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At least 1,153 records · Page 64Linked to original sources
PubMed1994

Comparison of three high affinity SPECT radiotracers for the dopamine D2 receptor.

The regional brain distribution and pharmacological specificity of three high affinity tracers for the dopamine (DA) D2 receptor: [123I]IBF, [123I]epidepride, and [123I]2'-ISP were assessed by SPECT imaging of non-human primates. The ratios of striatal-to-occipital activities at the time of peak striatal uptake were 2.2, 6.3 and 1.7, respectively. From the peak striatal activities, washout rates were 33, 4 and 16%/h for [123I]IBF, [123I]epidepride and [123I]2'-ISP, respectively. The reversibility of the striatal uptake of all three agents was demonstrated by the rapid displacement induced by the dopamine D2 selective antipsychotic agent raclopride, which increased washout rates to 96, 58 and 43%/h. The administration of d-amphetamine, which induces release of dopamine, had no noticeable effect on [123I]epidepride but increased the washout rate of [123I]IBF. These results suggest that, among these three agents, [123I]epidepride is the superior tracer for in vivo displacement studies because of its slow washout and high target-to-background ratios. However, for tracer kinetic modeling, [123I]IBF may be the superior agent because of its early time of peak uptake and its higher target-to-background ratios than [123I]2'-ISP.

Animals↗
PubMed1995

Specific, reversible binding of [18F]benperidol to baboon D2 receptors: PET evaluation of an improved 18F-labeled ligand.

[18F]Benperidol ([18F]BP), a positron-emitting analogue of the dopaminergic D2 antagonist benperidol, was evaluated as a radiopharmaceutical for use with positron emission tomography (PET). PET imaging of baboons after i.v. injection of [18F]BP indicated that the radiofluorinated ligand rapidly localized in vivo within dopaminergic receptor-rich cerebral tissues, and that selective disposition was retained for over 2 h. Pretreatment of an animal with unlabeled receptor-specific antagonists prior to injection of [18F]BP confirmed that the radioligand bound specifically to central D2 receptors in vivo, and not to S2 or D1 receptors. [18F]BP bound to D2 receptors in a reversible manner; unlabeled eticlopride displaced D2 receptor-bound [18F]BP in vivo. The radioligand was metabolized in the periphery to polar metabolites which are not expected to cross the blood-brain barrier. [18F]BP has advantages over other tracers as a radiopharmaceutical for PET study of central D2 receptor activity, and can be applied for noninvasive evaluation of the interaction of unlabeled drugs with central D2 receptor sites.

Animals↗
PubMed1996

Preparation of [76Br]FLB 457 and [76Br]FLB 463 for examination of striatal and extrastriatal dopamine D-2 receptors with PET.

Both FLB 457 and FLB 463, two substituted benzamides with high affinity for the dopamine D-2 receptors, were labeled with bromine-76 for PET investigations. [76Br]FLB 457 was prepared by electrophilic substitution of the tributyltin precursor. The radiochemical yield was 80%. [76Br]FLB 463 was prepared by a direct electrophilic substitution enhanced by the hydroxyl group of the debromo analogue, with a total radiochemical yield of 50%. Radiochemical and chemical purity values of the radioligands as analyzed by radio-TLC and HPLC were > 99%, and the specific radioactivity was -40 GBq/mumol. During PET examinations of [76Br]FLB 457 and [76Br]FLB 463 binding in baboons there was a rapid and high uptake in the striatum. The striatal radioactivity concentration reached a plateau 1 h postinjection (p.i.). The striatum-to-cerebellum radioactivity concentration ratio increased from 11 at 1 h p.i., to 28 at 4 h p.i. for [76Br]FLB 457, owing to a continuous wash-out from the cerebellum. For [76Br]FLB 463 the corresponding value increased from 10 to 19.5. [76Br]FLB 457 has in contrast to [76Br]FLB 463 a high uptake in thalamic structures and has therefore an additional potential as a radioligand for PET examination of extrastriatal dopamine D-2 receptors in the living human brain.

Animals↗
PubMedDate not supplied

Comparative study of the EEG profile of neuroleptics selective for D-1 or D-2 dopamine receptors in the rabbit.

The neuroleptics SCH 23390 and raclopride, which interact selectively with either D-1 or D-2 dopamine receptor, were studied for their effects on electroencephalographic (EEG) activity in the rabbit. Haloperidol (0.3 and 1 mg/kg intravenously, i.v.), which was used for comparison, induced synchronization of the cortical EEG activity. Spectral EEG analysis showed increase of power in the whole frequency range (0.1-38.5 Hz) and in all frequency bands in the cortex, whereas a slight decrease of slow and fast theta activity (3.7-7.2 and 7.2-12.2 Hz) was observed in the hippocampus. Animals appeared sedated and arousal response to somatosensory stimuli was markedly inhibited. SCH 23390 (0.03 and 0.3 mg/kg i.v.) induced periods of cortical synchronization and changes of spectral power qualitatively similar to those accompanying haloperidol administration. The drug slightly reduced the duration of arousal elicited by stimuli. Raclopride (1 and 3 mg/kg i.v.) induced weak EEG changes and little effect on arousal response to stimulation. There was an increase of slow wave activity which was particularly evident in the hippocampus. The data indicate that, although to a lesser degree, the D-1 receptor antagonist SCH 23390 induced EEG effects similar to those of haloperidol, whereas blockade of D-2 receptors by raclopride resulted in different patterns of EEG activity.

Animals↗
PubMed1995

Behavioural assessment in rats of the antipsychotic potential of the potent dopamine D2 receptor antagonist, (-)eticlopride.

The effects of the selective D2 DA receptor antagonist, (-)eticlopride, a drug belonging to the benzamide class, were investigated on the D2 DA agonist SND 919- and CQP 201-403-induced stereotyped behaviour and on CQP 201-403-induced shaking, in rats, and on isolation-induced aggression, in mice. (-)Eticlopride was also tested over a wide dose range (5-1200 micrograms kg-1, s.c.) for sedative and cataleptic activity, in rats. For comparison, some experiments were performed with (-)sulpiride (10 and 40 mg kg-1, s.c.) The data obtained show that (-)eticlopride differs from (-)sulpiride and potentially modifies animal behaviour, whether spontaneous or induced; moreover, they suggest a potential clinical use for this neuroleptic in the management of psychotic states.

Aggression↗
PubMed2004

Aromatic hydroxamic acids and hydrazides as inhibitors of the peroxidase activity of prostaglandin H2 synthase-2.

The cyclooxygenase activity of the bifunctional enzyme prostaglandin H(2) synthase-2 (PGHS-2) is the target of non-steroidal anti-inflammatory drugs. Inhibition of the peroxidase activity of PGHS has been less studied. Using Soret absorption changes, the binding of aromatic hydroxamic acids to the peroxidase site of PGHS-2 was examined to investigate the structural determinants of inhibition. Typical of mammalian peroxidases, the K(d) for benzhydroxamic acid (42mM) is much greater than that for salicylhydroxamic acid (475microM). Binding of the hydroxamic acid tepoxalin (25microM) resulted in only minor Soret changes. However, tepoxalin is an efficient reducing cosubstrate, indicating that it is an alternative electron donor rather than an inhibitor of the peroxidase activity. Aromatic hydrazides are metabolically activated inhibitors of peroxidases. 2-Naphthoichydrazide (2-NZH) caused the time- and concentration-dependent inhibition of both PGHS-2 peroxidase and cyclooxygenase activities. H(2)O(2) was required for the inactivation of both PGHS-2 activities and indomethacin (which binds at the cyclooxygenase site) did not affect the peroxidase inhibitory potency of 2-NZH. A series of aromatic hydrazides were found to be potent inhibitors of PGHS-2 peroxidase activity with IC(50) values in the 6-100microM range for 13 of the 18 hydrazides examined. Selective inhibition of PGHS-2 over myeloperoxidase and horseradish peroxidase isozyme C was increased by certain ring substitutions. In particular, a chloro group para to the hydrazide moiety increased the PGHS-2 selectivity relative to both myeloperoxidase and horseradish peroxidase isozyme C.

Humans↗
PubMed2006

Novel inhibitors of the trypanosome alternative oxidase inhibit Trypanosoma brucei brucei growth and respiration.

African trypanosomiasis is a deadly disease for which few chemotherapeutic options are available. The causative agents, Trypanosoma brucei rhodesiense and T. b. gambiense, utilize a non-cytochrome, alternative oxidase (AOX) for their cellular respiration. The absence of this enzyme in mammalian cells makes it a logical target for therapeutic agents. We designed three novel compounds, ACB41, ACD15, and ACD16, and investigated their effects on trypanosome alternative oxidase (TAO) enzymatic activity, parasite respiration, and parasite growth in vitro. All three compounds contain a 2-hydroxybenzoic acid moiety, analogous to that present in SHAM, and a prenyl side chain similar to that found in ubiquinol. ACD15 and ACD16 are further differentiated by the presence of a solubility-enhancing carbohydrate moiety. Kinetic studies with purified TAO show that all three compounds competitively inhibit TAO, and two compounds, ACB41 and ACD15, have inhibition constants five- and three-fold more potent than SHAM, respectively. All three compounds inhibited the respiration and growth of continuously cultured T. b. brucei bloodstream cells in a dose-dependent manner. None of the compounds interfered with respiration of rat liver mitochondria, nor did they inhibit the growth of a continuously cultured mammalian cell line. Collectively, the results suggest we have identified a new class of compounds that are inhibitors of TAO, have trypanocidal properties in vitro, and warrant further investigation in vivo.

Animals↗
PubMed2004

Rotenone-sensitive mitochondrial potential in Phytomonas serpens: electrophoretic Ca(2+) accumulation.

Phytomonas sp. are flagellated trypanosomatid plant parasites that cause diseases of economic importance in plantations of coffee, oil palm, cassava and coconuts. Here we investigated Ca(2+) uptake by the vanadate-insensitive compartments using permeabilized Phytomonas serpens promastigotes. This uptake occurs at a rate of 1.13+/-0.23 nmol Ca(2+) mg x protein(-1) min(-1). It is completely abolished by the H(+) ionophore FCCP and by valinomycin and nigericin. It is also inhibited by 2 microM ruthenium red, which, at this low concentration, is known to inhibit the mitochondrial calcium uniport. Furthermore, salicylhydroxamic acid (SHAM) and propylgallate, specific inhibitors of the alternative oxidase in plant and parasite mitochondria, are also effective as inhibitors of the Ca(2+) transport. These compounds abolish the membrane potential that is monitored with safranine O. Rotenone, an inhibitor of NADH-CoQ oxidoreductase, can also dissipate 100% of the membrane potential. It is suggested that the mitochondria of P. serpens can be energized via oxidation of NADH in a pathway involving the NADH-CoQ oxidoreductase and the alternative oxidase to regenerate the ubiquinone. The electrochemical H(+) gradient can be used to promote Ca(2+) uptake by the mitochondria.

Animals↗
PubMed2006

Dopamine agonists and antagonists can produce an attenuation of response bias in a temporal discrimination task depending on discriminability of target duration.

The current study examined the effects of the D2 agonist (quinpirole) and D2 antagonist (eticlopride) on temporal discrimination performance in a conditional discrimination task (Experiment I) and a delayed conditional discrimination task (Experiment II). In both experiments rats discriminated between a scheduled stimulus duration of 3 s versus 9 s. Consistent with previous reports, overall discrimination performance decreased in a dose-dependent manner with both drugs. Changes in response bias (the tendency to choose-short or choose-long irrespective of actual stimulus duration), however, were best characterized in terms of both drugs tending to attenuate the bias effects normally observed during baseline drug-free performance. Specifically, the 'choose-short' bias observed in Experiment I and at a relatively short, 0.1 s, delay in Experiment II became less extreme with increasing doses. In addition, the 'choose-long' bias observed at a relatively long, 6 s, delay in Experiment II also became less extreme with increasing doses. Thus, whether there was an apparent shift from a short response bias to long, or vice versa, was the product of the delay interval between stimulus presentation and choice rather than whether the drug in question was a D2 agonist or antagonist. Such an attenuation of bias may have arisen because of subjects confounding the delay interval with the actual discriminative stimulus duration.

Animals↗
PubMed2003

Acute effects of 3,4-methylenedioxymethamphetamine on striatal single-unit activity and behavior in freely moving rats: differential involvement of dopamine D(1) and D(2) receptors.

3,4-Methylenedioxymethamphetamine (MDMA) is a widely abused amphetamine derivative that increases dopamine (DA) and serotonin release via a reverse transport mechanism. Changes in the activity of striatal neurons in response to increased DA transmission may shape the behavioral patterns associated with amphetamine-like stimulants. To determine how the striatum participates in MDMA-induced locomotor activation, we recorded the activity of >100 single units in the striatum of freely moving rats in response to a dose that increased motor activation (5.0 mg/kg). MDMA had a predominantly excitatory effect on neuronal activity that was positively correlated with the magnitude of locomotor activation. Categorizing neurons according to baseline locomotor responsiveness revealed that MDMA excited significantly more neurons showing movement-related increases in activity compared to units that were non-movement-related or associated with movement-related decreases in activity. Further analysis revealed that the drug-induced striatal activation was not simply secondary to the behavioral change, indicating a primary action of MDMA on striatal motor circuits. Prior administration of SCH-23390 (0.2 mg/kg), a D(1) antagonist, resulted in a late onset of MDMA-induced locomotion, which correlated positively with delayed neuronal excitations. Conversely, prior administration of eticlopride (0.2 mg/kg), a D(2) antagonist, completely abolished MDMA-induced locomotion, which paralleled its blockade of MDMA-induced excitatory neuronal responses. Our results highlight the importance of striatal neuronal activity in shaping the behavioral response to MDMA, and suggest that DA D(1) and D(2) receptors have distinct functional roles in the expression of MDMA-induced striatal and locomotor activation.

Action Potentials↗
PubMed2004

Short-term, D2 receptor blockade induces synaptic degeneration, reduces levels of tyrosine hydroxylase and brain-derived neurotrophic factor, and enhances D2-mediated firing in the ventral pallidum.

Repeated treatments with neuroleptics are associated with biochemical and morphological alterations in forebrain neurons as well as an upregulation of D2-mediated changes in neuronal function. The present study evaluated the histological and physiological effects of three once-daily treatments with two chemically divergent neuroleptics, haloperidol (1 mg/kg i.p./day) and eticlopride (3 mg/kg i.p./day), measured in rats 24 h after the last injection. It was determined that this short-term antagonism of D2-like receptors induced fiber and terminal degeneration and significantly decreased tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF) immunoreactivity in the ventral pallidum (VP), as determined by optical density measurements. While other forebrain regions demonstrated changes in TH and BDNF, the neurodegeneration profile was unique to the VP. This was accompanied by an enhancement in the efficacy of the D2 agonist quinpirole to increase spiking rate of VP neurons recorded in chloral hydrate-anesthetized rats. These data indicate that short-term treatments with D2 antagonists are sufficient to induce changes in the biochemical and morphological profiles uniquely within the VP. Moreover, the functional ramifications of these changes appear to include profound alterations in the way dopamine regulates neuronal activity in this region.

Animals↗
PubMed2004

Music improves dopaminergic neurotransmission: demonstration based on the effect of music on blood pressure regulation.

The mechanism by which music modifies brain function is not clear. Clinical findings indicate that music reduces blood pressure in various patients. We investigated the effect of music on blood pressure in spontaneously hypertensive rats (SHR). Previous studies indicated that calcium increases brain dopamine (DA) synthesis through a calmodulin (CaM)-dependent system. Increased DA levels reduce blood pressure in SHR. In this study, we examined the effects of music on this pathway. Systolic blood pressure in SHR was reduced by exposure to Mozart's music (K.205), and the effect vanished when this pathway was inhibited. Exposure to music also significantly increased serum calcium levels and neostriatal DA levels. These results suggest that music leads to increased calcium/CaM-dependent DA synthesis in the brain, thus causing a reduction in blood pressure. Music might regulate and/or affect various brain functions through dopaminergic neurotransmission, and might therefore be effective for rectification of symptoms in various diseases that involve DA dysfunction.

Animals↗
PubMed2005

Dopamine manipulation alters immediate-early gene response of striatal parvalbumin interneurons to cortical stimulation.

Cortical projections provide the major excitatory inputs to the striatum. In addition to innervating medium spiny cells, these axons contact striatal interneurons that are parvalbumin-immunoreactive (PV-ir). PV-ir interneurons make synaptic connections with many medium spiny cells, and thus can modulate striatal output. The striatum also receives dopaminergic projections from the substantia nigra, but it has been challenging to study the impact of dopamine (DA) cell injury on corticostriatal activity in vivo due to limitations in the methods used to induce cortical activity. Using epidural application of the GABA(A) antagonist picrotoxin, which produces a topographically restricted region of striatal immediate-early gene expression, we have investigated the effect of DA cell injury or DA receptor antagonism on immediate-early gene (IEG) expression in striatal medium spiny cells and PV-ir interneurons. Epidural application of picrotoxin to the rat's M1 motor cortex induced Fos in ipsilateral dorsolateral striatum. Animals previously given 6-hydroxydopamine (6-OHDA) injections into the ascending DA pathways had greater total numbers of cortical stimulation-induced striatal Fos-ir cells but fewer Fos-ir/PV-ir cells, compared to sham-operates. In a separate experiment, rats given cortical stimulation and treated with the DA D2-class antagonist eticlopride (0.10 mg/kg) exhibited fewer Fos-ir/PV-ir cells than did vehicle-treated rats. Taken together, these results indicate that DA may importantly control striatal output via influences on PV-ir interneurons. Possible mechanisms for these influences are discussed.

Adrenergic Agents↗
PubMed2005

Cocaine-induced sex differences in D1 receptor activation and binding levels after acute cocaine administration.

Although it is established that female rats have a more robust behavioral response to acute cocaine administration than male rats, the neurobiological mechanisms underlying these differences remain unclear. The purpose of the present study was to determine whether dopamine (DA) receptor activation influences sex differences in cocaine-induced behaviors. A second study was performed to determine sex differences in D1/D2 receptor levels prior to and post-cocaine administration. Male and female Fischer rats were pre-treated with the D1 antagonist SCH-23390 (0.05, 0.1, and 0.25 mg/kg, i.p.), the D2 antagonist eticlopride (0.03, 0.1 mg/kg, i.p.), or vehicle (saline) 15 min before acute cocaine (20 mg/kg, i.p.) or saline administration. Cocaine-induced ambulatory and rearing activity was greater in female than male rats. Pre-treatment with SCH-23390 affected cocaine-induced ambulatory, rearing, and stereotypic activity in a sex-dependent manner; cocaine-induced ambulatory and stereotypic behavior in female rats was reduced by the lowest dose of SCH-23390. Eticlopride did not alter behavioral responses to cocaine in male or female rats. These results suggest that in both male and female rats, activation of the D1, but not the D2, receptor modulates cocaine's motor effects. There were no sex differences in baseline levels of D1, D2, and DA transporter binding in the caudate putamen (CPu) and the nucleus accumbens (NAc). Cocaine administration reduced D1 binding levels in the CPu only in male rats. Our findings suggest that the regulation of striatal D1 binding levels after acute cocaine administration is a sexually dimorphic process. We also hypothesize that the greater sensitivity to D1 receptor blockade in female rats, as compared to male rats, may contribute to their overall increased hyperactivity in response to acute cocaine. Taken together, the D1 receptor may be an important substrate in the regulation of sex differences to cocaine-induced locomotor activity.

Animals↗
PubMed2005

Evaluation of immobilized metal-ion affinity chromatography for the fractionation of natural Cu complexing ligands.

An immobilized metal-ion affinity chromatography (IMAC) method has been developed and validated for the separation of copper complexing ligands from soil solution. We first investigated the retention behavior of simple model ligands on the IMAC column and found that the ability to form ternary complexes of the structure Cu-IDA-ligand was the dominant factor influencing ligand retention on the IMAC column. The logK value of the Cu-complex was found to have only a minor influence on the retention. Legends containing only carboxylic acid functional groups were not retained on the column. To optimize reproducibility and quantitative recovery of copper ligands from soil solution, different composition and pH values of eluting buffer were tested. Soil solution chromatograms exhibited one non-retained fraction and two retained fractions. The elution times of the retained fractions were characteristic of peptides and proteins (first peak) and for compounds containing aromatic amines (second peak). The results show that IMAC is an effective tool for the fractionation of copper complexing ligands that are capable of forming ternary complexes.

2,2'-Dipyridyl↗
PubMed2005

Modulation of striatal dopamine release in vitro by agonists of the glycineB site of NMDA receptors; interaction with antipsychotics.

The N-methyl-D-aspartate (NMDA) glutamate receptor possesses an obligatory co-agonist site for D-serine and glycine, named the glycineB site. Several clinical trials indicate that glycineB agonists can improve negative and cognitive symptoms of schizophrenia when co-administered with antipsychotics. In the present study we have investigated the effects of glycineB agonists on the endogenous release of dopamine from preparations of rat striatal tissue prisms in static conditions. The glycineB agonists glycine (1 mM) and D-serine (10 microM), but not D-cycloserine (10 microM), substantially increased the spontaneous release of dopamine, but significantly reduced the release of dopamine evoked by NMDA. The effect of glycine on spontaneous release was abolished by the non-competitive NMDA antagonists 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine (MK-801, 10 microM) and ifenprodil (5 microM), but was only partially suppressed by the competitive antagonist 4-(3-phosphonopropyl)-piperazine-2-carboxylic acid (CPP, 10 microM). The selective inhibitor of the glial glycine transporter GlyT1 N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS, 10 microM) significantly increased the release of dopamine in an MK-801-sensitive manner. Interestingly, haloperidol (1 microM), but not clozapine (10 microM), prevented the effects of glycine. This study shows that glycineB modulators can control dopamine release by interacting with a distinctive NMDA receptor subtype with which some typical antipsychotics can interfere.

Animals↗
PubMed2004

Preliminary evidence of the role of hydrogen peroxide in the degradation of benzo[a]pyrene by a non-white rot fungus Fusarium solani.

In order to study the enzymatic mechanisms involved in the successive steps of BaP degradation by a Deuteromycete fungus Fusarium solani, we developed an indirect approach by using inhibitors of enzymes. We used either specific inhibitors of peroxidases (i.e. salicylhydroxamic acid) and of cytochrome P-450 (i.e. piperonyl butoxyde) or inhibitors of both enzymes (i.e. potassium cyanide). Surprisingly, no expected decrease of BaP degradation was observed with most inhibitors tested. On the contrary, more BaP was degraded. Only butylated hydroxytoluene, which acts as a free radical scavenger, inhibited BaP degradation. The inhibition of these enzymes, which use H(2)O(2) as a cosubstrate, might have resulted in an increase of hydrogen peroxide availability in the fungal cultures. This enhancement could induce formation of reactive oxygen species (ROS) which might be the agents that initiate benzo[a]pyrene oxidation. This study proposed a hypothetic alternative metabolic pathway involved in PAH metabolism by Fusarium solani.

Antioxidants↗
PubMed2005

Heterocyclic isosters of antimycobacterial salicylanilides.

A series of 64 derivatives of substituted heterocyclic analogues of salicylanilides was synthesized. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium avium and two strains of Mycobacterium kansasii. For the QSAR study, the combination of Free-Wilson approach with Hansch approach was used. The molecules were separated on the heterocyclic and salicyl moieties and the study of influences of electronic and hydrophobic properties was used as well. The compounds are a new group of potential anti-tuberculotics.

Anti-Bacterial Agents↗