Combination Of D1 Research Articles

The proper concentrations of dextrose and lidocaine in regenerative injection therapy: in vitro study.

BackgroundProlotherapy is a proliferation therapy as an alternative medicine. A combination of dextrose solution and lidocaine is usually used in prolotherapy. The concentrations of dextrose and lidocaine used in the clinical field are very high (dextrose 10%-25%, lidocaine 0.075%-1%). Several studies show about 1% dextrose and more than 0.2% lidocaine induced cell death in various cell types. We investigated the effects of low concentrations of dextrose and lidocaine in fibroblasts and suggest the optimal range of concentrations of dextrose and lidocaine in prolotherapy.MethodsVarious concentrations of dextrose and lidocaine were treated in NIH-3T3. Viability was examined with trypan blue exclusion assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Migration assay was performed for measuring the motile activity. Extracellular signal-regulated kinase (Erk) activation and protein expression of collagen I and α-smooth muscle actin (α-SMA) were determined with western blot analysis.ResultsThe cell viability was decreased in concentrations of more than 5% dextrose and 0.1% lidocaine. However, in the concentrations 1% dextrose (D1) and 0.01% lidocaine (L0.01), fibroblasts proliferated mildly. The ability of migration in fibroblast was increased in the D1, L0.01, and D1 + L0.01 groups sequentially. D1 and L0.01 increased Erk activation and the expression of collagen I and α-SMA and D1 + L0.01 further increased. The inhibition of Erk activation suppressed fibroblast proliferation and the synthesis of collagen I.ConclusionsD1, L0.01, and the combination of D1 and L0.01 induced fibroblast proliferation and increased collagen I synthesis via Erk activation.

Accurate IVIM model-based liver lesion characterisation can be achieved with only three b-value DWI.

The objective of this study was to evaluate a simplified intravoxel incoherent motion (IVIM) approach of diffusion-weighted imaging (DWI) with four b-values for liver lesion characterisation at 1.5 T. DWI data from a respiratory-gated MRI sequence with b = 0, 50, 250, 800 s/mm2 were retrospectively analysed in 173 lesions and 40 healthy livers. The apparent diffusion coefficient ADC = ADC(0,800) and IVIM-based parameters D1' = ADC(50,800), D2' =ADC(250,800), f1', f2', D*', ADClow = ADC(0,50), and ADCdiff=ADClow-D2' were calculated voxel-wise without fitting procedures. Differences between lesion groups were investigated. Focal nodular hyperplasias were best discriminated from all other lesions by f1' with an area under the curve (AUC) of 0.989. Haemangiomas were best discriminated by D1' (AUC of 0.994). For discrimination between malignant and benign lesions, ADC(0,800) and D1' were best suited (AUC of 0.915 and 0.858, respectively). Discriminatory power was further increased by using a combination of D1' and f1'. IVIM parameters D and f approximated from three b-values provided more discriminatory power between liver lesions than ADC determined from two b-values. The use of b = 0, 50, 800 s/mm2 was superior to that of b = 0, 250, 800 s/mm2. The acquisition of four instead of three b-values has no further benefit for lesion characterisation. • Diffusion and perfusion characteristics are assessable with only three b-values. • Association of b = 0, 50, 800 s/mm2is superior to b = 0, 250, 800 s/mm2. • A fourth acquired b-value has no benefit for differential diagnosis. • For liver lesion characterisation, simplified IVIM analysis is superior to ADC determination. • Simplified IVIM approach guarantees numerically stable, voxel-wise results and short acquisition times.

Gastric dysregulation induced by microinjection of 6-OHDA in the substantia nigra pars compacta of rats is determined by alterations in the brain-gut axis.

Idiopathic Parkinson's disease (PD) is a late-onset, chronic, and progressive motor dysfunction attributable to loss of nigrostriatal dopamine neurons. Patients with PD experience significant gastrointestinal (GI) issues, including gastroparesis. We aimed to evaluate whether 6-hydroxy-dopamine (6-OHDA)-induced degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) induces gastric dysmotility via dysfunctions of the brain-gut axis. 6-OHDA microinjection into the SNpc induced a >90% decrease in tyrosine hydroxylase-immunoreactivity (IR) on the injection site. The [13C]-octanoic acid breath test showed a delayed gastric emptying 4 wk after the 6-OHDA treatment. In control rats, microinjection of the indirect sympathomimetic, tyramine, in the dorsal vagal complex (DVC) decreased gastric tone and motility; this inhibition was prevented by the fourth ventricular application of either a combination of α1- and α2- or a combination of D1 and D2 receptor antagonists. Conversely, in 6-OHDA-treated rats, whereas DVC microinjection of tyramine had reduced effects on gastric tone or motility, DVC microinjection of thyrotropin-releasing hormone induced a similar increase in motility as in control rats. In 6-OHDA-treated rats, there was a decreased expression of choline acetyl transferase (ChAT)-IR and neuronal nitric oxide synthase (NOS)-IR in DVC neurons but an increase in dopamine-β-hydroxylase-IR in the A2 area. Within the myenteric plexus of the esophagus, stomach, and duodenum, there were no changes in the total number of neurons; however, the percentage of NOS-IR neurons increased, whereas that of ChAT-IR decreased. Our data suggest that the delayed gastric emptying in a 6-OHDA rat model of PD may be caused by neurochemical and neurophysiological alterations in the brain-gut axis.

Did hardening occur among smokers in England from 2000 to 2010?

Aims To assess trends in the prevalence of ‘hardcore’ smoking in England between 2000 and 2010, and to examine associations between hardcore smoking and socio-demographic variables.Design Secondary analysis of data from the United Kingdom's General Lifestyle Survey (GLF) and the Health Survey for England (HSE).Setting Households in England.Participants Self-reported adult current smokers resident in England aged 26 years and over.Measurements Hardcore smokers were defined in three ways: smokers who do not want to quit (D1), those who ‘usually’ smoke their first cigarette of the day within 30 minutes of waking (D2) and a combination of D1 and D2, termed D3. Multivariable logistic regression was used to explore associations between these variables and calendar year, age, sex and socio-economic status, and P-values for trends in odds were calculated.Findings The odds of smokers being defined as hardcore according to D3 increased over time in both the GLF (P < 0.001) and HSE (P = 0.04), even after adjusting for risk factors. Higher dependence (D2) was noted in men [odds ratio (OR): 1.19, 95% confidence interval (CI): 1.13–1.24], those of 50–59 years (OR: 1.94, 95% CI: 1.80–2.09) and smokers in lower occupational groups (OR: 2.11, 95% CI: (1.97–2.26). Lack of motivation to quit (D1) increased with age and was more likely in men.Conclusions The proportion of smokers in England with both low motivation to quit and high dependence appears to have increased between 2000 and 2010, independently of risk factors, suggesting that ‘hardening’ may be occurring in this smoker population.

Inhibition of 50-kHz ultrasonic vocalizations by dopamine receptor subtype-selective agonists and antagonists in adult rats

Adult rats emit ultrasonic calls at around 22 and 50 kHz, which are often elicited by aversive and rewarding stimuli, respectively. Dopamine (DA) plays a role in aspects of both reward and aversion. The purpose of this study is to investigate the effects of DA receptor subtype-selective agonists on 22- and 50-kHz call rates. Ultrasonic calls were recorded in adult male rats that were initially screened with amphetamine to eliminate low 50-kHz callers. The remaining subjects were tested after acute intraperitoneal or subcutaneous injection of the following DA receptor-selective agonists and antagonists: A68930 (D1-like agonist), quinpirole (D2-like agonist), PD 128907 (D3 agonist), PD 168077 (D4 agonist), SCH 39166 (D1-like antagonist), L-741,626 (D2 antagonist), NGB 2904 (D3 antagonist), and L-745,870 (D4 antagonist). The indirect DA/noradrenaline agonist amphetamine served as a positive control. As expected, amphetamine strongly increased 50-kHz call rates. In contrast, D1-, D2-, and D3-selective DA receptor agonists, when given alone, inhibited calling; combinations of D1- and D2-like agonists also decreased call rate. Given alone, the D1-like and D3 antagonists significantly decreased call rate, with a similar trend for the D2 antagonist. Agonist-antagonist combinations also decreased calling. The D4 agonist and antagonist did not significantly affect 50-kHz call rates. Twenty-two-kilohertz calls occurred infrequently under all drug conditions. Following systemic drug administration, tonic pharmacological activation of D1-like or D2-like DA receptors, either alone or in combination, does not appear sufficient to induce 50-kHz calls. Dopaminergic transmission through D1, D2, and D3 receptors appears necessary for spontaneous calling.

Direct Measurement of Oleocanthal and Oleacein Levels in Olive Oil by Quantitative 1H NMR. Establishment of a New Index for the Characterization of Extra Virgin Olive Oils

A new method for direct measurement of the oleocanthal and oleacein levels in olive oil by quantitative (1)H NMR was developed. The method was applied to the study of 175 monovarietal commercial Greek and California olive oil samples. The main findings were as follows: (1) There was a significant variation concerning the concentrations of oleocanthal and oleacein among the studied samples. Their concentrations ranged from nondetectable to 355 mg/kg and their sum (index D1) from 0 to 501 mg/kg. (2) There are olive varieties that independent of geographic origin and harvest time produce oil that contains both compounds in low levels. (3) There is a positive correlation of a high level of oleocanthal and oleacein in olive oils with the early time of harvest. Although there is a need for more extensive study, a new index for the characterization of extra virgin olive oils, which is a combination of D1 = oleocanthal + oleacein level and D2 = oleocanthal/oleacein ratio, seems to be very useful.

Improvement of an Optically Pumped Magnetometer Using a Combination of D1 and D2 Transitions

The magnetic resonance spectra of 133Cs vapor were obtained using a D1 transition, a D2 transition, and a combination of D1 and D2 transitions. Maximum intensity (Imax) and line width (Δf) in the spectra were measured, and an “α value” (i.e., Imax/Δf) was defined as an appropriate figure of merit for an optically pumped magnetometer (OPM). The α value obtained using the combination of D1 and D2 transitions was tenfold larger than that obtained using the D1 transition and 160 times larger than that obtained using the D2 transition. This result indicates that using the combination of D1 and D2 transitions improves the sensitivity of an OPM.

A new concept for olive oil classification based on the oleocanthal and oleacein content through H-NMR quantitation

Extra virgin olive oil contains multiple minor bioactive components, especially phenolic compounds. Among them, (-)- decarboxymethyl ligstroside aglycone, also known as oleocanthal, has been shown to possess strong anti-inflammatory and neuroprotective properties, while (-)- decarboxymethyl oleuropein aglycone, also known as oleacein is considered as the most powerful antioxidant of olive oil. We developed a method for direct measurement of the oleocanthal and oleacein levels by quantitative 1H-NMR in CDCl3 at 600 or 800MHz in order to identify possible differences between extra virgin olive oils. The method was applied on >200 monovarietal commercial olive oil samples from Greece and California. The main findings were: 1. There are olive varieties that independently from geographic origin and harvest time produce olive oil that contains both compounds in low levels 2. There are olive cultivars that are able to produce olive oil rich in these substances, depending on the harvest and milling conditions. 3. The oleacein to oleocanthal ratio seems to depend on the olive cultivar, whereas it is independent from the olive extraction procedure. We propose a new index to classify extra virgin olive oils as a combination of D1=oleocanthal + oleacein and D2=oleacein/oleocanthal. The significant differences between the samples regarding the D1 (0–451mg/L) and D2 (0–1.3) could be used to discriminate the olive oils according to their possible health effects, organoleptic properties and varietal/geographic origin.

Efficient bulk heterojunction solar cells based on low band gap bisazo dyes containing anthracene and/or pyrrole units

2,5-Bis(2-anthracenyldiazo)-1H-pyrrole (dye D1) and 2,2′-[1,4-phenylenebis(azo)]bis-1H-pyrrole (dye D2) were synthesized by four- and two-step reactions, respectively. Their absorption spectra were broad with thin film absorption onset at 829 and 738 nm corresponding to an optical band gap of 1.39 and 1.68 eV for D1 and D2, respectively. The solution processed bulk heterojunction (BHJ) photovoltaic devices fabricated from D1 and D2 as donor blended with PCBM as an acceptor showed power conversion efficiency (PCE) up to 2.13% and 1.59%, respectively. The PCE has been further improved up to 2.42% and 2.18%, after thermal annealing of the D1:PCBM and D2:PCBM layers, respectively. The higher PCE of the photovoltaic devices based on the D1:PCBM blend as compared to D2:PCBM is attributed to the higher hole mobility and lower band gap of D1 relative to D2. The combination of D1 with D2 and PCBM allows not only a broad absorption, but also tuning of the inter energy level leading to a higher short circuit current ( J sc) and open circuit voltage ( V oc). The best performance device exhibited PCE of about 3.61% with the thermally annealed D1: D2:PCBM photoactive layer. Such a high PCE using small molecules is due to the increased values of both J sc and V oc.

Corticostriatal Up-Regulation of Activity-Regulated Cytoskeletal-Associated Protein Expression after Repeated Exposure to Cocaine

We provide evidence that cocaine evokes short- and long-lasting increases in activity-regulated cytoskeletal-associated protein (Arc) expression after a finely tuned, time-dependent and regional-selective expression profile. Acute experiments revealed that cocaine up-regulates Arc expression primarily in striatum and prefrontal cortex through a dopamine D1-dependent mechanism and a combination of D1- and D2-dependent mechanisms, respectively. Aside from cocaine-dependent Arc elevation, we show for the first time that D1 and D2 receptors tonically regulate basal Arc expression following a regional-selective profile. As opposed to the effects of a single cocaine injection on Arc expression, which dissipate within 24 h, subchronic (five daily injections) or chronic (14 daily injections) cocaine administration, with animals sacrificed hours or days after the last treatment, demonstrated that Arc expression is still up-regulated long after treatment cessation, suggesting that adaptive changes have been set in motion by the prolonged administration of the psychostimulant. In summary, our findings are the first to demonstrate that repeated exposure to cocaine leads to long-lasting dysregulation of Arc expression in the corticostriatal network, thus establishing a molecular basis to explain, at least partially, the impaired synaptic transmission caused by cocaine abuse at this level. Furthermore, given the role exerted by Arc in cytoarchitectural rearrangements, it is conceivable to speculate that it mediates changes in synaptic connectivity brought about by cocaine. Our findings thus pinpoint this molecule as a neuropathological underpinning and molecular bridge that connects short- and long-term neuronal modifications associated with cocaine abuse.

Butyrates and decitabine cooperate to induce histone acetylation and granulocytic maturation of t(8;21) acute myeloid leukemia blasts

Core histones are proteins organized in octamers, to which DNA is wrapped more or less tightly, depending on their acetylation status. Gene transcription is regulated by a complex series of epigenetic modifications, i.e., histone modification such as methylation and acetylation, events determined by the enzymatic activity of histone methyltransferases, and histone acetyltransferases, respectively, the latter counterbalanced by histone deacetylases (HDAC). Acetylation of histones facilitates destabilization of DNA-nucleosome interaction and renders DNA more accessible to transcription factors. Methylation of different specific lysine residues of histones is differently linked to euchromatin (transcripted DNA) or heterochromatin (silenced DNA). On the other hand, methylation of the promoter regions of some genes by DNA methyltransferases (DNMT) leads to transcriptional silencing and is a common mechanism to regulate gene expression. In normal eukaryotic cells, DNA methylation and histone acetylation are interdependent and maintain equilibrium, allowing temporal expression of genes. In neoplastic cells, this balance is frequently disrupted. In leukemic cells, hypermethylation of CpG islands in the promoter region of genes critical for cell cycle and maturation is frequent, and DNMTs were found to be overexpressed, findings paralleled by evidence of transcriptional repression of downstream genes. Therefore, the combination of HDAC and DNMT inhibitors has been considered to be a possible therapeutic approach to restore normal gene expression in acute myeloid leukemia (AML) and other diseases. Human AML1/ETO Kasumi cells were exposed to the HDAC inhibitor D1 (O-n-butanoil-2,3-O-isopropylidene-alpha-D: -mannofuranoside) and 5-aza-deoxycytidine (decitabine) alone and in combination. Histone acetylation as measured by flow cytometry was increased following treatment with D1 and the combination of D1 and decitabine. Addition of D1 alone or in combination with decitabine also led to inhibition of cell proliferation and induction of apoptosis. Thus, treatment of AML with HDAC inhibitors such as D1 and DNMT inhibitors such as decitabine might have clinical benefit for patients, especially these presenting subtypes of AML, like AML1/ETO, in which the leukemogenic mechanism involves corepressor protein complexes containing HDAC and DNMT.

When Two Receptors Are Different from One

The D1 and D2 types of dopamine receptors are members of distinct subfamilies but appear to act together in a number of systems where combinations of specific agonists produce distinct biological effects from those produced by D1- or D2-specific agonists alone. Lee et al . now propose that this may reflect the fact that D1 and D2 receptors physically interact, and in doing so produce distinct signals not mediated by either receptor alone. D1 and D2 receptors are G protein-coupled receptors that signal predominantly through G s or G olf , or G i or G o , respectively, to adenylyl cyclase. However when both D1 and D2 dopamine receptors were stably expressed in cultured cells, treatment of the cells with a combination of D1- and D2-selective agonists caused a rapid increase in the intracellular concentration of free calcium ([Ca 2+ ] i ). The increase in ([Ca 2+ ] i ) was prevented when cells were treated with the phospholipase C inhibitor U73122 and was not present if cells were treated with only one of the agonists or if cells expressed only one of the receptors. Immunohistochemical analysis of rat and human brain cells indicated that the D1 and D2 receptors are expressed and localized together in some cells. Furthermore, D2 receptors were detected by immunoblotting in association with D1 receptors immunoprecipitated from membranes of rat striatal neurons. Thus, the combination of D1 and D2 receptors appears to produce a signal (presumably through coupling to a new G protein, G q , which then regulates phospholipase C) that is distinct from those produced by either receptor alone. Such behavior may underlie some of the diverse effects of dopamine in the brain. S. P. Lee, C. H. So, A. J. Rashid, G. Varghese, R. Cheng, A. J. Lança, B. F. O'Dowd, S. R. George, Dopamine D1 and D2 receptor co-activation generates a novel phospholipase C-mediated calcium signal. J. Biol. Chem. 279 , 35671-35678 (2004). [Abstract] [Full Text]

Alterations in D1/D2 synergism may account for enhanced stereotypy and reduced climbing in mice lacking dopamine D2L receptor

Concurrent activation of dopamine D1 and D2 receptors (D1 and D2) is required for the expression of certain dopamine (DA)-mediated responses, such as climbing and stereotyped behaviors. Such interactions between D1 and D2 (i.e. D1/D2 synergism) represent an important aspect of dopaminergic function and plasticity. The D2 receptor exists in two isoforms: D2L and D2S. We have generated mice that selectively lack D2L (D2L−/−). Here we showed that treatment with the indirect DA agonist amphetamine, the direct DA agonist apomorphine, or combination of D1 and D2 agonists elicited intense climbing in wild type mice (which express predominantly D2L in the striatum), but this behavior was absent or reduced in D2L−/− mice. On the other hand, apomorphine, the D2 agonist quinpirole, or combination of quinpirole and the D1 agonist SKF 81297 induced more stereotyped behavior such as biting or head movements in D2L−/− mice (which express only D2S) than in wild type mice. The D1 receptor functioned normally in D2L−/− mice. Taken together, these results suggest that D2L and D1 interactions may play a greater role in DA agonist-induced climbing, whereas D2S and D1 interactions may have a larger impact on DA agonist-induced stereotypy (and possibly psychosis). DA agonists, which are clinically used to treat Parkinson’s disease and attention-deficit hyperactivity disorder (ADHD), are known to induce psychotic side effects. Thus, our findings may provide novel insights for designing anti-parkinsonian, anti-ADHD and antipsychotic drugs with greater therapeutic efficacy and fewer side effects.

The stay green mutations d1 and d2 increase water stress susceptibility in soybeans

The stay green mutant genotype d1d1d2d2 inhibits the breakdown of chloroplast components in senescing leaves of soybean ( Glycine max L. Merr.). Together with G (a gene that preserves chlorophyll in the seed coat) they may extend photosynthetic activity in some conditions. While wild‐type soybeans maintain high leaf water potentials right up to abscission, leaves of (GG)d1d1d2d2 dehydrate late in senescence, which suggests that water relations may be altered in the mutant. Three‐week‐old plants were subjected to a moderate water deficit (soil water potential=−0.7 MPa) for 7–10 d. Leaf water potential and relative water content decreased significantly more in response to water deficit in unifoliate leaves of GGd1d1d2d2 than in a near‐isogenic wild‐type line. Down‐regulation of stomatal conductance in response to drought was similar in mutant and wild‐type leaves. Likewise, exogenously applied ABA reduced stomatal conductance to a similar extent in the mutant and the wild type, and applied ABA failed to restore water deficit tolerance in GGd1d1d2d2 . Experiments with explants lacking roots indicate that the accelerated dehydration of GGd1d1d2d2 is probably not due to alterations in the roots. In a comparison of near‐isogenic lines carrying different combinations of d1 , d2 and G , only d1d1d2d2 and GGd1d1d2d2 (i.e. the genotypes that cause the stay green phenotype) were more suscept ible to water deficit than the wild type. These data suggest that pathways involved in chloroplast disassembly and in the regulation of stress responses may be intertwined and controlled by the same factors.

Antiparkinsonian Action of a δ Opioid Agonist in Rodent and Primate Models of Parkinson's Disease

The opioid peptides localized in striatal projection neurons are of great relevance to Parkinson's disease, not only as a consequence of their distribution, but also due to the pronounced changes in expression seen in Parkinson's disease. It has long been suspected that increased expression of enkephalin may represent one of the many mechanisms that compensate for dopamine (DA) depletion in Parkinson's disease. Here we demonstrate that a systemically delivered, selective δ opioid agonist (SNC80) has potent antiparkinsonian actions in both rat and primate models of Parkinson's disease. In rats treated with either the D2-preferring DA antagonist haloperidol (1 mg/kg) or the selective D1 antagonist SCH23390 (1 mg/kg), but not a combination of D1 and D2 antagonists, SNC80 (10 mg/kg) completely reversed the catalepsy induced by DA antagonists. In rats rendered immobile by treatment with reserpine, SNC80 dose-dependently reversed akinesia (EC50 7.49 mg/kg). These effects were dose-dependently inhibited (IC50 1.05 mg/kg) by a selective δ opioid antagonist (naltrindole) and by SCH23390 (1 mg/kg), but not by haloperidol (1 mg/kg). SNC80 also reversed parkinsonian symptoms in the MPTP-treated marmoset. At 10 mg/kg (ip), scores measuring bradykinesia and posture were significantly reduced and motor activity increased to levels comparable with pre-MPTP-treatment scores. Any treatment that serves to increase δ opioid receptor activation may be a useful therapeutic strategy for the treatment of Parkinson's disease, either in the early stages or as an adjunct to dopamine replacement therapy. Furthermore, enhanced enkephalin expression observed in Parkinson's disease may serve to potentiate dopamine acting preferentially at D1 receptors.

Use of fractal analysis for discrimination of particles from primary and reworked jökulhlaup deposits in SE Iceland

The morphology of sideromelane particles from jökulhlaup deposits in southeastern Iceland has been studied by fractal analysis to assess post-depositional changes associated with reworking. Fractal dimensions of particle boundaries were calculated from data obtained by the caliper and dilation methods. Most particles exhibit multifractal relationships with a textural (D1) and structural (D2) fractal dimension. Particles from primary jökulhlaup deposits have significantly greater textural and structural fractal dimensions compared to reworked deposits. Differences in the fractal dimensions indicate that reworking in the littoral zone has reduced both the amount of fine scale features on particle surfaces and the complexity of the overall particle shapes. The caliper and dilation methods yield similar values of textural fractal dimension for each particle. For the same particles, the dilation method yields higher values of structural fractal dimension. Reworked particles used in this study can be effectively discriminated from primary particles using a combination of D1 and D2 fractal dimensions. The results indicate that fractal analysis provides a useful quantitative characterization of complex volcanic particles and can be utilized to examine aspects of particle origin, transport and deposition.

Dopamine Selectively Inhibits the Direct Cortical Pathway to the CA1 Hippocampal Region

The perforant path input (pp) is a major direct source of specific sensory information for the CA1 hippocampal region. The termination area of this pathway, the stratum lacunosum-moleculare, has the highest concentration of dopamine receptors in the hippocampus. We have examined the properties of the pp input and its modulation by dopamine. The input is glutamatergic and has a larger NMDA component than the Schaffer collateral (sc) input. Dopamine strongly inhibits the response to pp stimulation (IC50 approximately 3 microM) but not the response to sc stimulation. Dopamine reduces both the NMDA and AMPA components of transmission at the pp and increases paired-pulse facilitation. In the sc, the NMDA component but not the AMPA component is decreased, and paired-pulse facilitation is not affected. The effect of dopamine on the pp does not depend on GABAA inhibition but is reduced by the antagonists of both D1 and D2 families of dopamine receptors. The effect is not completely blocked by the combination of D1 and D2 antagonists, but is completely blocked by the atypical neuroleptic clozapine. Our results provide the first evidence for strong dopaminergic control of transmission in the perforant path. By inhibiting this pathway, dopamine hyperfunction and/or NMDA hypofunction abnormalities implicated in schizophrenia may isolate CA1 from its main source of sensory information.

Removal of domain D2 or D3 of the human urokinase receptor does not affect ligand affinity

The main ligand-binding determinant of the human urokinase receptor (uPAR) is located in the amino terminal domain D1, but when isolated this domain presents a 1500 fold lower affinity than the intact three-domain uPAR (D1D2D3) [1]. uPAR mutants missing either domain 2 (D1HD3) or domain 3 (D1D2) were expressed in murine LB6 cells and showed to be properly GPI-anchored to the cell surface. Binding assays with [ 125I]ATF demonstrated that these mutants possessed a normal (D1D2) or slightly reduced (D1HD3) affinity, indicating that a high ligand-affinity may be achieved by a combination of D1 with domain D2 or D3.

Modem psychopharmacological treatment in schizophrenia from receptor proteins to antipsychotic effect

Research into new antipsychotics is in a fruitful development. The molecular identification of various subtypes of receptors, and also transporters, for dopamine and serotonin has led to promising possibilities for developing new, better, and more side effect-Free antipsychotics. New and selective dopamine antagonists will emerge, with varying therapeutic effects, but with fewer side effects than current neuroleptics. DI antagonists are interesting in this respect, but it may be that combinations of D1, D2, D3 and D4 receptor blockers represent the strongest possibilities (i.e. clozapine). Serotonin agents, given separately or incorporated into a neuroleptic, are another area of considerable potential. The new antipsychotic risperidone, acting through a combination of strong 5HT2/D2 receptor antagonism. may contribute to our understanding of the importance of SHT2 antagonism in antipsychotic drugs. The observation of a beneficial effect of selective serotonin reuptdke inhibitors in subgroups of schizophre...

Synergistic and persistent interaction between the D2 agonist, bromocriptine, and the D1 selective agonist, CY 208–243

In mice pretreated with reserpine and α- methyl- dl -p- tyrosin (αMPT) to deplete central catecholamines, the D2 dopamine receptor-selective agonist, bromocriptine, at a dose to 10 mg/kg produced no locomotor activity. The D1-selective agonist, CY 208–243, generated a dose-dependent locomotor response in this animal model for Parkinson's disease; low doses elicited little or no effect while higher doses resulted in a short burst of locomotor activity (2 h). The combination of CY 208–243 and bromocriptine had a dramatic synergistic effect on locomotion. Most importantly, this combination of D1 and D2 agonists converted a brief (2 h) effect on locomotion to one which persisted for up to 6 h. These results suggest that the combination of D1 and D2 dopamine receptor agonists can affect both the intensity and the persistence of a locomotor response.