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At least 1,045 records · Page 58Linked to original sources
PubMed1994

The noncompetitive NMDA antagonist MK-801 fails to block amphetamine-induced place conditioning in rats.

The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 prevents the development of sensitization to the locomotor-activating effects of amphetamine. In the present study, the possibility that the NMDA receptor might also play a role in the rewarding effects of amphetamine (as measured in the conditioned place preference paradigm) was investigated. Male Sprague-Dawley rats received amphetamine (2.0 mg/kg IP) paired with one side of a two-compartment box and saline paired with the other side. During these pairings locomotor activity was measured. On the test day, the amount of time drug-free rats spent in each compartment was determined. Rats trained with amphetamine alone showed a significant increase in time spent on the drug-paired side from pre- to postconditioning, indicating a place preference. When rats were injected with MK-801 (0.03, 0.1, or 0.3 mg/kg SC) prior to amphetamine, no significant effects on amphetamine place conditioning were observed. Rats treated with MK-801 alone showed significant place conditioning, but only at the intermediate dose. On conditioning days, MK-801 produced a dose-dependent enhancement of amphetamine-induced locomotor activity; however, MK-801 alone caused a similar increase in activity. The preferential D2 dopamine receptor antagonist eticlopride (0.01, 0.05, or 0.1 mg/kg SC) significantly reduced amphetamine locomotor activity, and the highest dose blocked place conditioning. These data suggest that the NMDA receptor is not involved in either the rewarding or locomotor-activating effects of amphetamine.

Animals↗
PubMed1994

High doses of oxytocin cause sedation and low doses cause an anxiolytic-like effect in male rats.

The aim of the present investigation was to explore dose relationships for effects of oxytocin on spontaneous motor activity in the rat. Oxytocin in doses from 1-1000 micrograms/kg was given SC to male Sprague-Dawley rats, and spontaneous motor behavior was measured by means of photocell-operated open-field observations. In the rats treated with low doses of oxytocin (1-4 micrograms/kg), there was a decrease in peripheral locomotor activity. With increasing doses (250-1000 micrograms/kg), there were clear signs of sedative effects as indicated by a suppression of locomotor activity and rearing. The time course for the effect of oxytocin on peripheral activity (1 microgram/kg) and rearing (1 mg/kg) was tested. A maximal effect was obtained within 1 h and, thereafter, the behavior gradually returned to normal within 24 h. This spectrum of effects caused by oxytocin was similar to that of midazolam but different from that induced by raclopride.

Animals↗
PubMed1994

Effects of intraaccumbens injections of dopamine agonists and antagonists on sucrose and sucrose-ethanol reinforced responding.

The present experiment tested the effects of intraaccumbens injections of dopamine (DA) agonists and antagonists on operant responding reinforced by sucrose and sucrose/ethanol solutions. The mixed DA agonist d-amphetamine (20.0 micrograms/microliters) significantly reduced responding reinforced by a low concentration sucrose solution (2% w/v) by 48% and 38% compared to no injection and sham control values, respectively. The addition of ethanol (10%) to a low concentration sucrose solution (3%) presented as the reinforcer changed the response pattern from a continuous moderate response rate, over a 30 min session, to an initial high response rate that terminated after approximately 10 min. With sucrose/ethanol reinforcement, d-amphetamine slowed the initial high response rate but extended responding throughout the 30 min sessions. However, no significant changes were observed in number of responses per session. When 75% sucrose (w/v) was presented as the reinforcer, d-amphetamine did not change the total number of responses/session, but response patterns were again altered from high initial rates with early offset to slow steady rates that continued for the duration of sessions. The D2 DA antagonist raclopride (0.1-5.0 micrograms/microliters) resulted in a dose-dependent decrease in responding reinforced by 75% sucrose. The baseline patterns, response totals, and effects of the DA antagonists resemble our previously reported findings with 10% ethanol (v/v) reinforcement. These data support the conclusion that mesolimbic DA activity may be a common mechanism in ethanol reinforced behavior and behavior reinforced by other substances, but suggest that the nature of behavioral change may depend upon the reinforcer.

Animals↗
PubMed1995

Dopamine D2 receptors: a potential pharmacological target for nomifensine and tranylcypromine but not other antidepressant treatments.

Treatment for 1 or 14 days by IP injection with the antidepressants, amitriptyline (10 mg/kg), bupropion (30 mg/kg), desipramine (10 mg/kg), GBR 12909 (10 mg/kg), sibutramine HCl (3 mg/kg), mianserin (5 mg/kg), and zimeldine (10 mg/kg), did not affect the number or affinity of dopamine D2 receptors determined by [3H]raclopride binding to rat striatal membranes. Similarly, neither did a single, nor repeated (five times over 10 days), electroconvulsive shock, given under halothane anaesthesia, have any effect on [3H]raclopride binding parameters. By contrast, the noradrenaline and dopamine reuptake inhibitor, nomifensine (5 mg/kg), and the monoamine oxidase inhibitor, tranylcypromine (5 mg/kg), decreased the number of dopamine D2 receptors by 12% and 11%, respectively, when given for 14 days. Administration of the D2 receptor antagonist, haloperidol (1 mg/kg), for 14 days increased the number of [3H]raclopride binding sites by 17%. Thus, the data demonstrate that although nomifensine and tranylcypromine decrease D2 receptor number after 14 days administration, this adaptive change is not observed with other antidepressant treatments. However, the findings do not preclude a contribution of altered dopamine D2 receptor function to the efficacy of those drugs with potent effects on dopaminergic neuronal function.

Animals↗
PubMed1996

Brain dopamine response in isolated 10-day-old rats: assessment using D2 binding and dopamine turnover.

A single 5-min isolation from the nest, dam, and siblings in 10-day-old rat pups was investigated for its effect on brain dopamine systems. The release of dopamine in innervated brain regions was measured in separate studies using in vivo ligand binding of 3H-raclopride, ex vivo binding using 3H-raclopride, and neurochemical measurement of the dopamine turnover using levels of DOPAC and dopamine. In addition, in vitro homogenate binding was performed to determine baseline Bmax and Kd values for 3H-raclopride binding sites across treatments. Isolation for 5 min in a "novel" environment resulted in decreased 3H-raclopride binding in striatum and septum as determined by both in vivo and ex vivo binding, as well as increased dopamine turnover. There was no difference in Bmax and Kd values for 3H-raclopride in these brain regions after the 5-min isolation, indicating that the binding decreases were due to an increase of available dopamine, presumably from terminal release. The convergence of results from three different techniques supports the interpretation that dopamine is released during the 5-min isolation in both brain regions.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

Raclopride reduces sucrose preference in rats.

Dopaminergic D1 and D2 antagonists decrease the intake of sweet solutions during sham feeding. Because the decreased intake of 10% sucrose produced by the D1 and D2 antagonists has been demonstrated to occur in the absence of significant deficits in the initiation of ingestion, or of its motor performance, we investigated the hypothesis that raclopride decreases intake by lowering the reinforcing potency of the orosensory stimulation provided by sucrose during sham feeding. Rats were adapted to ingest two differently flavored 10% sucrose solutions for 5 min in one-bottle tests. The flavored solution that rats preferred was paired with pretreatment with a dose of raclopride (400 micrograms/kg, IP, 15 min) that produced a mean decrease of intake of 55%. The other flavored 10% sucrose solution was paired with vehicle (0.15 M NaCl) injections. After three or six pairings with raclopride or vehicle injection, two two-bottle preference tests were given without raclopride pretreatment. Preference for the flavored 10% sucrose solution previously paired with raclopride decreased significantly in both tests. We interpret this decreased preference as evidence that raclopride decreased the reinforcing potency of flavored 10% sucrose during one-bottle tests. This is consistent with our hypothesis and with the more general hypothesis of Wise that central dopaminergic mechanisms mediate the reinforcing effect of food.

Animals↗
PubMed1996

Influence of eticlopride on cocaine- and DA D2 agonist-induced behavioral effects in rats.

The influence of the DA D2 antagonist (-) eticlopride on cocaine- and DA D2 agonist-induced behavioral effects was investigated by means of two series of experiments, in rats. In the first 10-day series, coadministration of (-) eticlopride (10 and 50 micrograms/kg, SC) always potently inhibited cocaine (15 mg/kg, IP)-induced hypermotility but did not modify the penile erection (PE)-enhancement produced by the drug at the first injection; it actually counteracted the inhibitory effect of subchronic cocaine on PE. In the second series, (-) eticlopride, at the same doses, antagonized PE elicited by various DA D2 agonists at nonstereotyping doses; when, along with PE, stereotyped behavior was induced, only the latter was inhibited by (-) eticlopride, which even increased PE.

Animals↗
PubMed1996

Effects of selective dopamine D1- and D2-agonists and antagonists on timing performance in rats.

Dopamine (DA) D1- and D2-agonists and antagonists were administered at fixed doses to assess putative dopaminergic involvement in timing behavior in rats performing under a peak-interval schedule. Significant shifts in response distributions to the left (consistent with the overestimation of the passage of time) were observed after treatment with the D1- and D2-agonists SKF 38393 and quinpirole, respectively. Both DA antagonists, eticlopride (D2) and SCH 23390 (D1), shifted the response distributions to the right (consistent with the underestimation of the passage of time), but neither drug produced statistically significant shifts. Based on percent shift in peak time from predrug baseline values, no significant differences were detected between agents as a function of their reported affinities for the D1- or D2-receptors. Results indicate the need for a systematic evaluation of each drug at various doses and a more detailed examination of the use of temporal schedules in predicting the efficacy of psychotherapeutic agents.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1996

Role of dopaminergic mechanisms in the stimulatory effects of MK-801 injected into the ventral tegmental area and the nucleus accumbens.

The bilateral administration of 10 micrograms of (+)MK-801, but not (-)MK-801, into either the VTA or the N.Ac. stimulated locomotor activity. The stimulation induced by (+)MK-801 at both sites was inhibited by reserpine (5 mg/kg, SC) and the D1 antagonist, SCH 23390 (0.1 mg/kg, SC). Eticlopride (0.03 mg/kg, SC), a D2 antagonist, inhibited the stimulation produced by MK-801 in the VTA but not in the N.Ac. Baclofen (32 ng), a GABAB receptor agonist, injected into the VTA inhibited the stimulatory response to MK-801 injected systemically, into the VTA, or into the N.Ac., but did not significantly inhibit spontaneous locomotion or the stimulatory response to apomorphine (5 mg/kg, SC). These observations suggest that the stimulatory effects of MK-801 in the VTA and the N.Ac. are dependent on endogenous dopamine. In addition, the effects produced by MK-801 injected into the VTA closely resemble those produced by the systemic administration of low doses of MK-801, suggesting that this is the primary site of action of MK-801.

Adrenergic Uptake Inhibitors↗
PubMed1996

The advantage of using positron emission tomography in drug research.

A large problem in drug discovery is to find relevant in vitro or in vivo animal models and to be able to extrapolate the results obtained to humans. Drug research now benefits from the fast development of imaging technologies that trace radiolabelled molecules directly in the human brain. Positron emission tomography (PET) and allied techniques use molecules that are labelled with short-lived radioisotopes and injected intravenously. The most straightforward approach is to radiolabel a new potential drug and then to trace its anatomical distribution and binding in the brain. An indirect approach is to study how the unlabelled drug inhibits specific radioligand binding. The demonstration of quantitative relationships between drug binding in vivo and drug effects in patients is used to validate targets for drug action and to optimize clinical treatment.

Antipsychotic Agents↗
PubMed1980

Evidence for a branched electron transport chain in Trypanosoma brucei.

The flow of electrons the terminal oxidases present in the bloodstream and procyclic trypomastigotes of Trypanosoma brucei LUMP 1026 has been investigated by the use of salicylhydroxamic acid (SHAM) and cyanide. Respiration in bloodstream trypomastigotes was completely inhibited by 0.5 mM SHAM with a Ki below 10 microM. The Ki for SHAM in procyclic trypomastigotes was 70 microM. In procyclic trypomastigotes there are at least three terminal oxidases of which the two major ones are cytochrome aa3 oxidase, sensitive to cyanide inhibition, and alpha-glycerophosphate oxidase (GPO), sensitive to SHAM inhibition. These two oxidases contribute 60 and 30%, respectively, to total cell respiration. Inhibition of the cytochrome system with cyanide causes an increase in the flow of electrons through the GPO system, and inhibition of the GPO system with SHAM stimulates electron flow in the cytochrome system. Succinate oxidation in the mitochondrial fraction is partially inhibited by SHAM and this SHAM-sensitive respiration is not inhibited by antimycin A. The kinetic data of respiration by procyclic trypomastigotes fit a model proposed by Bahr and Bonner to determine the maximum rates of two competing electron transport pathways. It is concluded that the electron transport chain in T. brucei is branched.

Animals↗
PubMed1980

Effect of inhibitors of electron transport and oxidative phosphorylation on Trypanosoma cruzi respiration and growth.

Antimycin A and 2-heptyl-4-hydroxyquinoline N-oxide, two specific inhibitors of the b-c1 segment of the respiratory chain, affected the respiration of Trypanosoma cruzi epimastigote forms. The half-maximum inhibitory concentrations were about 0.05 and 4.0 micrograms/mg cells (dry wt.), respectively. The maximum effect of antimycin (about 80% inhibition of respiration) was at about 0.1 microgram antimycin/mg cells. Differential spectrophotometry of T. cruzi epimastigotes in the presence of antimycin, cyanide (or sulfide) and uncouplers, revealed the presence of functional cytochromes aa3, b and c558. In the stationary growth phase respiration by T. cruzi was completely inhibited by cyanide and effectively inhibited by sulfide, but in the exponential growth phase respiration was about 20% insensitive to 5 mM cyanide. Cyanide- and antimycin-insensitive respiration was completely inhibited by salicylhydroxamic acid (2 mM). Antimycin inhibited the operation of the tricarboxylic acids cycle in T. cruzi, as shown by the lesser production of 14CO2 and by the modification of 14C distribution in epimastigotes incubated with [1-14C]glucose, [2-14C]acetate or NaH14CO3. The inhibition of electron transport by antimycin increased the rate of the fumarate reductase reaction, an alternative electron pathway for the oxidation of reduced pyridine nucleotides. Addition of carbonyl cyanide 3-chlorophenylhydrazone to epimastigotes increased the rate of respiration and promoted the oxidation of reduced cytochrome b components, thus showing that these components are subject to respiratory (acceptor) control. Pentachlorophenol similarly affected the cytochrome b redox level but did not modify the rate of respiration. The uncouplers released N,N'-dicyclohexylcarbodiimide inhibition of respiration, and uncouplers and cyanide significantly decreased the ATP level in epimastigotes. The combined effects of the assay inhibitors on respiration, cytochrome b redox level, ATP content and energy charge confirmed the operation of oxidative phosphorylation in T. cruzi epimastigotes. Antimycin, uncouplers and N,N'-dicyclohexylcarbodiimide inhibited growth of T. cruzi, thus proving the essential role of oxidative phosphorylation for the parasite.

Adenosine Triphosphate↗
PubMed1980

Metabolic studies on the new fasciolicidal drug, closantel.

Studies of the metabolic disturbances caused in Fasciola hepatica by closantel have been carried out in vitro and in fluke recovered from treated sheep. Fluke exposed to the anthelmintic under both conditions exhibit increased carbohydrate mobilisation, increased end-product formation, especially of succinate, diminished ATP synthesis, increased oxaloacetate/malate ratios, and increased internal concentrations of pyruvate. No specific enzyme inhibition was detected. These results are consistent with the view that closantel acts as an uncoupler of oxidative phosphorylation by increasing mitochondrial permeability.

Adenosine Triphosphate↗
PubMed1980

Trypanosoma brucei brucei: patterns of glycolysis at 37 degrees C in vitro.

In the absence of mammalian cells, freshly isolated monomorphic bloodstream forms of Trypanosoma brucei brucei maintain a constant and high level of aerobic glycolysis in vitro for at least 4 h at 37 degrees C when suspended in RPMI medium 1640 containing 20% heat-inactivated and dialyzed fetal calf serum and 25 mM Hepes at an initial pH of 8. In the absence of nutrients other than glucose, salts and protein, some cell death and a decrease in the rate of glycolysis are observed. In the absence of protein, extensive cell death and a decrease in the rate of glycolysis are seen. These observations may be useful in the design of short-term in vitro metabolic studies with T. b. brucei.

Animals↗
PubMed1981

Trypanosoma brucei brucei: a systematic screening for alternatives to the salicylhydroxamic acid-glycerol combination.

Salicylhydroxamic acid (SHAM) and glycerol, when administered together, cause destruction of bloodstream forms of Trypanosoma brucei brucei, both in vitro and in vivo, but the dose required is exceedingly high. In an attempt to improve the efficacy of this drug combination, we examined the ability of various polyols and hydroxamic acids to substitute for glycerol and SHAM, respectively. No satisfactory substitute for glycerol was found. The inhibition of the trypanosomal alpha-glycerophosphate oxidase system (GPO) by SHAM (Ki 21 microM) was uncompetitive. Only primary and secondary aromatic hydroxamates were inhibitory. Among a series of 19 benzhydroxamates, no correlation existed between their acidity or their affinity for iron and their inhibition of the GPO in a cell free preparation. The Ki's of most of the primary hydroxamates ranged from 10 to 24 microM, with the more lipophilic derivatives being slightly more active. The Ki's of secondary hydroxamates were more variable, the best having Ki's of about 10 microM. Several other classes of iron chelators were also evaluated. Tropolones were active with 3-bromo-4,5-benzotropolone being as active as SHAM. 3,4-Dihydroxybenzaldehyde (Ki 15 microM) also inhibited the GPO. On the other hand, diphenylamine and 8-hydroxyquinoline, known inhibitors of the GPO, were 30 to 50 times less active. The results suggest that a lipophilic aromatic iron-chelating agent may be useful as a substitute for SHAM in combination therapy.

Animals↗
PubMed1981

Studies of the effect of diamphenethide and oxyclozanide on the metabolism of Fasciola hepatica.

Studies were made of the effects of diamphenethide-amine on glucose transport, glycogen breakdown, adenine nucleotides, metabolites and excretory products in both parenchymal and bile duct flukes in vitro and in bile duct flukes in vivo. The most consistent and pronounced effect observed was an elevation of malate levels. There appeared to be no differences between responses of parenchymal and of bile duct flukes to diamphenethide-amine. For comparative purposes the effect of oxydozanide was assessed on most of these parameters in bile duct flukes in vitro. Not all the changes caused by oxyclozanide were characteristic of an uncoupler; however, the pattern of changes in the metabolites was markedly different from that caused by diamphenethide-amine.

Acetanilides↗
PubMed1986

p-Alkyloxybenzhydroxamic acids, effective inhibitors of the trypanosome glycerol-3-phosphate oxidase.

Energy production in bloodstream forms of African trypanosomes of the genus Trypanosoma involves two pathways unique to the parasite and which can be blocked by a combination of salicylhydroxamic acid (SHAM) and glycerol. Although this leads to rapid parasite destruction both in vitro and in vivo, the toxicity of SHAM precludes practical use of SHAM/glycerol as a therapeutic regimen. Based on our hypothesis that SHAM operates by interfering with ubiquinone, we attempted to develop this approach by synthesizing and screening a series of hydroxamic acids which more closely resemble ubiquinone: the p-n-alkyloxybenzhydroxamic acids. We also examined a variety of mono-, di- and trisubstituted benzhydroxamic acids together with a selected group of secondary heterocyclic hydroxamic acids. We found an increase in activity of the p-n-alkyloxy compounds with increasing chain length up to 12 carbon atoms with longer chains offering little advantage. The most active compound, p-n-tetradecyloxybenzhydroxamic acid, had an apparent Ki of 0.43 microM indicating a specific activity 70 times greater than SHAM. Although this represents a vast improvement, the low water solubility of these compounds reduces their bioavailability to the point where they are not practical substitutes for SHAM. Consequently, improvement in the SHAM/glycerol approach to chemotherapy appears to lie with improving solubility by altering lipophilicity of the alkyl side chain.

Animals↗
PubMed1986

Inhibitors of the mitochondrial cytochrome b-c1 complex inhibit the cyanide-insensitive respiration of Trypanosoma brucei.

The cyanide-insensitive respiration of bloodstream trypomastigote forms of Trypanosoma brucei (75 +/- 8 nmol O2 min-1(mg protein)-1) is completely inhibited by the mitochondrial ubiquinone-like inhibitors 2-hydroxy-3-undecyl-1,4-naphthoquinone (UHNQ) and 5-n-undecyl-6-hydroxy-4,7-dioxobenzothiazole (UHDBT). The Ki values for UHDBT (30 nM) and UHNQ (2 microM) are much lower than the reported Ki for salicylhydroxamic acid (SHAM) (5 microM), a widely used inhibitor of the cyanide-insensitive oxidase. UHNQ also stimulated the glycerol-3-phosphate-dependent reduction of phenazine methosulfate, demonstrating that the site of UHNQ inhibition is on the terminal oxidase of the cyanide-insensitive respiration of T. brucei. These results suggest that a ubiquinone-like compound may act as an electron carrier between the two enzymatic components of the cyanide-insensitive glycerol-3-phosphate oxidase.

Animals↗