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PubMed1978

The alternate respiratory pathway of Candida albicans.

Candida albicans contains a cryptic cyanide and antimycin A insensitive respiratory system. This alternate oxidase was found (i) at all growth rates from mu = 0.05 to 0.26 in a chemostat culture and (ii) in both mycelial and yeast forms of the organism. Neither chloramphenicol nor cycloheximide prevented the expression of the alternate oxidase. Salicylhydroxamic acid was a potent inhibitor of the cyanide insensitive respiration. The respiration of mitochondria grown in the presence of antimycin A was not inhibited by cyanide or antimycin A but was inhibited by salicylhydroxamic acid.

Antifungal Agents↗
PubMed1989

Optimization of tetrachlorosalicylanilide and ultraviolet A doses at sensitization and challenge for contact photosensitivity in the mouse.

We studied contact photosensitivity (CPS) to tetrachlorosalicylanilide (TCSA) in BALB/cJ mice with various doses of TCSA and UVA at sensitization and challenge. From these studies we recommend the following protocol: sensitization on days 0 and 1 with 50 microliters of 1% TCSA followed by 3 J/cm2 of UVA, and challenge on day 7 with 10 microliters of 3% TCSA followed by 6 J/cm2 of UVA. This gave an ear swelling response of 27.4 +/- 0.6 x 10(-3) (mean +/- standard error). We also demonstrated that there is reciprocity between volume and concentration of TCSA at sensitization but not between TCSA and UVA doses at sensitization.

Allergens↗
PubMed1985

Antimycin A- and hydroxamate-insensitive respiration in yeasts.

In this paper evidence is presented for the mitochondrial localization of the antimycin A (AA) + salicylhydroxamate (SHAM)-insensitive respiration of the yeasts Kluyveromyces lactis, Endomycopsis capsularis and Hansenula saturnus. Such a respiration, which can be sustained by NADH and NADPH but not by succinate, is inhibited by high concentrations of azide. AA + SHAM-insensitive respiration is not phosphorylating and its postulated physiological role is to oxidize NADH.

Antifungal Agents↗
PubMed1989

Radial-arm maze performance in rats is impaired by a combination of nicotinic-cholinergic and D2 dopaminergic antagonist drugs.

Performance on the radial-arm maze depends on the integrity of both cholinergic and dopaminergic systems. We have previously found that administration of either the nicotinic-cholinergic antagonist, mecamylamine, or the muscarinic-cholinergic antagonist, scopolamine, impairs choice accuracy in the radial-arm maze. Co-administration of the dopaminergic antagonist, haloperidol, ameliorated the performance deficit caused by scopolamine but exacerbated the deficit caused by mecamylamine. Furthermore, antagonism of the effect of scopolamine is due specifically to blockade of D1 receptors. In the present experiment behaviorally subthreshold doses of mecamylamine and the D2 antagonist raclopride impaired maze performance when administered together. No interactive effects were observed between mecamylamine and the D1 antagonist SCH 23390. Although several of the drug treatments studied significantly increased choice latency, an index of motor behavior, there was no perfect relationship between choice accuracy and choice latency. These data indicate that nicotinic-cholinergic and muscarinic-cholinergic systems interact selectively and differentially with D1 and D2 dopaminergic systems.

Animals↗
PubMed1989

Effects of D2 dopamine receptor blockade with raclopride on intracranial self-stimulation and food-reinforced operant behaviour.

To examine the involvement of D2 dopamine receptors in the neural mechanism of reinforcement, raclopride tartrate, a D2 specific dopamine antagonist with a relatively fast central action, was injected into 32 rats. The D2 antagonist reduced bar-pressing responses reinforced with electrical stimulation of the ventral tegmental area (ED50 = 0.079 mumol/kg) and those reinforced with food (ED50 = 0.58 mumol/kg) in 18-30 min after IP injection. The reduction in response rates could not be attributed to an interference with motor functions. An increase in the frequency of brain-stimulation pulses and a change in the schedule of food reinforcement, which respectively increased the baseline rate of responding, did not alter the effectiveness of raclopride. SCH 23,390, a D1-specific dopamine antagonist, was sensitive to similar manipulation of reinforcement. These results seem to suggest that D1 and D2 antagonists may be acting at different locations in the neural mechanism underlying the reinforcement of operant behaviour.

Animals↗
PubMed1989

Chronic neuroleptic-induced mouth movements in the rat: suppression by CCK and selective dopamine D1 and D2 receptor antagonists.

Fluphenazine decanoate (25 mg/kg IM every 3 weeks x 6) resulted in spontaneous vacuous chewing mouth movements and jaw tremor in male Sprague-Dawley rats. These movements could be suppressed by the selective D1 or D2 dopamine antagonists SCH 23390 (0.5 mg/kg) and raclopride (0.5 mg/kg), respectively, and by CCK-8S (50 micrograms/kg). Fluphenazine-induced mouth movements were unaffected by the selective CCK antagonist MK-329, and by a dose of physostigmine (50 micrograms/kg) sufficient to stimulate mouth movements in placebo treated rats. Scopolamine (0.1 mg/kg) suppressed spontaneous mouth movements in placebo-treated rats, but the effect on fluphenazine-induced mouth movements was not significant. A higher dose of scopolamine (0.5 mg/kg) did suppress the neuroleptic-induced mouth movements, but also induced hyperactivity, characterized by increased sniffing and grooming. These findings indicate that mouth movements resulting from the chronic administration of neuroleptics to the rat may serve as a useful pharmacological model of tardive dyskinesia in the human, and suggest that a relative increase of D1 activity as well as impaired CCK function may contribute to the pathogenesis of this disorder.

Animals↗
PubMed1986

The effect of the dopamine agonist pergolide on tyrosine hydroxylase activity in rat striatal and limbic miniprisms in vitro: a model for the dopamine autoreceptor?

A method for the assay of tyrosine hydroxylase activity in rat striatal and limbic (nucleus accumbens + olfactory tubercle) brain miniprisms is described. The dopamine agonists apomorphine (1 mumol/l) and pergolide (0.01-100 mumol/l) inhibited the tyrosine hydroxylase activity in both regions. The inhibition produced by 1 mumol/l pergolide was antagonised partially in striatal miniprisms and completely in limbic miniprisms by 1 mumol/l haloperidol. The dopamine D2-selective antagonist raclopride, at concentrations up to 300 nmol/l, did not antagonise the inhibition produced by pergolide in striatal miniprisms, but appeared partially to antagonise the inhibition in limbic miniprisms. It is concluded that whilst pergolide potently inhibits tyrosine hydroxylase activity in striatal and limbic miniprisms, the inhibition is of doubtful value as a predictive model of dopamine autoreceptor function in striatal miniprisms, but may be useful when limbic miniprisms are used.

Animals↗
PubMed1988

Induction of contact photosensitivity to TCSA using photohapten-modified syngeneic spleen cells.

We investigated the induction and transfer of contact photosensitivity (CPS) to the photohapten 3,3',4',5-tetrachlorosalicylanilide (TCSA) using photo-TCSA-coupled syngeneic cells in mice. PhotoTCSA-modified spleen cells (photoTCSA-SC) with efficient immunogenicity were prepared with ultraviolet A (UVA) irradiation of spleen cells suspended in TCSA solution. Subcutaneous inoculation of photoTCSA-SC into syngeneic mice induced a highly specific CPS response detected by ear swelling upon epicutaneous challenge with TCSA painting plus UVA irradiation. The sensitivity was determined to be a cell-mediated, delayed-type hypersensitivity reaction from the time course of the reactivity, the characteristic histology, and the successful transfer of the sensitivity into syngeneic naive recipients by immune lymph node T cells with the phenotype of L3T4+, Lyt-2-. In contrast to the conventional TCSA painting plus UVA irradiation method, this immunization procedure did not evoke an ordinary contact sensitivity reaction to TCSA. The present procedure represented a new way to induce CPS.

Animals↗
PubMed1988

An open label trial of raclopride in acute schizophrenia. Confirmation of D2-dopamine receptor occupancy by PET.

Raclopride, a highly selective D2-dopamine receptor antagonist, was administered in doses up to 4 mg b.i.d. to ten schizophrenic patients in an open label non-comparative study lasting 4 weeks. Safety, tolerability, potential antipsychotic effect, prolactin response and drug effect on plasma homovanillic acid were evaluated. Central D2-dopamine receptor occupancy was determined by positron emission tomography (PET). No major deviations were found in biochemical and physiological safety parameters. Raclopride was well tolerated. The mean BPRS score was reduced by 55% at endpoint. In the global evaluation seven patients were "very much" or "much" improved. Extrapyramidal side effects were recorded in four patients and disappeared after dose reduction or single doses of biperiden. An increase in plasma prolactin of short duration was observed in both sexes. A significant decrease of plasma HVA was obtained after 4 weeks of treatment. In two of the patients the central D2-dopamine receptors occupancy was measured using PET. The receptor occupancy was 68 and 72% which is the same as that found in patients treated with conventional neuroleptics.

Acute Disease↗
PubMed1990

Maps of receptor binding parameters in the human brain--a kinetic analysis of PET measurements.

A kinetic method is described for the estimation of neuroreceptor density as well as the rate constants for association and dissociation of rapidly equilibrating radioligands. The method is exemplified by positron emission tomographic measurements of the human brain using 11C-raclopride, a D 2 dopamine receptor antagonist, and 11C-Ro 15-1788, a benzodiazepine receptor antagonist. Using a linear non iterative algorithm, regional binding characteristics were calculated and displayed pixel by pixel in brain maps. Data from repeated experiments on the same subject with different amounts of the unlabeled ligand were utilized. The binding characteristics were determined according to a two step procedure in which the time course of the free radioligand concentration was estimated from a reference region considered to be free of specific receptor binding sites. Alternative methods to determine the concentration of free radioligand are discussed.

Algorithms↗
PubMed1990

The effect of the hydrogen ionophore closantel upon the pharmacology and ultrastructure of the adult liver fluke Fasciola hepatica.

The present study describes the effects of the H+ ionophore and anthelmintic closantel upon the in vitro motility and in vivo ultrastructure of the liver fluke, Fasciola hepatica. At a concentration of 50 micrograms/ml, closantel caused an initial stimulation, then suppression of activity, which was accompanied by an increase in muscle tone and led to a spastic paralysis within 2 h. The pattern of response was similar at lower concentrations, although the initial stimulation was not always evident, but the onset of paralysis could be reached more quickly. Scanning electron microscopy revealed gross surface damage from 24 h onwards in vivo, in the form of erosion of the anterior and posterior extremities of the fluke and large-scale sloughing of the tegument on both dorsal and ventral surfaces. Tegumental changes prior to sloughing included some swelling of the basal infolds and an apical accumulation of T1 secretory bodies. In the underlying tegumental cells there was reduced secretory activity and the mitochondria were consistently swollen and deformed. Reduced secretory activity was a feature of the gastrodermal cells as well; these cells were characterized by swollen, electron-lucent mitochondria, vesiculated GER cisternae and apical blebbing of packets of cytoplasm. The vitelline follicles became severely disrupted as a result of the breakdown of the nurse cell cytoplasm. The stem and intermediate type 1 (It1) cells rounded up and showed nuclear abnormalities. There did not appear to be a severe disruption of shell protein production in the intermediate vitelline cells, but there was a noticeable absence of glycogen in the mature vitelline cells. The effects of closantel are discussed in relation to its proposed mode of action as an uncoupler of oxidative phosphorylation.

Animals↗
PubMed1992

Specific [3H]raclopride binding to neostriatal dopamine D2 receptors: role of disulfide and sulfhydryl groups.

Receptor binding studies were performed in rabbit neostriatum (caudate-putamen) using the dopamine D2 antagonist [3H]raclopride. Treatment of the membrane preparations with the reducing agent L-dithiothreitol (L-DTT) as well as with the alkylating compound N-ethylmaleimide (NEM), produced dose-dependent decreases of specific [3H]raclopride binding; the IC50 values were of 3.1 and 1.2 mM, respectively. Saturation experiments showed that the reduction of disulfide (-S-S-) bonds by L-DTT (1 mM) decreased the number of binding sites, with only a slight increase in the affinity. On the other hand, alkylation of sulfhydryl (-SH) groups by NEM (1 mM) decreased both receptor number and affinity. The properties of the remaining binding sites were examined in competition curves with the physiological substrate dopamine and the dopaminergic antagonist (+)butaclamol. The IC50 values for (+)butaclamol in control and in L-DTT and NEM treated membranes were between 3.4 and 4.8 nM, with Hill coefficients (nH) of 1, indicating that the remaining binding sites conserved a high affinity for antagonist binding. In the case of dopamine, the curves were shallow (nH 0.45-0.64) and both compounds increased the IC50 from 0.7 microM (control) to 8 microM and 11 microM, for L-DTT and NEM respectively. Iterative analysis revealed that L-DTT produced a very important (greater than 60%) decrease in the number of high-affinity (RH) binding. After NEM, there was a decrease in both the number of (RH) and the affinity (KH) of the high-affinity binding sites, and in the affinity (KL) of the low-affinity sites. These results demonstrate the participation of -S-S- and -SH groups in the agonist conformation of the primary ligand recognition site of the dopamine D2 receptor. Alternatively, -S-S- and -SH groups could be related to the coupling of the primary ligand recognition protein with adenylate cyclase by means of an inhibitory type of G protein.

Alkylation↗
PubMed1982

In vitro and in vivo evaluation of the tissue-to-blood partition coefficient for physiological pharmacokinetic models.

An important parameter used in physiologically based pharmacokinetic models is the partition coefficient (Kp), which is defined as the ratio of tissue drug concentration to the concentration of drug in the emergent venous blood of the tissue. Since Kp is governed by reversible binding to protein and other constituents in blood and tissue, an attempt was made here to estimate the Kp values for a model drug ethoxybenzamide (EB) by means of in vitro binding studies and to compare these Kp values to those obtained from in vivo kinetic parameters observed following the administration of EB by two different routes, i.e., i.v. bolus injection and constant rate infusion. The Kp values obtained by using these three different methods were in reasonably good agreement suggesting that binding data obtained in vitro can successfully be used to estimate in vivo distribution.

Animals↗
PubMed1982

Physiological pharmacokinetics of ethoxybenzamide based on biochemical data obtained in vitro as well as on physiological data.

Ethoxybenzamide (EB) concentrations in plasma and various tissues were simulated using a physiological pharmacokinetic model. The biochemical parameters, such as plasma and tissue binding constants and Michaelis-Menten constants for EB deethylation, which were needed for these simulations, were, however, obtained from in vitro data. The simulations predicted well the observed data in plasma and various tissues of the rat. Furthermore, animal scale-up predicted reasonably well the concentrations of EB in plasma and various tissues of the rabbit from data gathered in rats.

Animals↗
PubMed1993

Use of a fluorescent dye to measure secretion from intact bovine anterior pituitary cells.

The fluorescent dye FM1-43 has been used to indicate membrane changes in individual bovine anterior pituitary cells exposed to secretory stimuli. After ten minutes incubation with FM1-43 (2 microM), cells showed three patterns of dye fluorescence: annular, partly filled and uniformly filled. FM1-43 fluorescence was increased in 61% of the cells by TRH (40 nM), a physiological stimulus for prolactin secretion, and in 89% of the cells by 60 mM external K+. The fluorescence also increased when cells incubated in the presence of quinpirole, a dopamine D2-receptor agonist which inhibits prolactin secretion, were exposed to raclopride, a D-2 antagonist. The increases in FM1-43 fluorescence caused by these treatments suggests that the dye acts as an indicator of secretion, possibly through incorporation into secretory vesicle membranes exposed on the cell surface during exocytosis. If the dye was washed away after loading, the fluorescence of partly and uniformly filled cells was retained and a rise in fluorescence could still be seen on stimulation by TRH. This suggests that some dye had been taken up by endocytosis and trapped in an intracellular compartment, which expanded through membrane recapture after TRH stimulation. FM1-43 could therefore be a useful probe for membrane cycling associated with secretory responses.

Animals↗
PubMed1985

Systemic activity of closantel for control of lone star ticks, Amblyomma americanum (L.), on cattle.

Cattle were treated once at 5 mg/kg orally or subcutaneously or daily at 0.1-5 mg/kg orally or 0.1-1 mg/kg subcutaneously with closantel, N-[5-chloro-4-[(4-chlorophenyl)cyanomethyl]-2-methylphenyl]-2-hydroxy-3, 5-diiodobenzamide, and numbers and weights of engorged females, weights of egg masses and hatch of eggs of lone star ticks, Amblyomma americanum, were recorded. Effectiveness of treatments on reproduction was determined by comparing total estimated larvae (EL) (EL = wt. egg mass X est. % hatch X 20000) of ticks from treated cattle with that of ticks from untreated cattle. With certain treatments, we also determined the effect of manure of treated cattle on survival of larvae of the horn fly, Haematobia irritans, or effect on survival and of fecundity of adult horn flies or stable flies, Stomoxys calcitrans, fed on blood from treated animals. The single oral treatment afforded essentially complete control of total EL only of ticks placed on the animal on the day of treatment, while the single subcutaneous treatment afforded greater than 92% control of total EL of ticks placed on animal on treatment day and for 6 weeks posttreatment. Daily treatments of 0.5 mg/kg or greater orally and 0.1 mg/kg or greater subcutaneously afforded essentially complete control of total EL of ticks throughout the treatment period (3-12 weeks) and for 1-7 weeks after treatment was discontinued. An estimated concentration of greater than 9 micrograms/ml of blood was calculated by probit analysis to be necessary to provide greater than 90% control of total EL of lone star ticks; that same concentration also provided greater than 90% control of hatch of eggs laid by treated females. A higher concentration (40 micrograms/ml) was necessary to prevent engorging of the females. No treatments tested were effective against larvae of the horn fly or adult horn flies or stable flies.

Animals↗
PubMed1988

In vivo labelling of rat brain dopamine D-2 receptors. Stereoselective blockade by the D-2 antagonist raclopride and its enantiomer of 3H-spiperone, 3H-N,N-propylnorapomorphine and 3H-raclopride binding in the rat brain.

The stereospecific blockade by raclopride and FLB472 (the R enantiomer of raclopride) of the specific in vivo binding of [3H]-spiperone, [3H]-N,N-propylnorapomorphine (NPA) and [3H]-raclopride was studied in seven brain regions (e.g., caudate nucleus, olfactory tubercle, septum, hippocampus, frontal cortex, substantia nigra, pituitary gland) of the male albino rat. The binding of all three ligands was dose-dependently blocked by raclopride and FLB472. The blockade by FLB472 occurred at doses 50-100 times higher than that obtained by raclopride. The maximal blockade by raclopride of [3H]-spiperone binding differed between brain areas. Thus, the largest blockade was obtained in the substantia nigra (95%), septum (90%), caudate nucleus (60%) and olfactory tubercle (60%), while the blockade of [3H]-spiperone binding in the frontal cortex and pituitary gland did not exceed 30% and 50%, respectively. In contrast to [3H]-spiperone, the in vivo binding of [3H]-NPA and [3H]-raclopride was prevented by 90-100% in all brain areas examined. Taken together, the present findings indicate that the in vivo binding of three radioactive ligands to a central dopamine D-2 receptor can be stereoselectively blocked by the enantiomers of raclopride. The findings suggest that, under in vivo conditions, [3H]-raclopride and [3H]-NPA may label a closely related receptor site. However only some of the [3H]-spiperone binding sites may be identical to the [3H]-raclopride binding sites. The findings indicate furthermore that the relative overlap of D-2 sites shared by [3H]-spiperone and [3H]-raclopride may vary between brain regions.

Animals↗
PubMed1991

Antipsychotic-like profile of combined treatment with raclopride and 8-OH-DPAT in the rat: enhancement of antipsychotic-like effects without catalepsy.

The administration of the 5-HT1A agonist 8-OH-DPAT, 0.1 mg kg-1 sc-20 min, produced a moderate suppression of conditioned avoidance behavior (60% of controls) in the rat. This effect, however, was not seen after administration of higher doses, 0.4 and 1.6 mg kg-1 sc. The number of intertrial crosses were not affected by the lower dose but significantly increased by administration of the two higher doses of 8-OH-DPAT. The dopamine D2 receptor blocking agent raclopride, 0.05 mg kg-1, by itself did not suppress the avoidance behavior, but in combination with 8-OH-DPAT produced suppression of avoidance behavior (30% of controls) as well as intertrial crosses. Open field locomotor activity was suppressed by raclopride, 0.1 mg kg-1 sc, or by 8-OH-DPAT, 0.1 mg kg-1 sc. The combined treatment produced a further suppression of locomotor activity and a marked increase in "immobility" (stationary movements). Treadmill locomotion, however, was not affected by either compound by itself, whereas the combined treatment impaired treadmill performance. Suppression of treadmill performance by a higher dose of raclopride, 0.4 mg kg-1 sc, was not altered by the additional treatment with 8-OH-DPAT, 0.1 mg kg-1. In contrast to the additive effects of 8-OH-DPAT and raclopride on conditioned avoidance behavior, open field locomotion and treadmill performance, the catalepsy produced by raclopride, 16 mg kg-1 was completely antagonised by treatment with 8-OH-DPAT 0.1 mg kg-1. Taken together, the present findings demonstrate strong interactions between a 5-HT agonist and a DA D2 antagonist on some critical tests for antipsychotic-like actions and extrapyramidal motor effects in rats, and suggest new possibilities in the search for new antipsychotic drugs with higher clinical efficacy and less extrapyramidal side effects.

8-Hydroxy-2-(di-n-propylamino)tetralin↗