequent studies. Both sexes of F344 rats and B6C3F1 mice were given 0, 1.5, 3, 6, 12, and 24 mg/kg doses of APT every other day for 90 d by ip injection. There were no clinical signs of toxicity nor gross or microscopic lesions in mice that could be attributed to toxicity of APT, although elevated concentrations of antimony were detected in the liver and spleen of mice. Rats were more sensitive than mice to the toxic effects of APT, exhibiting dose-related mortality, body weight decrements, and hepatotoxicity. The concentrations of antimony measured in liver, blood, kidney, spleen, and heart of rats were proportional to dose, but there were no biochemical changes indicative of toxicity except in the liver. Hepatocellular degeneration and necrosis occurred in association with dose-related elevations in activities of the liver-specific serum enzymes sorbitol dehydrogenase and alanine aminotransferase. By alternating the site of abdominal injection and the days of treatment, mesenteric inflammation at the site of administration was minimized in the rats and mice, indicating that the ip route would be suitable for chronic studies.(ABSTRACT TRUNCATED AT 400 WORDS)     

Central 5-HT(4) receptors and dopamine-dependent motor behaviors: searching for a functional role

In this study, we evaluated the role of central 5-HT(4) receptors in the control of motor behaviors related to change of nigrostriatal dopamine (DA) transmission, namely, stereotyped behavior and catalepsy in rats. Indeed, given that 5-HT(4) receptors indirectly modulate nigrostriatal DA neuron activity, we hypothesized that these receptors would regulate nigrostriatal DA transmission in the basal ganglia, and consequently, associated motor responses. Stereotypy was induced either by an acute administration of apomorphine (0.3 and 1.5 mg/kg sc), or by a single morphine administration (15 mg/kg sc) in chronically morphine-treated (15 mg/kg sc, twice daily for 10 days) rats. Catalepsy was induced by the typical neuroleptic haloperidol (HAL; 1 mg/kg sc). The selective 5-HT(4) antagonist, GR 125487 (1 mg/kg ip), modified neither apomorphine- nor morphine-induced stereotypy. HAL-induced catalepsy, while reduced by the systemic administration of the 5-HT(1A) agonist 8-OH-DPAT (0.1 mg/kg sc), was insensitive to GR 125487, systemically (1, 3, 10 mg/kg ip) or locally (20 and 40 nmol/20 microl) administered into the third ventricle. Also, HAL-induced catalepsy was not affected by the selective 5-HT(4) antagonist GR 113808 (3 mg/kg ip). The obtained results indicate that 5-HT(4) receptor antagonism does not modulate motor behaviors related to change of striatal DA transmission.