B. Ellen Scanley

Serotonergic mechanisms of cocaine effects in humans

The objective of this study was to investigate the role of serotonin (5-HT) in mediating the effects of cocaine in humans. To accomplish this, 12 subjects each participated in two randomized, double-blind test sessions separated by 1 week. In one session, subjects underwent acute depletion of the 5-HT amino acid precursor tryptophan (TRP), followed by a test dose of intranasal cocaine. In the other session, the cocaine test dose was preceded by sham depletion. Subject ratings of cocaine “high” were significantly lower following active TRP depletion than after the sham procedure. Subjects also showed an earlier but less sustained rise in self-rated nervousness during active TRP depletion. These findings are consistent with the hypothesis that 5-HT may be involved in mediating the euphorigenic and modulating the anxiogenic effects of cocaine in humans, either directly or through actions on other (e.g., dopaminergic) systems.

Changes in rat cerebral blood volume due to modulation of the 5-HT1A receptor measured with susceptibility enhanced contrast MRI

Brain blood volume changes in the rat in response to 5-HT(1A) agonist and antagonist administration were measured using susceptibility contrast enhanced magnetic resonance imaging (MRI). Administration of the 5-HT(1A) agonist 8-OH-DPAT resulted in decreases in fractional brain blood volumes. Administration of the 5-HT(1A) antagonist WAY-100635 following a dose of 8-OH-DPAT resulted in increases in fractional blood volumes greatest in hippocampus and cortex and smallest in thalamus and caudate-putamen. The magnitude of the regional increases in blood volumes paralleled the distribution of 5-HT(1A) receptors in the rat brain. Administration of WAY-100635 alone resulted in decreases in cortical blood volume and increases in cerebellar blood volume.

Combinatorial development of antibacterial Zr-Cu-Al-Ag thin film metallic glasses.

Metallic alloys are normally composed of multiple constituent elements in order to achieve integration of a plurality of properties required in technological applications. However, conventional alloy development paradigm, by sequential trial-and-error approach, requires completely unrelated strategies to optimize compositions out of a vast phase space, making alloy development time consuming and labor intensive. Here, we challenge the conventional paradigm by proposing a combinatorial strategy that enables parallel screening of a multitude of alloys. Utilizing a typical metallic glass forming alloy system Zr-Cu-Al-Ag as an example, we demonstrate how glass formation and antibacterial activity, two unrelated properties, can be simultaneously characterized and the optimal composition can be efficiently identified. We found that in the Zr-Cu-Al-Ag alloy system fully glassy phase can be obtained in a wide compositional range by co-sputtering, and antibacterial activity is strongly dependent on alloy compositions. Our results indicate that antibacterial activity is sensitive to Cu and Ag while essentially remains unchanged within a wide range of Zr and Al. The proposed strategy not only facilitates development of high-performing alloys, but also provides a tool to unveil the composition dependence of properties in a highly parallel fashion, which helps the development of new materials by design.

Changes in CBF-BOLD coupling detected by MRI during and after repeated transient hypercapnia in rat

The effect of hypercapnia on the cerebral metabolic rate of oxygen consumption (CMRO2) remains incompletely understood. This study examined the relationship between susceptibility (blood oxygenation level dependent (BOLD)) and perfusion‐weighted (flow‐sensitive alternating inversion recovery (FAIR)) MRI techniques both during induction of repeated transient hypercapnia (THC) and after return to normocapnia during whisker barrel functional activation. During induction of THC the FAIR signal became significantly elevated over control after 100 s of hypercapnia (P = 0.039), with a trend of increasing significance to 5 min (P = 0.000008). The FAIR signal in the activated cortex during subsequent normocapnia was significantly increased compared to pre‐THC control after each successive period of THC. The mean grouped FAIR signal increased by 81% ± 63% after one exposure (P = 0.021), by 163% ± 55% after the second exposure (P = 0.0002), and by 240% ± 54% after the third exposure (P = 0.000002). The mean grouped BOLD signal trended upward, but did not increase significantly during or after exposure 1, 2, or 3. These data demonstrate increased uncoupling of perfusion‐weighted from susceptibility imaging techniques, both in nonactivated cortex during hypercapnia, and with activation after multiple exposures to THC. These results are consistent with saturation of BOLD contrast as well as with increases in CMRO2 with stimulation after multiple exposures to THC. Magn Reson Med 48:262–270, 2002.

Comparison of [123I]beta-CIT and [123I]IPCIT as single-photon emission tomography radiotracers for the dopamine transporter in nonhuman primates.

Single-photon emission tomographic (SPET) imaging with the radiotracer [123I]2β-carbomethoxy-3β-(4-iodophenyl)tropane ([123I]β-CIT) has been reported to be a useful in vivo measure of dopamine (DA) transporters. However, in addition to its high DA transporter affinity,β-CIT also binds with high affinity to serotonin (5-HT) transporters. 2β-Carboisopropoxy-3β-(4-iodophenyl)tropane (IPCIT) has been demonstrated by in vitro studies to have higher selectivity for the DA transporter. We compared [123I]β-CIT and [123I]IPCIT SPET imaging and plasma metabolite analyses in baboons to evaluate the potential advantages of [123I]IPCIT for quantitative in vivo measurements of DA transporter densities. Both tracers had low levels (2% of total plasma123I activity) of lipophilic radiolabeled metabolites at 420 min. [123I]IPCIT had significantly higher binding to plasma proteins. The average percent free (nonprotein bound) [123I]β-CIT and [123I]IPCIT were 52%±7% and 14%±6%, respectively. Region of interest uptake data were normalized by injected dose and body weight. Consistent with the high density of 5-HT transporters in the midbrain and the lower 5-HT transporter affinity of IPCIT, the normalized peak specific midbrain uptake of [123I]β-CIT (1.7±0.5) was higher than that of [123I]IPCIT (0.4±0.2). Consistent with its greater lipophilicity, [123I]IPCIT had higher nonspecific uptake, such that normalized cerebellar uptake of [123I]IPCIT was about twice that of [123I]β-CIT. The ratio of specific to nonspecific uptake in striatum was greater for [123I]β-CIT compared to [123I]IPCIT; however, striatal binding potentials and distribution volumes were not significantly different. In conclusion, [123I]IPCIT demonstrated in vivo a higher DA transporter selectivity and higher level of nonspecific uptake.

Determination of critical cooling rates in metallic glass forming alloy libraries through laser spike annealing

The glass forming ability (GFA) of metallic glasses (MGs) is quantified by the critical cooling rate (RC). Despite its key role in MG research, experimental challenges have limited measured RC to a minute fraction of known glass formers. We present a combinatorial approach to directly measure RC for large compositional ranges. This is realized through the use of compositionally-graded alloy libraries, which were photo-thermally heated by scanning laser spike annealing of an absorbing layer, then melted and cooled at various rates. Coupled with X-ray diffraction mapping, GFA is determined from direct RC measurements. We exemplify this technique for the Au-Cu-Si system, where we identify Au56Cu27Si17 as the alloy with the highest GFA. In general, this method enables measurements of RC over large compositional areas, which is powerful for materials discovery and, when correlating with chemistry and other properties, for a deeper understanding of MG formation.

Characterization of the dopamine transporter in nonhuman primate brain: Homogenate binding, whole body imaging, and ex vivo autoradiography using [125I]and [123I]IPCIT

IPCIT [2 beta-carboisopropoxy-3 beta-(4-iodophenyl)tropane; also designated RTI-121] is the isopropyl ester of beta-CIT [2 beta-carbomethoxy-3 beta-(4-iodophenyl) tropane]. Although beta-CIT binds to dopamine (DA), serotonin (5-HT) and norepinephrine (NE) transporters, IPCIT has been reported to be selective for the DA transporter. IPCIT was labeled with 125I and its receptor binding to membranes prepared from baboon striatum was compared with that of [125I] beta-CIT. These studies confirmed the relative selectivity of IPCIT for the DA transporter in comparison to 5-HT and NE transporters. The nonspecific binding of [125I]IPCIT was almost four times greater than that of [125I] beta-CIT. The biodistribution of IPCIT was examined in two baboons with whole body imaging for 24-30 h after administration of 3 mCi of 123I-labeled tracer. The brain uptake peaked within the first hour at 9.2% of the injected dose and the majority of activity in the body cleared through the hepatobiliary system. The distribution of activity within the brain was examined with ex vivo autoradiography in one monkey injected with [123I]IPCIT. Activity was concentrated in the caudate and putamen and had values of 5 and 7 microCi/cm3 per microCi/g, respectively. The distribution in brain regions receiving moderately dense serotonergic innervation (e.g. superior colliculus and thalamus) had levels of activity equivalent to that in cerebellum. This study confirmed the in vitro and in vivo selectivity of IPCIT for the DA transporter but also showed that [125I]IPCIT had higher in vitro nonspecific binding than [125I] beta-CIT.