伯氏鼠疟原虫(Plasmodium berghei)对咯萘啶抗药性的研究

用本所传代已二十余年、对药物敏感的伯氏鼠疟原虫作种源,每转种一代给小白鼠口服单次量咯萘啶。第1代剂量为8 mg/kg,其后剂量每代增加2 mg/kg。转种至第23代,剂量达2,400mg/kg时,虽部分小鼠死亡,存活小鼠的原虫血症仍不转阴,此时原虫的抗药性为亲代原虫的300倍以上。抗咯萘啶鼠疟原虫(RPB₂)对氯喹、喹哌、吡咯喹、M-6407、阿的平与青蒿素等有一定程度的交叉抗药性。用对亲代原虫有效量的3～10倍治疗RPB₂原虫时,不能使原虫血症转阴。如不再用药,连续转种5代,RPB₂可恢复对咯萘啶的敏感性。     

三氟甲基氨酚喹类似物的合成及其抗疟活性

本文报道了22个7-三氟甲基和2-甲基-7-三氟甲基氨酚喹类似物的合成。用伯氏疟原虫(plasmodium berghei)ANKA正常株感染小鼠作抑制性治疗试验,在剂量为(10 mg/kg)/d×4和(20 mg/kg)/d×4时,有11个化合物(Ⅰ_1～9,Ⅱ₃和Ⅱ₆)对疟原虫完全抑制。其中3个化合物(Ⅰ₂,Ⅰ₆和Ⅰ₇)在剂量为(5 mg/kg)/d×4时,就能对原虫完全抑制。12个化合物(Ⅰ_1～10,Ⅱ₃和Ⅱ₆)用伯氏疟原虫ANKA抗氯喹株感染小鼠作治疗试验,剂量为(20 mg/kg)/d×4,2个化合物(Ⅰ₄和Ⅱ₃)在受试的5只小鼠中,原虫完全被抑制的鼠分别为3和4只,用相同剂量的对照药物盐酸氨酚喹治疗,原虫仍为阳性。     

维生素D缺乏和过剩对大鼠脑内P-糖蛋白和乳腺癌耐药蛋白表达的影响

目的 研究维生素D缺乏和过剩对大鼠脑内P-糖蛋白（P-gp）和乳腺癌耐药蛋白（BCRP）功能和表达的影响。方法 18只雄性SD大鼠随机分为对照组、去维生素D（NVD）组和高维生素D（HVD）组,分别使用标准饲料（1 000 IU/kg维生素D）、去维生素D（0 IU/kg维生素D）饲料和高维生素D（20 000 IU/kg维生素D）饲料饲养12周,诱导维生素D缺乏和过剩模型,测定大鼠血清中25-羟基维生素D₃[25（OH） D₃]、1α,25二羟基维生素D₃[1α,25（OH）₂D₃]水平以确证模型。造模成功后,尾iv含罗丹明123（0.2 mg/kg）、哌唑嗪（1 mg/kg）和荧光素钠（2 mg/kg）的混合探针,采用LC-FLU或LC-MS法分别测定大鼠脑皮层、海马和血浆中罗丹明123、哌唑嗪和荧光素钠的浓度,计算脑血比,评价P-gp、BCRP功能和血脑屏障完整性;采用Western blotting法测定大鼠脑皮层和海马P-gp和BCRP的相对表达量。用25（OH） D₃、1α,25（OH）₂D₃分别温孵人微血管内皮细胞（hCMEC/D3）,以罗丹明123、哌唑嗪为探针评价细胞中P-gp和BCRP的功能。结果 维生素D缺乏大鼠脑内P-gp功能和表达下调,而维生素D过剩大鼠脑内P-gp功能和表达上调,维生素D缺乏和过剩均不影响大鼠脑内BCRP的功能和表达。25（OH） D₃不影响hCMEC/D3细胞P-gp和BCRP的功能,而1α,25（OH）₂D₃上调hCMEC/D3细胞中P-gp的功能。结论 维生素D缺乏导致的体内1α,25（OH）₂D₃水平降低可能是下调大鼠脑内P-gp的功能和表达的原因之一,而维生素D过剩导致的体内1α,25（OH）₂D₃水平升高可能是上调大鼠脑内P-gp的功能和表达的原因之一。     

米非司酮对大鼠的抗着床作用研究

研究了米非司酮对大鼠的抗着床作用。大鼠在妊娠d₁、d₂或d₃口服米非司酮10mg/kg,每天1次,连续3d,有显著的抗着床作用、大鼠妊娠d1单次给米非司酮40mg/ks无抗着床作用,妊娠d₂给40mg/ks,d₃给10mg/kg有显著的抗着床作用。给药组大鼠子宫内膜发育延迟,蜕膜不能形成,影响孕卵着床。     

抗疟药咯萘啶在兔体内的药代动力学

本文报道抗疟药咯萘啶iv,im和ig给药后在兔体内的药代动力学。用NONLIN程序对血药—时间数据进行拟合。一次快速iv 6 mg/kg后的血药—时间过程符合线性三室开模型。药代动力学参数(±SD):t 1/2_β为59±10h;V_c2.418±0.287L/kg;V_d(ss),29±6 L/kg;总清除率Cl_T为0.442±0.131 L/kg·h。Im和ig给药后的动力学过程以线性二室开模型描述。im 6 mg/kg,吸收速率常数K_a为33.5±21.8 h^-1,t 1/2_β为52±8 h,吸收完全。Ig 30或60 mg/kg后的k_a为2.41±1.26 h^-1,t 1/2_β为55±5 h,吸收程度为34.6%。咯萘啶在血中呈不均一分布,im后1～96 h,球/浆浓度比为3～6。     

Respective roles of dopamine D<Subscript>2</Subscript> and D<Subscript>3</Subscript> receptors in food-seeking behaviour in rats

Abstract Rationale. Dopaminergic mechanisms are thought to be critically involved in reward-related processes and seeking behaviour. Objective. To examine the involvement of dopamine in seeking behaviour supported by a natural reinforcer, food, and assess the role of D₂ and D₃ receptor subtypes in food-seeking, using an operant reinstatement procedure. Methods. Wistar rats were subjected to a within-session extinction procedure. Experimental sessions consisted of a 15-min rewarded period during which each right lever press delivered one food pellet and initiated a 10-s time out period (FR1:TO_10s), followed by a 45-min extinction period during which responding was no longer rewarded. The reinstating effects of dopaminergic drugs, food priming, or the combination of both treatments, were investigated during spaced test sessions. In dose range studies, dopamine receptor ligands were administered 20 or 30 min into the test sessions. In interaction studies, antagonists were injected immediately before testing. Food priming consisted of two pellets non-contingently delivered 45 min into the test sessions. Results. Well trained rats emitted many responses during the rewarded period but almost none during extinction. During the last 15 min of the test sessions, non-rewarded responding was reinstated by the D₂/D₃ agonist, apomorphine (0.125–0.25 mg/kg, SC), and the D₃ preferring agonist, 7-OH-DPAT (2–4 mg/kg, SC), but not by quinelorane (0.004–2 mg/kg, SC), another D₃ preferring agonist. In interaction studies, the D₂ preferring antagonist, raclopride (0.06–0.125 mg/kg, IP), and the D₃ preferring antagonist, l-nafadotride (1 mg/kg, IP), counteracted the reinstating effect of apomorphine and 7-OH-DPAT. Pellets non-contingently delivered during extinction, reinstated modest, but significant, responding. Such food-primed food-seeking was altered by neither nafadotride (0.015–1 mg/kg, IP) nor the D₂/D₃ antagonists, amisulpride (0.25–1 mg/kg, IP) or sulpiride (2–4 mg/kg, IP). Food- and apomorphine-induced response reinstatement were additive, and food-primed food-seeking behaviour was potentiated by 7-OH-DPAT (0.125–1 mg/kg, SC) and quinelorane (7.5–15 μg/kg, SC). Such a potentiation was reversed by two D₂ antagonists, haloperidol (0.05 mg/kg, IP) and raclopride (0.125 mg/kg, IP), but not by nafadotride (1 mg/kg, IP) and another D₃ preferring antagonist, S 33084 (0.25–2 mg/kg, SC). Conclusion. These results indicate that reinstatement of non-reinforced responding by non-contingent food delivery and by dopamine agonists probably depend on different mechanisms. The properties of D₂/D₃ receptor agonists, to reinstate food seeking at larger doses, and to potentiate food-primed response reinstatement at lower doses, are preferentially mediated by D₂ rather than by D₃ receptors. Electronic Publication     

伯氏鼠疟原虫(Plasmodium berghei)对咯萘啶抗药性的研究

用本所传代已二十余年、对药物敏感的伯氏鼠疟原虫作种源,每转种一代给小白鼠口服单次量咯萘啶。第1代剂量为8 mg/kg,其后剂量每代增加2 mg/kg。转种至第23代,剂量达2,400mg/kg时,虽部分小鼠死亡,存活小鼠的原虫血症仍不转阴,此时原虫的抗药性为亲代原虫的300倍以上。抗咯萘啶鼠疟原虫(RPB_2)对氯喹、喹哌、吡咯喹、M-6407、阿的平与青蒿素等有一定程度的交叉抗药性。用对亲代原虫有效量的3～10倍治疗RPB_2原虫时,不能使原虫血症转阴。如不再用药,连续转种5代,RPB_2可恢复对咯萘啶的敏感性。     

补血益母丸哺乳期暴露对大鼠亲代和子代发育毒性的研究

目的 观察补血益母丸对哺乳期的亲代母鼠及子代生长发育的影响,探讨其安全性。方法 妊娠大鼠100只,随机分为4组,即对照组（去离子水）和补血益母丸低、中、高剂量（3.8、11.4、34.2 g生药/kg）组,每组25只。F₀母鼠于哺乳期第0天开始ig给药,连续给药至哺乳期结束,每日l次。F₀母鼠观察一般状况、体质量、摄食量、分娩及哺乳情况;F1代大鼠观察仔鼠的外观、体质量、生理发育、神经反射、行为及生殖功能等。结果 未发现补血益母丸对F₀母鼠哺乳期以及胚胎和F1代大鼠生长发育有明显毒性和干扰作用。结论 补血益母丸对F₀代母鼠哺乳期及F1子代均无明显毒性,未见毒性反应的剂量（NOAEL）为34.2 g生药/kg,相当于临床人用剂量的53倍。     

常咯啉给药速率对血药浓度和心电图的影响

本文采用三种速率(A组10mg/kg/min×2分;B组1mg/kg/min×30分;C组0.13mg/kg/min×120分)静脉给药,观察给药速率对麻醉犬血浆药物浓度和心电图改变的影响。结果表明:以C组速率给药,可避免A组给药时血浓度急骤上升和下降的缺点,剂量虽比A组增加一半,但心电图改变稍轻;与B组相比,剂量降低一倍,心电图改变明显好转(P<0.05),而维持一定血浓度值的时间却显著延长(P<0.05),因此,临床以低速率滴注为宜。在C组给药初期,心率稍有加快,达5μg/ml浓度时,心率开始变慢并出现P-R延长和QRS综合波增宽,显示常咯啉有“奎尼丁样”作用;浓度在8μg/ml以下时,P-R和QRS阻滞未超过Ⅰ度;心电图改变与血浓度呈线性关系,其线性方程为y₁=0.00484X+0.0652(P-R间期);y₂=0.00190X+0.0456(QRS综合波),显示常咯啉对房室传导较室内传导为敏感。本文就血浓度和心电图改变的关系,对常咯啉和奎尼丁进行了讨论。     

前胡丙素与硝苯啶对大鼠工作心脏缺血再灌注损伤的保护作用

大鼠ip前胡丙素(Pra-C 15 mg/kg,bid×3d)和硝苯啶(Nif 60μg/kg,bid×3d),使离体缺血再灌注工作心脏的收缩(AP,LVSP,+dP/dt_max)舒张(-dP/dt_max LVEDP和T值)性能在35min时得到改善,尤以舒张性能改善明显,并能促进CO,CF,SV及HR恢复,改善心脏工作效率,减少CK释放和心肌线粒体钙含量,表明Pra-C和Nif对心肌缺血都有保护作用,Pra-C的效应与Nif相近。     

Effects of selective dopamine D1- and D2-type receptor antagonists on the development of behavioral sensitization to 7-OH-DPAT

The primary objective of this study was to determine whether the development of behavioral sensitization to the putative dopamine D₃ receptor agonist 7-OH-DPAT could be prevented by either selective D₁-type or D₂-type dopamine receptor antagonists. In three experiments, male Wistar rats (250–350 g) were given seven to nine injections (at 48-h intervals) of 7-OH-DPAT (1.0 mg/kg, SC) or vehicle in combination with the D₂-type dopamine antagonist eticlopride (0.3 mg/kg, SC), the D₁-type dopamine antagonist SCH 23390 (0.1 or 0.2 mg/kg, SC), or vehicle. After the injections, the rats were tested for locomotor activity in photocell arenas for 2 h. In the first two experiments, after seven injections, all rats were tested for activity following vehicle injections to test for possible conditioning effects. In each experiment, after the last pre-exposure session, all rats were given a challenge injection of 7-OH-DPAT (1.0 mg/kg, SC) and tested for activity. Major findings were as follows: a) 7-OH-DPAT treatments produced a progressively greater increase in locomotor activity with repeated treatment; b) concurrent treatment with eticlopride or SCH 23390 (0.1 and 0.2 mg/kg) blocked the acute locomotor-activating effects of 7-OH-DPAT across days; c) eticlopride, but not SCH 23390, completely blocked the development of behavioral sensitization to 7-OH-DPAT. Although the low dose of SCH 23390 (0.1 mg/kg) produced a partial attenuation of sensitization, the higher dose (0.2 mg/kg) of SCH 23390 appeared to augment, rather than block, sensitization to 7-OH-DPAT; d) rats previously treated with SCH 23390 (0.2 mg/kg, but not 0.1 mg/kg) without 7-OH-DPAT displayed a hyperactive response to the 7-OH-DPAT challenge injection; and e) after vehicle injections, rats previously given 7-OH-DPAT, SCH 23390, or eticlopride either alone or in combination were more active than vehicle control rats. These findings suggest that the neurochemical mechanisms mediating the development of behavioral sensitization to 7-OH-DPAT may differ from those of other dopamine D₂-type agonists such as quinpirole or bromocriptine. Moreover, these results demonstrate that hyperactivity responses following vehicle injections in drug-pretreated animals do not necessarily reflect conditioning mechanisms. Received: 28 May 1997/Final version: 2 April 1998     

Effects of morphine on EEG in rats and their possible relations to hypo- and hyperkinesia

It was previously shown in rats that administration of cocaine ord-amphetamine in moderate doses produced alterations in EEG characteristic for activation of D₁ dopamine receptors, whereas large doses induced alterations resembling activation of D₂ dopamine receptors. Since morphine, among other effects, enhances the dopaminergic transmission, it was investigated whether this effect might be apparent in the EEG which was recorded telemetrically in awake, not restrained rats. In a moderate dose (3 mg/kg IP), morphine produced a desynchronisation and a general decrease of power in all of the frequency bands except beta-2. This effect was antagonized by naloxone (0.5 mg/kg IP) but only in part by the blocker of D₁ receptors SCH 23390 (0.2 mg/kg IP) and not by haloperidol in a dose which mainly blocks D₂ receptors (0.1 mg/kg IP). The dose of morphine used (3 mg/kg IP) produced only slight signs of behavioural activation. The results suggest that the decrease in power observed after this dose of morphine was only in part due to an activation of dopaminergic mechanisms via D₁ receptors and partly must be explained by other actions of morphine. A large dose of morphine (15 mg/kg IP) at the beginning produced catalepsy and muscular rigidity and subsequent behavioural activation; in the EEG during both behavioural phases a general increase in power in all of the frequency bands was observed which was most pronounced in the alpha-2 band (9.75–12.50 Hz). After repeated administration of this dose (14 times during a period of 21 days) a test dose of 15 mg/kg morphine led to a reversal of these effects resulting in behavioural activation and a decrease in power in most of the frequency bands. Accordingly, most but not all experimental conditions used led to consistent correlations between behavioural signs and EEG alterations after administration of morphine.     

Selective antagonism of dopamine D1 and D2 receptors does not block the development of behavioral sensitization to cocaine

The objective of this study was to determine whether the development of behavioral sensitization to cocaine could be prevented by either D₁ or D₂ selective dopamine receptor antagonists. Male Wistar rats were treated daily for 7 days with either cocaine (15 mg/kg, IP) or vehicle in combination with the D₁ dopamine antagonist SCH 23390 (0.3 mg/kg, SC), the D₂ dopamine antagonist sulpiride (100 mg/kg, IP), or vehicle. After the daily injections, the rats were tested for locomotor activity in photocell arenas. Twenty-four hours after the last pre-exposure test session, all rats were given a challenge injection of cocaine (15 mg/kg, IP) and tested for activity. Cocaine treatments produced a greater relative increase in locomotor activity with repeated exposure (i.e. sensitization). Moreover, this increase in cocaine-induced locomotor activity was attenuated by both SCH 23390 and sulpiride. In contrast, neither sulpiride nor SCH 23390 blocked the development of behavioral sensitization to cocaine. That is, rats pretreated with sulpiride or SCH 23390 and cocaine did not differ from rats pre-exposed only to cocaine when given a cocaine challenge injection. These results suggest that behavioral sensitization to cocaine may develop through either D₁ or D₂ dopamine receptor stimulation or possibly through stimulation of some non-dopaminergic receptor.Portions of this paper were presented at the 1992 Society for Neuroscience meetings, Anaheim, Cal., USA     

Subnanomolar dopamine D3 receptor antagonism coupled to moderate D2 affinity results in favourable antipsychotic-like activity in rodent models: II. behavioural characterisation of RG-15

RG-15 (trans-N-{4-[2-[4-(3-cyano-5-trifluoromethyl -phenyl) –piperazine –1 -yl] -ethyl] -cyclohexyl} -3 –pyridinesulfonic amide dihydro-chloride), is a highly selective dopamine D₃/D₂ receptor antagonist with subnanomolar affinity for the D₃ receptor and nanomolar affinity for the D₂ receptor. We found that RG-15 showed a good oral bioavailability (54%) and high brain levels (approx. 900 ng/g) in rats and demonstrated antipsychotic efficacy in amphetamine-induced hyperactivity and conditioned avoidance response tests in rats, yielding ED₅₀ (median effective dose) values of 8.6 and 12 mg/kg orally, respectively. At six- to eightfold higher doses, RG-15 blocked spontaneous motor activity, while a 30 mg/kg dose of the compound caused an increase in the home-cage motility of rats. The drug did not produce catalepsy up to 160 mg/kg oral dose; moreover, it inhibited haloperidol-induced catalepsy in the range 15–60 mg/kg. RG-15 (10 mg/kg orally) restored the impaired learning performance of scopolamine- or diazepam-treated rats in a water-labyrinth paradigm. It is assumed that the motor activating, anticataleptic and cognitive-enhancing properties of RG-15 result from its potent D₃ antagonism. In this regard, RG 15 clearly differs from other antipsychotics. Olanzapine, clozapine and amisulpride all showed efficacy against amphetamine-induced hyperactivity and on conditioned avoidance, but compared to RG-15, they proved to be more cataleptogenic and depressed or did not change the home-cage activity of animals. Olanzapine was also inactive in the learning paradigm. Our results suggest that subnanomolar dopamine D₃ receptor antagonism coupled to moderate D₂ affinity may result in an antipsychotic profile characterised by a lack of extrapyramidal side effects and secondary negative symptoms with simultaneous efficacy on positive and cognitive symptoms of schizophrenia.     

Antipsychotic regulation of dopamine D1, D2 and D3 receptor mRNA

A range of antipsychotic drugs, both “typical” and “atypical”, was administered to rats over a time course and at several different dosages. The mRNA levels of dopamine D₁ , D₂ and D₃ receptor were measured in either whole brain or dissected brain regions. D₃ receptor mRNA was up-regulated in whole brain by clozapine (10 and 30 but not 3 mg/kg/day), sulphide (50 and 100 but not 20 mg/kg/day), haloperidol (3 but not 1 or 0.3 mg/kg/day), flupenthixol (3 but not 1 or 0.3 mg/kg/day), pimozide (4.5 but not 1.5 or 0.5 mg/kg/day) and loxapine (1.2 and 4 mg/kg/day but not 0.4 mg/kg/day). Sulphide (100 mg/kg/day), clozapine (30 mg/kg/ day) and haloperidol (3 mg/kg/day) all up-regulated the D₃ receptor mRNA in nucleus accumbens and olfactory tubercles but not striatum. D₁ and D₂ receptor mRNA was up-regulated in whole brain by haloperidol and loxapine only, and in the case of haloperidol this was localized to striatum and prefrontal cortex. Haloperidol, clozapine and sulphide all down-regulated D₁ mRNA in hippocampus and additionally haloperidol and sulpiride down-regulated it in the cerebellum. This work shows that all the drugs tested upregulated D₃ receptor, but effects on D₁ and D₂ receptors were less general.     

7-OH-DPAT,a dopamine D3-selective receptor agonist,produces contralateral rotation in 6-hydroxydopamine-lesioned rats

The purpose of the present study was to characterize the rotational behavior in unilateral 6-OHDA-lesioned rats produced by the high affinity and selective dopamine D₃ receptor ligand 7-OH-DPAT. Qualitatively similar to the direct-acting DA agonist apomorphine, 7-OH-DPAT causes rats to rotate in a direction contralateral to the side of the nigrostriatal DA pathway lesion. This effect is dose-dependent and the minimum effective dose is 0.03 mg (0.12 m?mol)/kg. 7-OH-DPAT-induced rotation is blocked in a dose-dependent manner by oral pretreatment with the “D₂-like” receptor antagonists haloperidol, eticlopride, or clozapine, but not by the “D₁-like” antagonist SCH 23390. The rank order potency for inhibition of 7-OH-DPAT rotation for haloperidol [ID₅₀ = 0.067 mg (0.18 m?mol)/kg], eticlopride [ID₅₀ = 0.41 mg (1.2 m?mol)/kg], clozapine [ID₅₀ = 13 mg (40 m?mol)/kg], and SCH 23390 [ID₅₀ > 90 mg (313 m?mol)/kg] closely parallels their rank order affinity for binding to either the D₂ or the D₃ receptor. Pretreatment with the non-DA receptor antagonists ritanserin (serotonin 5HT₂), scopolamine (muscarinic cholinergic), propranolol (betaadrenergic), or naltrexone (opiate), each at relevant pharmacological doses, failed to reduce 7-OH-DPAT rotation. Taken together, these results are consistent with mediation of 7-OH-DPAT-induced rotational behavior via an agonist interaction with one or more DA receptors. ©1995 Wiley-Liss, Inc.     

Repeated 7-OH-DPAT treatments: behavioral sensitization,dopamine synthesis and subsequent sensitivity to apomorphine and cocaine

Male Wistar rats (250–350 g) were injected (SC) daily with the putative selective dopamine D₃ receptor agonist, 7-OH-DPAT (0.01, 0.10, or 1.0 g/kg) or vehicle for 10 days. Fifteen minutes after each injection, the rats were tested for locomotor activity in photocell arenas for 20 min or 2 h. In two experiments, following this subchronic treatment, all rats received a challenge injection of apomorphine (1.0 mg/kg, SC), or cocaine (10 mg/kg, IP) on day 11, and were tested for locomotor activity. In a third experiment, dopamine synthesis in striatal and mesolimbic (nucleus accumbens-olfactory turbercle) tissue was assessed following acute or chronic 7-OH-DPAT treatments by measuring the accumulation of dihydroxyphenylalanine (DOPA) after treatment with a DOPA decarboxylase inhibitor. Major findings were as follows: a) acute 7-OH-DPAT treatment produced a dose-dependent decrease in locomotor activity; b) when tested for 2 h, the 1.0 mg/kg dose of 7-OH-DPAT produced a progressively greater increase in activity across the 10 test days (i.e., behavioral sensitization); c) subchronic treatment with 7-OH-DPAT did not result in cross-sensitization to either apomorphine or cocaine; d) acute treatment with the 1.0 mg/kg dose of 7-OH-DPAT significantly decreased dopamine synthesis in both striatal and mesolimbic regions; and e) chronic 7-OH-DPAT treatments did not affect basal dopamine synthesis in either brain region. Although the behavioral effects of 7-OH-DPAT were similar to the reported effects of the D₂/D₃ dopamine agonist quinpirole, the effects of repeated 7-OH-DPAT treatments differed from those of quinpirole in terms of cross-sensitization and basal dopamine synthesis. These results suggest that locomotor inhibition produced by low doses of 7-OH-DPAT is not related to dopamine autoreceptor stimulation, and the development of behavioral sensitization to high doses of 7-OH-DPAT is not due to the development of dopamine autoreceptor subsensitivity.     

Effects of selective D1 and D2 dopamine antagonists on the development of behavioral sensitization to apomorphine

The objective of the present study was to determine whether the development of behavioral sensitization to apomorphine could be blocked by either D₁ or D₂ selective dopamine antagonists. In three experiments, male rats received 10–21 daily injections of a selective D₁ (SCH 23390; 0 or 0.5 mg/kg IP) or D₂ (sulpiride; 0, 30, or 100 mg/kg IP) antagonist followed by an apomorphine (0 or 1.0 mg/kg SC) injection. In two experiments, the rats were tested for locomotor activity in photocell arenas after the daily injections. In all experiments, the rats were tested for sensitization to apomorphine following the training phase. The results indicated that apomorphine produced a progressively greater increase in locomotor activity with each injection, and this apomorphine-induced increase in activity was completely blocked by both sulpiride and SCH 23390 treatments. However, although both sulpiride and SCH 23390 blocked apomorphine-induced activity, only SCH 23390 injections prevented the development of sensitization to apomorphine. That is, rats pretreated with sulpiride and apomorphine displayed significant sensitization when subsequently tested with a challenge dose of apomorphine alone. These findings suggest that the development of behavioral sensitization to apomorphine is related specifically to the stimulation of dopamine D₁ receptors.Portions of this paper were presented at the 1990 Society for Neuroscience meetings, St. Louis, MO, USA     

Teratogenic Evaluation of Tributyltin Chloride in Rats Following Oral Exposure

ABSTRACT

The teratogenicity of tri-n-butyltin chloride (TBTC1) was examined in Wistar rats. The pregnant rats were administered orally 25, 15, 9, 5 and 0(Control) mg of TBTCl/kg of body weight/day from day 7 to 15 of pregnancy. Maternal toxicity, as evidenced by both of decreased body weight gain and food consumption was observed at 25, 15 and 9 mg/kg/day dose group. However, only in the 25 mg/kg/day dose group some clinical signs of toxicity (sedation, diarrhoea and salivation) were observed and 70 percent of the dams were dead. In the 25 mg/kg/day dose group, all fetuses were dead. Statistically significant reductions in the female fetal body weight were observed in 9 and 5 mg/kg/day dose groups. In all groups treated with TBTC1 except the 25 mg/kg/day dose group, no significant differences in the numbers of live fetuses and intrauterine death (dead fetuses and resorptions) or sex ratios of fetuses were found between the TBTC1-treated and control groups. Fetal external, skeletal and internal malformations were not observed at any of the dose levels. However, several types of skeletal and internal variations including delayed ossifications were observed in some groups treated with TBTC1, but the incidences were not significantly different from controls. Also, two fetuses with dilatation of the renal pelvis were found in 9 and 5 mg/kg/day dose group. Statistically significant increases of placental weight in all TBTC1-treated groups were observed when compared to that of control group. In conclusion, TBTC1 administered orally to Wistar rats during days 7–15 of pregnancy produced related signs of fetal toxicity but no evidence of teratogenicity and induced a marked increase in placental weight.