1,721,828 research outputs found
The onset of large-scale turbulence in the interstellar medium of spiral galaxies
No full textDFG thanks the European Research Council (ADG-2011 ECOGAL), and Brazilian agencies CAPES (3400-13-1) and FAPESP (no.2011/12909-8) for financial support. IB acknowledges the European Research Council (ADG-2011 ECOGAL) for financial support. GK acknowledges support from FAPESP (grants no. 2013/04073-2 and 2013/18815-0).Turbulence is ubiquitous in the interstellar medium (ISM) of the Milky Way and other spiral galaxies. The energy source for this turbulence has been much debated with many possible origins proposed. The universality of turbulence, its reported large-scale driving, and that it occurs also in starless molecular clouds, challenges models invoking any stellar source. A more general process is needed to explain the observations. In this work, we study the role of galactic spiral arms. This is accomplished by means of three-dimensional hydrodynamical simulations which follow the dynamical evolution of interstellar diffuse clouds (similar to 100 cm-3) interacting with the gravitational potential field of the spiral pattern. We find that the tidal effects of the arm's potential on the cloud result in internal vorticity, fragmentation and hydrodynamical instabilities. The triggered turbulence results in large-scale driving, on sizes of the ISM inhomogeneities, i.e. as large as similar to 100 pc, and efficiencies in converting potential energy into turbulence in the range similar to 10-25 per cent per arm crossing. This efficiency is much higher than those found in previous models. The statistics of the turbulence in our simulations are strikingly similar to the observed power spectrum and Larson scaling relations of molecular clouds and the general ISM. The dependence found from different models indicate that the ISM turbulence is mainly related to local spiral arm properties, such as its mass density and width. This correlation seems in agreement with recent high angular resolution observations of spiral galaxies, e.g. M51 and M33.Peer reviewe
On the alignment of PNe and local magnetic field at the Galactic centre : magnetohydrodynamical numerical simulations
No full textDFG thanks the European Research Council (ADG-2011 ECOGAL), and Brazilian agencies CNPq (no. 300382/2008-1), CAPES (3400-13-1) and FAPESP (no.2011/12909-8) for financial support. HM thanks CNPq grant 573648/2008-5 and FAPEMIG grants APQ-02030-10 and CEX-PPM-00235-12.For the past decade, observations of the alignment of planetary nebulae (PNe) symmetries with respect to the Galactic disc have led to conflicting results. Recently, the first direct observational evidence for a real alignment between PNe and local interstellar magnetic fields in the central part of the Galaxy (b 100 μG are required in order to be dynamically dominant. This is found to occur only at later evolutionary stages, therefore, being unable to change the general morphology of the nebula. However, the symmetry axis of bipolar and elliptical nebulae end up aligned to the external field. This result can explain why different samples of PNe result in different conclusions regarding the alignment of PNe. Objects located at high Galactic latitudes, or at large radii, should present no preferential alignment with respect to the Galactic plane. PNe located at the Galactic centre and low latitudes would, on the other hand, be preferentially aligned to the disc. Finally, we present synthetic polarization maps of the nebulae to show that the polarization vectors, as well as the field lines at the expanding shell, are not uniform even in the strongly magnetized case, indicating that polarization maps of nebulae are not adequate in probing the orientation, or intensity, of the dominant external field.Peer reviewe
Potential Antagonism of Cocaine Effects on Extracellular Dopamine: Microdialysis Studies with GBR 12909
No full textv, 39 p.It is well known that cocaine increases striatal extracellular dopamine (ECDA) levels in
vivo. Previous studies have also shown that GBR 12909 1-[2-[bis(fluorophenyl)methoxy ]ethyl]-4-[3-pheynyl-propyl]piperazine increases in vivo
ECDA levels and pretreatment with GBR 12909 attenuates the ability of cocaine to
increase extracellular levels of dopamine (DA) in the rat striatum. In the present study, in
vivo microdialysis was utilized to determine the effect of cocaine, GBR 12909, or their
combination on ECDA levels after direct infusion into the striatum of anesthetized rats. A
20 minute infusion of artificial cerebrospinal fluid containing either 1 00 ~ cocaine or
100 µM GBR 12909 increased ECDA levels albeit with significantly different efficacies.
GBR 12909 increased ECDA levels by 188% and cocaine resulted in a 1063% increase
in striatal ECDA levels. In animals exposed transiently to GBR 12909 (20 minutes, 100
µM), the effect of cocaine (administered 1 hr after GBR 12909 exposure) on ECDA was
significantly reduced (620% increase over baseline, p <0.05). The results suggest that
after a brief exposure to GBR 12909 and a subsequent return of ECDA to basal
conditions, the effectiveness of cocaine to elevate ECDA was compromised. The results
also demonstrate that although qualitatively similar, the quantitative effects of equimolar
doses of cocaine and GBR 12909 are vastly different even when perfused directly into the
brain. This suggests that GBR 12909 may be less efficacious than cocaine and thus may act
as a partial agonist. Since GBR 12909 binding is highly selective for the DA transporter,
the results support the concept that the effect of cocaine on ECDA may include actions
distal to the DA transporter, such as its effect on serotonin or norepinephrine. These
results may prove GBR 12909 as a potential therapeutic drug for cocaine addiction.Department of Psychiatry and Behavioral Neurosciences. School of Medicine. Wayne State University. Detroit, Michigan
Synthesis and Biological Evaluation of Novel GBR 12909 Tropane and Azetidine Hybrid Analogues
Get PDFThe high affinity, selective dopamine transporter ligand GBR 12909 has served as a template for the design of two novel classes of dopamine transporter ligands. A series of 3-[2- (diarylmethoxyethyidenyl)]-N-substituted tropane derivatives were synthesized and the binding affinities of these compounds were determined at the dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporters in rat brain tissue preparations. The tropane derivatives were found to exhibit more potent affinity and selectivity for DAT than GBR 12909. From the SAR of the tropane analogues and GBR 12909, a novel series of 3-[2-(diarylmethoxyethylidenyl)]-Nsubstituted azetidine derivatives has been developed
Differential Reinforcing Effects of Cocaine and GBR-12909: Biochemical Evidence for Divergent Neuroadaptive Changes in the Mesolimbic Dopaminergic System
No full textThe dopamine (DA) transporter is thought to be the primary mediator of reinforcing effects of cocaine. In the present study, an intravenous drug self-administration procedure,in vitroautoradiography, and HPLC methods were used to investigate possible differences in reinforcing and neuroadaptive responses to cocaine versus GBR-12909, a selective inhibitor of the DA transporter with a postulated therapeutic use in cocaine abuse. Drug-naive rats readily acquired and subsequently maintained cocaine self-administration behavior during 2 hr daily sessions over a prolonged period. In contrast, although GBR-12909 was initially self-administered, both cocaine-naive and cocaine-trained rats failed to maintain self-administration behavior for GBR-12909 over prolonged periods of time. After self-administration responding decreased with GBR-12909, rats showed a delay of 6.6 ± 1.3 sessions in reacquiring consistent cocaine self-administration. Moreover, when GBR-12909 was again substituted for cocaine, they failed to self-administer GBR-12909, even during the initial days of testing. In contrast, after extinction of self-administration responding by water substitution, rats readily self-administered both cocaine and GBR-12909. Cocaine self-administration upregulated DA transporters, whereas water-substituted cocaine withdrawal upregulated both DA transporters and D1 receptors. Unlike cocaine, GBR-12909 self-administration by itself altered neither DA transporters nor D1 or D2 receptors. Nevertheless, substitution of GBR-12909 for cocaine reversed the cocaine-induced upregulation of DA transporters and reduced DA and dihydroxyphenylacetic acid levels in the mesolimbic system. These data suggest that cocaine and GBR-12909 differentially affect dopaminergic systems and also cause different reinforcing and neuroadaptive effects. GBR-12909-like compounds may be useful pharmacotherapeutic agents for cocaine addiction. Upregulation of DA transporters and D1 receptors might play important roles in the neuroadaptive cascade that leads to cocaine addiction and withdrawal.</jats:p
Synthesis of [ 18 F]GBR 12909, a dopamine reuptake inhibitor
Get PDFPreparation of no‐carrier‐added fluorine‐18 labeled GBR 12909 (1‐[2‐(bis(4‐fluorophenyl)methoxy)ethyl]‐4‐(3‐phenylpropyl)piperazine), a specific and high affinity inhibitor of dopamine reuptake, is described. 4‐Fluoro‐4′‐[ 18 F]fluorobenzophenone was prepared by [ 18 F]fluoride ion substitution of the corresponding trimethylammonium trifluoromethanesulfonate salt. The [ 18 F]benzophenone was reduced to the benzhydrol, chlorinated, then used to alkylate 1‐(2‐hydroxyethyl)‐4‐(3‐phenyl‐propyl)piperazine to yield [ 18 F]GBR 12909 in high specific activity (≥2000 Ci/mmol) and overall yields of 10–16% (corrected, 140 min synthesis).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90171/1/2580280708_ftp.pd
Effects of GBR 12909 and cocaine on cocaine-maintained behavior in rhesus monkeys
Get PDFThe reinforcing effect of the high affinity dopamine reuptake inhibitor GBR 12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl)-4(3-phenylpropyl)piperazine) was compared with that of cocaine, and the effects of both GBR 12909 and cocaine pretreatments were evaluated on behaviour maintained by cocaine in rhesus monkeys. Increasing dose per injection of intravenously-delivered GBR 12909 or cocaine led to increased rates of lever-press responding. Maximum cocaine-maintained rates were higher and occurred at a smaller dose than maximum rates of GBR 12909-maintained responding. Presession intravenous administration of either GBR 12909 or cocaine (0.32, 1.0 or 3.2 mg/kg) resulted in dose-dependent decreases in rates of cocaine-maintained responding when high doses of cocaine, which engendered high response rates, were available early in the session. Under these conditions, the decrease in response rates was associated primarily with decreases in running rate rather than with a lengthening in post-reinforcement pause times. The decreases in running rate produced by both cocaine and GBR 12909 probably reflect an unconditioned rate-disruptive effect of these drugs on cocaine-reinforced responding rather than a reduction in the reinforcing efficacy of cocaine.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30750/1/0000400.pd
Chronic GBR 12909 administration differentially alters prodynorphin gene expression compared to cocaine
No full textThe effect of the selective dopamine uptake inhibitor 1-[2-[bis(4-flourophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine dihydrochloride (GBR 12909) was examined on prodynorphin gene expression. GBR 12909 or vehicle was continuously infused for 7 days via osmotic minipump, or injected daily into male rats. Both continuous infusions and daily injections of GBR 12909 produced significant decreases in prodynorphin expression in the hypothalamus (37% and 31% decreases, respectively). There were no significant changes in the caudate putamen, hippocampus or nucleus accumbens. One injection of GBR 12909 had no effects on prodynorphin expression in any of the brain regions studied, suggesting that the effect in the hypothalamus is not an acute effect. As previously reported for other treatment regimens, continuous infusion of cocaine produced a 35% significant decrease in the hypothalamus, consistent with the effects of GBR 12909. In contrast to GBR 12909, however, cocaine also produced a significant increase in prodynorphin expression in the caudate putamen. Thus, chronic inhibition of dopamine uptake can regulate prodynorphin expression in the hypothalamus. In contrast, the increase in the caudate putamen following cocaine administration may not be related to the inhibition of dopamine uptake, since it was not produced by a selective dopamine uptake inhibitor. These findings suggest that regulation of prodynorphin gene expression by cocaine in the caudate putamen may be mediated by the inhibition of norepinephrine or serotonin uptake, by a combination of effects on two or three monoamine transporters, or by a mechanism unrelated to transporter inhibition
Chronic GBR 12909 administration differentially alters prodynorphin gene expression compared to cocaine
No full textThe effect of the selective dopamine uptake inhibitor 1-[2-[
bis(4-flourophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine dihydrochloride (GBR 12909) was examined on prodynorphin gene expression. GBR 12909 or vehicle was continuously infused for 7 days via osmotic minipump, or injected daily into male rats. Both continuous infusions and daily injections of GBR 12909 produced significant decreases in prodynorphin expression in the hypothalamus (37% and 31% decreases, respectively). There were no significant changes in the caudate putamen, hippocampus or nucleus accumbens. One injection of GBR 12909 had no effects on prodynorphin expression in any of the brain regions studied, suggesting that the effect in the hypothalamus is not an acute effect. As previously reported for other treatment regimens, continuous infusion of cocaine produced a 35% significant decrease in the hypothalamus, consistent with the effects of GBR 12909. In contrast to GBR 12909, however, cocaine also produced a significant increase in prodynorphin expression in the caudate putamen. Thus, chronic inhibition of dopamine uptake can regulate prodynorphin expression in the hypothalamus. In contrast, the increase in the caudate putamen following cocaine administration may not be related to the inhibition of dopamine uptake, since it was not produced by a selective dopamine uptake inhibitor. These findings suggest that regulation of prodynorphin gene expression by cocaine in the caudate putamen may be mediated by the inhibition of norepinephrine or serotonin uptake, by a combination of effects on two or three monoamine transporters, or by a mechanism unrelated to transporter inhibition
Chronic GBR 12909 administration differentially alters prodynorphin gene expression compared to cocaine
No full textThe effect of the selective dopamine uptake inhibitor 1-[2-[bis(4-flourophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine dihydrochloride (GBR 12909) was examined on prodynorphin gene expression. GBR 12909 or vehicle was continuously infused for 7 days via osmotic minipump, or injected daily into male rats. Both continuous infusions and daily injections of GBR 12909 produced significant decreases in prodynorphin expression in the hypothalamus (37% and 31% decreases, respectively). There were no significant changes in the caudate putamen, hippocampus or nucleus accumbens. One injection of GBR 12909 had no effects on prodynorphin expression in any of the brain regions studied, suggesting that the effect in the hypothalamus is not an acute effect. As previously reported for other treatment regimens, continuous infusion of cocaine produced a 35% significant decrease in the hypothalamus, consistent with the effects of GBR 12909. In contrast to GBR 12909, however, cocaine also produced a significant increase in prodynorphin expression in the caudate putamen. Thus, chronic inhibition of dopamine uptake can regulate prodynorphin expression in the hypothalamus. In contrast, the increase in the caudate putamen following cocaine administration may not be related to the inhibition of dopamine uptake, since it was not produced by a selective dopamine uptake inhibitor. These findings suggest that regulation of prodynorphin gene expression by cocaine in the caudate putamen may be mediated by the inhibition of norepinephrine or serotonin uptake, by a combination of effects on two or three monoamine transporters, or by a mechanism unrelated to transporter inhibition. © 2001 Published by Elsevier Science B.V
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