Inflammatory cytokine gene expression in THP-1 cells exposed to Stachybotrys chartarum and Aspergillus versicolor

Very little is known about the mechanisms that occur in human cells upon exposure to fungi as well as their mycotoxins. A better understanding of toxin‐regulated gene expression would be helpful to identify safe levels of exposure and could eventually be the basis for establishing guidelines for remediation scenarios following a water intrusion event. In this research, cytokine mRNA expression patterns were investigated in the human monocytic THP‐1 cell line exposed to fungal extracts of various fragment sizes obtained from Stachybotrys chartarum RTI 5802 and/or Aspergillus versicolor RTI 3843, two common and well‐studied mycotoxin producing fungi. Cytokine mRNA expression was generally upregulated 2–10 times following a 24 h exposure to fungal extracts. Expression of the proinflammatory interleukin‐1β, interleukin‐8, and tumor necrosis factor‐α genes increased while the anti‐inflammatory gene interleukin‐10 also increased albeit at very low level, suggesting that negative feedback regulation mechanism of production of proinflammatory cytokines initiated upon 24 h of incubation. In addition, submicron size extracts of A. versicolor caused significant death of THP‐1 cells, whereas extracts of S. chartarum caused no cell death while the mixture of the two fungi had an intermediate effect. There was no general correlation between gene expression and fragment sizes, which suggests that all submicron fragments may contribute to inflammatory response. © 2011 Wiley Periodicals, Inc. Environ Toxicol, 2013.     

The chemical basis for the blockade of the D-1 dopamine receptor by SCH 23390

SCH 23390 (R(+)-7-chloro-8-hydroxy-2,3,4,5-tetrahydro-3-methyl-1-phenyl-1H-3 -benzazepine) is a potent, relatively selective antagonist of the D-1 dopamine receptor ( Iorio et al., J. Pharmacol. Exp. Ther. 226, 462). Because SKF 75670, the 7-OH analogue of SCH 23390, is a partial D-1 agonist, we conclude that the 7-Cl substituent of SCH 23390 contributes to its D-1 antagonist activity. Because SKF 83509, the desmethyl analogue of SCH 23390, is a selective D-1 antagonist, we conclude that the N-methyl substituent of SCH 23390 is not essential for its D-1 antagonist activity.     

Synergistic effects between D-1 and D-2 dopamine antagonists on catalepsy in rats

The effect of selective D-1 and D-2 dopamine agonists on catalepsy induced by various dopamine antagonists was studied. A potent and selective D-2 antagonist, YM-09151 (YM-09151-2) at a dose of 1.2 mg/kg, SC and a selective D-1 antagonist, SCH 23390 at 1.0 mg/kg, SC induced catalepsy in rats. Mixed D-1/D-2 antagonists, haloperidol (HPD) and cis-flupentixol (FLU) also induced catalepsy at doses of 2.0 and 0.8 mg/kg, SC, respectively. A mixed D-1/D-2 agonist, apomorphine (1.0 mg/kg, SC), a selective D-2 agonist, bromocriptine (10 mg/kg, IP) and a muscarinic antagonist, scopolamine (1.0 mg/kg, SC), prevented or markedly reduced the incidence of catalepsy by the tested antagonists. In contrast, a selective D-1 agonist, SKF 38393 (4.0 mg/kg, SC) did not reduce the cataleptogenic effects of HPD, FLU and SCH 23390, but did reduce the effect of YM-09151. Moreover, co-administration of YM-09151 with SCH 23390 produced a marked increase in the incidence of catalepsy. The incidence seen after the combination of YM-09151 and SCH 23390 at low doses was significantly different from that seen after each drug alone at the doubled dose. Thus, D-1 and D-2 antagonists potentiated each other's effect in producing catalepsy. These results suggest an important role of both D-1 and D-2 receptors in the catalepsy and the existence of synergistic effects of D-1 and D-2 receptor blockade.     

Enhancement by a single dose of reserpine (plus alpha methyl-p-tyrosine) of the central stimulatory effects evoked by dopamine D-1 and D-2 agonists in the mouse

Summary With the advent of selective dopamine D-1 and D-2 agonists such as SKF38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine HCl) and quinpirole (LY171555, trans-4,4a,5,6,7,8a,9-octahydro-5-propyl-2H-pyrazolo [3,4-g]-quinoline), it has become possible to examine the functional role of the two dopamine receptor subtypes as well as their interrelationship. In the present study, we pretreated mice with the granule-depleting agent reserpine (5 mg/kg sc) and tested the mice from 4 h to 10 days later. In all the studies, each mouse also received an injection of the dopamine synthesis inhibitor alpha methyl-p-tyrosine (200 mg/kg ip) 1 h before agonist challenge. Where the reserpine was given 2 or more days before testing, a second dose of reserpine was given 4 h before agonist challenge. While producing no significant locomotor stimulation 4 h after reserpine, SKF38393 produced a dose-dependent increase in coordinated locomotion 24 h and 3 days after the reserpine. Likewise, quinpirole itself produced no significant alteration in activity at 4 h, but significantly increased activity at 24 h and 3 days. The new selective D-1 agonist CY208-243 ((–)-4,6,6a,7,8,12b-hexahydro-7-methyl-indolo [4,3-ab] phenanthridine), unlike SKF38393, produced some increase in activity 4 h after reserpine, but much greater activity was seen 1 and 3 days after reserpine. The enhancement with SKF38393, CY208-243 and quinpirole was most marked 3 days after the reserpine. The behavioural stimulation produced by the mixed D-1/D-2 agonist apomorphine was also greater 3 days after reserpine pretreatment than after 4 h. The combination of SKF38393 and quinpirole produced greater locomotor stimulation than either drug alone, and the increased response, while evident 4 h after reserpine, was most marked 3 days after, and had essentially disappeared by 10 days. A similar interaction was seen between CY208243 and quinpirole. At 3 days, there was also a supersensitive response of the mice to the rearing and sniffing produced by SKF38393 plus quinpirole. Striatal binding studies with the D-1 selective ligand [³H]-SCH23390 (R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7ol) and with the D-2 selective ligand [³H]-spiperone indicated that there were no changes in K _d or B _max of the D-1 or D-2 receptors at the time of maximum behavioural supersensitivity (3 days). Thus, the behavioural supersensitivity to apomorphine, SKF38393, CY208-243 and to quinpirole was not accompanied by any change in D-1 or D-2 binding in the striatum indicating that the biochemical modulation of the supersensitivity is either outside the striatum and/or associated with neurochemical alterations in the striatum other than changes in the D-1 and D-2 recognition sites. Send offprint requests to D. M. Jackson at the above address     

Effects of selective D-1 and D-2 dopamine antagonists on development of methamphetamine-induced behavioral sensitization

The present study examined effects of selective antagonists of D-1 and D-2 dopamine receptors on the development of behavioral sensitization produced by repeated methamphetamine (MAP) administration. Male Sprague-Dawley rats were divided into four groups. Each group received a daily injection of saline (control group), 4 mg/kg MAP (MAP group), 1 mg/kg YM-09151-2 plus 4 mg/kg MAP (YM+MAP group) or 0.5 mg/kg SCH 23390 plus 4 mg/kg MAP (SCH+MAP group) for 14 days. During daily injection for 14 days, the MAP group exhibited a progressive augmentation in locomotor and stereotyped behavior, whereas the progression of such behaviors in the YM+MAP and SCH+MAP group was completely prevented. After an abstinence period of 7 days, all groups received a challenge of 2 mg/kg MAP. The MAP challenge reproduced hyperlocomotion and intense stereotyped behavior only in the MAP group. However, neither the YM+MAP group nor the SCH+MAP group showed sterotypy. The manner in which both groups showed only hyperlocomotion was similar to that observed in the control group. These results indicate that both selective D-1 antagonists and selective D-2 antagonists not only reverse MAP-induced motor effects at each injection but also prevent the development of behavioral sensitization induced by repeated MAP administration.     

Motor activity following the administration of selective D-1 and D-2 dopaminergic drugs to normal common marmosets

In normal common marmosets administration of the D-1/D-2 agonist apomorphine or the selective D-2 agonist quinpirole caused a dose-dependent increase in motor activity and induced stereotyped behaviour. Both the selective D-2 antagonist raclopride and the selective D-1 antagonist SCH 23390 inhibited normal locomotor activity and induced catalepsy. Quinpirole- and apomorphine-induced motor activity were potently inhibited by pretreatment with raclopride. The effects of quinpirole, but not apomorphine, were weakly inhibited by SCH 23390. The selective D-1 partial agonist SKF 38393 decreased motor activity and did not induce grooming, oral movements or other behaviours. SKF 38393 inhibited motor activity induced by the administration of quinpirole but did not alter apomorphine-induced motor behaviour. Locomotor activity in normal common marmosets appears to be mediated mainly via D-2 systems. In contrast to rodents, administration of SKF 38393 does not induce behavioural activation and there does not appear to be a facilitating effect of D-1 systems on D-2 function in the normal common marmoset. However, the ability of both SKF 38393 and SCH 23390 to inhibit quinpirole locomotor activity suggests some interaction between D-1 and D-2 systems to occur in this species.     

The induction of grooming and vacuous chewing by a series of selective D-1 dopamine receptor agonists: two directions of D-1:D-2 interaction

A range of 3- and 6-substituted 1-phenyl-1H-3-benzazepine analogues of SK & F 38393 with D-1 agonist activity were compared for their behavioural effects in the intact adult rat and for their relative affinities for D-1 and D-2 dopamine receptors in vitro. All compounds showed selective affinity for D-1 receptors and induced prominent grooming behaviour, but those with the lower D-1: D-2 selectivity ratios also induced additional episodes of non-stereotyped sniffing, locomotion and rearing. No vacuous chewing was noted. There were marked differences in in vivo potency, extending over a 100-fold range. These responses to the most potent agonist, SK & F 77434 (3N-allyl-SK & F 38393) were reduced enantioselectively by the D-1 antagonist R-SK & F 83566. They were also reduced enantioselectively by the D-2 antagonist R-piquindone, but this pretreatment additionally released a marked vacuous chewing response to SK & F 77434. Prominent grooming may be a characteristic behavioural response to a range of D-1 agonists. It is suggested that there may be at least two forms of functional interaction between D-1 and D-2 systems, manifested concurrently in distinct elements of behaviour: one co-operative, as in the regulation of grooming, and with correlates in the regulation of pallidal neural activity; the other oppositional, as in the regulation of vacuous chewing, and with correlates in the regulation of striatal adenylate cyclase activity.     

Effects of the putative D-1 antagonist SCH 23390 on stereotyped behaviour induced by the D-2 agonist RU24213

The effects of the putative selective dopamine D-1 antagonist benzazepine SCH 23390 and of the selective dopamine D-2 antagonist Ro22-2586 on stereotypy induced by the selective D-2 agonist RU24213 were compared. RU24213 (0.5–15 mg/kg) dose-dependently induced stereotyped behaviour characterised by continuous downward sniffing and locomotion. These responses were antagonised, as expected, by 40–200 g/kg Ro22-2586, but surprisingly blocked by 40–200 g/kg SCH 23390. The selectivities of these compounds for dopamine receptor subtypes were verified in terms of their relative abilities to displace the in vitro binding of ³H-piflutixol to striatal D-1 receptors and of ³H-spiperone to D-2 receptors. As SCH 23390 fails to influence D-2 mediated prolactin secretion or emesis in vivo, there appears to be no significant formation of an active metabolite of SCH 23390 with D-2 antagonist activity. Because SCH 23390 has some affinity for 5-hydroxytryptamine receptors, any effect on the serotonergic behavioural syndrome induced by 10 mg/kg 5-methoxy-N,N-dimethyltryptamine was also studied. The serotonergic responses of hind limb abduction, reciprocal forepaw treading and Straub tail were unaltered after 40–200 g/kg SCH 23390, indicating no significant 5-HT blockade or non-specific depressant action at these doses which might influence the expression of stereotypy. Thus, these data are consistent with blockade of tonic D-1 dopaminergic activity that may influence the expression of behaviours initiated byD-2 dopaminergic stimulation.     

Aspergillus sp.D-1专一性还原左旋一叶萩碱

目的筛选具有还原左旋一叶碱能力的微生物菌株。方法通过TLC分析进行菌株的筛选,利用RP HPLC测定左旋一叶碱和产物的浓度,利用硅胶柱色谱法分离纯化产物,通过光谱分析鉴定了产物的化学结构。结果与结论筛选到一菌株Aspergillussp.D 1能够专一性地还原左旋一叶碱的γ,δ双键产生14,15二氢一叶碱。在丝状真菌中发现了一种新型的生物催化的还原反应。     

Drugs acting at D-1 and D-2 dopamine receptors induce identical purposeless chewing in rats which can be differentiated by cholinergic manipulation

Purposeless chewing in rats was dose dependently increased by acute administration of the dopamine D-1 receptor agonist SKF 38393 (5–20 mg/kg), the D-2 receptor antagonist sulpiride (10–100 mg/kg) and the D-2 receptor agonist quinpirole (0.05–0.25 mg/kg). Only high doses of the D-1 receptor antagonist SCH 23390 (1 and 5 mg/kg) induced purposeless chewing. SCH 23390 (0.05 mg/kg) blocked SKF 38393 (20 mg/kg)-induced purposeless chewing, but had no effect on the purposeless chewing induced by sulpiride (100 mg/kg) or quinpirole (0.1 mg/kg). A dose of SKF 38393 (5 mg/kg) which did not itself induce chewing, potentiated the increase in purposeless chewing observed after administration of sulpiride (100 mg/kg). Administration of SKF 38393 (20 mg/kg) and quinpirole (0.1 mg/kg) did not induce purposeless chewing but stereotyped licking was observed. Administration of sulpiride (100 mg/kg) with quinpirole (0.1 mg/kg) produced an incidence of purposeless chewing not different from that observed when either compound was administered alone. Acute administration of the cholinergic agonist pilocarpine (0.5–4.0 mg/kg) or the cholinesterase inhibitor physostigmine (0.05–0.2 mg/kg) increased the frequency of purposeless chewing in rats. Co-administration of pilocarpine (0.5 mg/kg) with sulpiride (100 mg/kg) increased the frequency of purposeless chewing above that seen when either compound was administered alone. Co-administration of pilocarpine (0.5 mg/kg) with SKF 38393 (20 mg/kg) increased the frequency of purposeless chewing in an additive manner. Co-administration of physostigmine (0.1 mg/kg) with sulpiride (100 mg/kg) but not SKF 38393 (20 mg/kg), increased the frequency of purposeless chewing above that observed when either compound was administered alone. Quinpirole (0.1 mg/kg)-induced purposeless chewing was not affected by co-administration with either pilocarpine (0.5 mg/kg) or physostigmine (0.1 mg/kg). The anticholinergic agent scopolamine (0.1 mg/kg) blocked the purposeless chewing induced by either SKF 38393 (20 mg/kg) or sulpiride (100 mg/kg), but had no effect on the purposeless chewing induced by quinpirole (0.1 mg/kg). Contrary to previous reports, acute manipulation of D-1 or D-2 receptor function can both enhance purposeless chewing behaviour in rats. These apparently identical behaviours can be differentiated by the response to cholinergic manipulation.     

Differential ability of selective and non-selective dopamine agonists to induce climbing in the rat indicates the involvement of both D-1 and D-2 receptors in this behaviour

Approximately 50% of female Wistar rats examined exhibited a continuous climbing response to a screening dose of apomorphine. In animals identified as climbing, the mixed D-1/D-2 agonists apomorphine, pergolide andl-dopa, and the indirectly acting agonists nomifensine and (+)-amphetamine, induced a dose-related climbing response. The selective D-1 agonist SKF 38393 caused only minimal climbing, and the selective D-2 agonists bromocriptine, lisuride and LY 141865 induced a weak climbing response. All agonists examined, except SKF 38393, caused a dose-related stereotypy response. The selective D-1 antagonist SCH 23390, and the selective D-2 antagonist sulpiride, both produced maximum inhibition of apomorphine-induced climbing. SCH 23390 also inhibited stereotyped behaviour, but sulpiride was less effective. In animals identified as non-climbers using the screening dose of apomorphine, onlyl-dopa induced a marked climbing response. Nomifensine and bromocriptine produced weak or discontinuous climbing in this group, while the other agonists examined had little or no effect. In contrast all drugs examined, except SKF 38393, induced stereotyped behaviour of the same intensity observed in the climbers. It is concluded that stimulation of both D-1 and D-2 receptors is necessary to induce a continuous climbing behaviour in rats. D-2, but not D-1 stimulation, alone can induce a weak or discontinuous climbing response, but concomitant stimulation of D-1 receptors potentiates this effect. Failure of some rats to climb does not appear to be related to relative degrees of D-1 and D-2 stimulation.     

Differential inhibition by dopamine D-1 and D-2 antagonists of circling behaviour induced by dopamine agonists in rats with unilateral 6-hydroxydopamine lesions

The selective dopamine (DA) D-1 antagonist SCH 23390 antagonized the contralateral circling behaviour induced by the DA D-1 agonist SK & F 38393 in rats lesioned unilaterally with 6-hydroxy-DA but had a 600 times weaker effect against the preferential DA D-2 agonist pergolide. The D-2 antagonists clebopride and spiroperidol had the reverse selectivity. The mixed D-1/D-2 antagonists cis(Z)-flupentixol and cis(Z)-clopenthixol blocked the circling induced by either agonist. It is concluded that circling behaviour is mediated by closely related but independent DA D-1 and D-2 receptor sites.     

Opposing roles for D-1 and D-2 dopamine receptors in regulating the excitability of growth hormone-producing cells in the snail Lymnaea stagnalis

Dopamine hyperpolarizes growth hormone-producing cells (GHC) in the CNS of Lymnaea stagnalis. This effect of dopamine was mimicked by the D-2 receptor agonist LY 141865 and antagonized by the D-2 receptor antagonists (-)-sulpiride and YM 09151-2. SKF 38393, a selective D-1 receptor agonist, increased the excitability of the GHC. This effect was mimicked by intracellular injection of cyclic AMP and antagonized by the D-1 receptor antagonist SCH 23390. Dopamine (in the presence of (-)-sulpiride) also increased the excitability of the GHC. It is concluded that both a D-1 and a D-2 receptor regulate the electrical activity of the GHC in the CNS of Lymnaea stagnalis.     

Behavioural effects of selective dopamine D-1 and D-2 agonists and antagonists in guinea-pigs

This study describes specific behaviours in guinea-pigs after dopamine D-1 and D-2 receptor activation which differed to those described in other rodent species. Intraperitoneal (IP) administration of the dopamine D-2 receptor agonist quinpirole (1.5, 3 and 6 mg/kg) to guinea-pigs dose-dependently initiated locomotor activity and other behaviours including rearing, head-down sniffing, chewing, circling, licking and head/body shaking. Locomotor activity induced by quinpirole (3 mg/kg) was reduced by the D-2 receptor antagonists sulpiride, (100 mg/kg IP) and raclopride (10 mg/kg IP). The dopamine D-1 receptor agonist SKF 38393 (8, 16 and 32 mg/kg IP) produced little or no behavioural effect, nor did the D-1 receptor antagonist SCH 23390 (0.2 and 0.4 mg/kg IP). A 16 mg/kg dose of SKF 38393, given in combination with 3 mg/kg quinpirole, produced responses similar to quinpirole alone, whereas 32 mg/kg SKF 38393 combined with quinpirole induced vacuous oral chewing, with attenuation of locomotor activity and circling, but not other behaviours produced by this dose of quinpirole. In contrast to previous studies in rats, the responses to quinpirole (3 mg/kg) were not significantly affected by SCH 23390 (0.2 and 0.4 mg/kg). It is concluded that the guinea-pig may be a useful and interesting species for study of the behavioural effects of D-1 and D-2 agonists and antagonists, as its responses appear to differ from those of other rodent species, but are similar to some responses to D-1 agonists observed in primates.     

Further evidence for two directions of D-1:D-2 dopamine receptor interaction revealed concurrently in distinct elements of typical and atypical behaviour: studies with the new enantioselective D-2 agonist LY 163502

The new, extremely potent and enantioselective D-2 agonist LY 163502 failed to induce compulsive stereotyped behaviour. Very low doses (3–6 g/kg) inhibited spontaneous sniffing and locomotion, while higher doses (12–50 g/kg) induced episodes of non-stereotyped sniffing and chewing; these actions showed complete enantioselectivity. Up to 200-fold higher doses modestly induced only locomotion. Responsivity to LY 163502 was enantioselectively blocked by the selective D-2 antagonist R-piquindone. This responsivity was also enantioselectively blocked by the selective D-1 antagonist R-SK&F 83566 but, additionally, episodes of atypical limb/body jerking behaviour were released; thus, LY 163502 induced such jerking only when tonic D-1 activity was suppressed. These data extend our notion that there may be at least two forms of functional interaction between D-1 and D-2 receptor systems: one cooperative, as in the regulation of typical sniffing, and another oppositional, as in the regulation of atypical jerking.     

Antistereotypic effects of dopamine D-1 and D-2 antagonists after intrastriatal injection in rats. pharmacological and regional specificity

Summary Apomorphine antagonistic effects of a range of dopamine (DA) antagonists were studied after intracerebral and after peripheral injection. Inhibitory activity was found selectively within the ventral striatum with a D-1 antagonist (SCH 23390), D-2 antagonists (benzamides, butyrophenones) and mixed D-1/D-2 antagonists (thioxanthenes, phenothiazines), whereas -adrenoceptor antagonists, muscarinic- and serotonin S₂-antagonists were ineffective. Great differences in absolute potencies and in peripheral versus intrastriatal potency ratios were observed. High peripheral versus central selectivity ratios and high intrastriatal potencies were found with the hydrophilic compounds (-)-sulpiride, veralipride and domperidone which do not readily cross the blood-brain barrier. High intrastriatal potency was also observed for the benzamide, YM 09151-2, haloperidol and spiroperidol although these compounds had lower peripheral versus intrastriatal selectivity ratios. Neuroleptic potency after intracerebral administration did not depend solely on DA receptor affinity but additionally on physicochemical properties. On the basis of the peripheral vs. intrastriatal potency ratios, it is concluded that only few of the neuroleptics tested in this study are suited for topographical studies of DA receptor function using intracerebral injection but that (-)-sulpiride is one example combining high potency, high central selectivity, high DA D-2 receptor specificity stereoselectivity and long duration of action. The siteselectivity of apomorphine-antagonistic effects was further studied using (-)-sulpiride as a model compound. Inhibitory activity against oral stereotypy was preferentially found after injection into the ventral striatum, whereas the lowcomponent patterns of apomorphine stereotypy (sniffing, rearing, motility) were blocked equally well in the ventral striatum and nucleus accumbens. In contrast, a facilitation of oral stereotypy was induced by (-)-sulpiride in the dorsal striatum. No effect on apomorphine-stereotypy was found after injection into frontal cortex, supragenual cortex, septum, amygdala, substantia nigra or thalamus. These results support data obtained in lesion studies indicating the ventral striatum as the important site mediating inhibition of oral stereotypy after DA receptor blockade. However, the differentiation between striatum and accumbens in medition of stereotypy and hyperactivity was not as absolute as has been suggested by lesion studies     

云芝多糖B对大鼠单核细胞趋化蛋白—1基因表达的影响

目的:探究野生云芝多糖水溶性新组分CVPS-B对大鼠脾细胞单核细胞趋化蛋白-1(MCP-1)基因表达的影响.方法:以β-actin为内标准物,用逆转录聚合酶链式反应(RT-PCR)检测CVPS-B分别对正常情况下以及脂多糖(LPS)诱导下大鼠脾细胞MCP-I基因表达的影响,并对RT-PCR产物进行测序,以证实其特异性.结果:(1)正常情况下大鼠脾细胞MCP-1 mRNA的表达(MCP-1/β-actin的比值)生理盐水对照组为1.4±0.3;CVPS-B三个剂量组(10、30和50mg·kg~(-1)·d~(-1),ip,连续4d)分别为:1.6±0.4、1.7±0.5和1.5±0.4,后三组与对照组无显著差异(P>0.05);(2)大鼠腹腔给药LPS(10μg·kg~(-1)可使脾细胞MCP-1 mRNA的表达增加114％.(3)CVPS-B4个剂量组(5、10、30和50mg·kg~(-1)·d~(-1),ip,连续4d)可使LPS(10μg·kg~(-1),ip)诱导的脾细胞MCP-1 mRNA的表达分别减低51％,70％,84％和99％(n=6).结论:CVPS-B可预防性抑制LPS对大鼠脾细胞MCP-1基因表达的诱导作用,且呈剂量依赖性,但对正常情况下大鼠脾细胞MCP-1 mRNA的表达则无明显影响.     

Differential involvement of dopamine D-1 and D-2 receptors in the circling behaviour induced by apomorphine,SK & F 38393, pergolide and LY 171555 in 6-hydroxydopamine-lesioned rats

The antagonistic effect of dopamine (DA) D-1 and D-2 antagonists against circling behaviour induced by various DA agonists in 6-OHDA-lesioned rats has been investigated. DA D-1/D-2 selectivity of agonists in vitro was measured by the stimulatory effect on DA-sensitive adenylate cyclase in rat striatal homogenates (D-1), the inhibitory effect on electrically-induced release of ³H-DA in rabbit striatal slices (D-2) and the affinity to ³H-piflutixol (D-1) and ³H-spiroperidol (D-2) binding sites in rat striatal membranes. The contralateral circling behaviour induced by the DA D-1 agonist SK & F 38393 was blocked by the DA D-1 antagonist, SCH 23390, and by the mixed DA D-1/D-2 antagonist cis(Z)-flupentixol, but was not influenced by the DA D-2 antagonists spiroperidol and clebopride. In contrast, circling behaviour induced by the preferential DA D-2 agonists pergolide and LY 171555 was blocked by clebopride, spiroperidol, and cis(Z)-flupentixol, but weakly or not influenced by SCH 23390. Apomorphine-induced circling behaviour was blocked by cis(Z)-flupentixol, partially antagonized by SCH 23390 and clebopride but not inhibited by spiroperidol, although the time-course of circling was changed. Combinations of SCH 23390 with spiroperidol or clebopride in low doses completely blocked the effect of apomorphine. These results indicate that DA D-1 and D-2 receptors mediate circling behaviour through separate mechanisms which can be independently manipulated with respective agonists and antagonists. Furthermore, the results indicate that both DA D-1 and D-2 receptors are involved in the effect of apomorphine, since selective antagonists induced maximally 50% inhibition. Complete blockade was only found in combination experiments and by the mixed D-1/D-2 antagonists cis(Z)-flupentixol, cis(Z)-clopenthixol, and clozapine.     

Reward-potentiating effects of D-1 dopamine receptor agonist and AMPAR GluR1 antagonist in nucleus accumbens shell and their modulation by food restriction

RATIONALE: Previous studies have suggested that chronic food restriction (FR) increases sensitivity of a neural substrate for drug reward. The neuroanatomical site(s) of key neuroadaptations may include nucleus accumbens (NAc) where changes in D-1 dopamine (DA) receptor-mediated cell signaling and gene expression have been documented. OBJECTIVES: The purpose of the present study was to begin bridging the behavioral and tissue studies by microinjecting drugs directly into NAc medial shell and assessing behavioral effects in free-feeding and FR subjects. MATERIALS AND METHODS: Rats were implanted with microinjection cannulae in NAc medial shell and a subset were implanted with a stimulating electrode in lateral hypothalamus. Reward-potentiating effects of the D-1 DA receptor agonist, SKF-82958, AMPAR antagonist, DNXQ, and polyamine GluR1 antagonist, 1-na spermine, were assessed using the curve-shift method of self-stimulation testing. Motor-activating effects of SKF-82958 were also assessed. RESULTS: SKF-82958 (2.0 and 5.0 mug) produced greater reward-potentiating and motor-activating effects in FR than ad libitum fed (AL) rats. DNQX (1.0 mug) and 1-na spermine (1.0 and 2.5 mug) selectively decreased the x-axis intercept of rate-frequency curves in FR subjects, reflecting increased responding for previously subthreshold stimulation. CONCLUSIONS: Results suggest that FR may facilitate reward-directed behavior via multiple neuroadaptations in NAc medial shell including upregulation of D-1 DA receptor function involved in the selection and expression of goal-directed behavior, and increased GluR1-mediated activation of cells that inhibit nonreinforced responses.     

屈头鸡果对内毒素致小鼠急性肺损伤的保护作用

目的 研究屈头鸡果在内毒素致小鼠急性肺损伤中的作用及其机制.方法 将40只SPF级雄性BALB/c小鼠分为正常组、对照组、模型组和实验组,每组各10只.经鼻滴入20 mg·kg-1脂多糖构建内毒素致小鼠急性肺损伤模型,其中对照组和实验组分别灌胃屈头鸡果2.16 g·kg-1,正常组和模型组灌胃等量生理盐水.观察各组小鼠...