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Biomedical subjects

S R Jones

Publications and source records attributed to S R Jones.

At least 55 records · Page 3Linked to original sources
PubMed1998

The aminosterol antibiotic squalamine permeabilizes large unilamellar phospholipid vesicles.

The ability of the shark antimicrobial aminosterol squalamine to induce the leakage of polar fluorescent dyes from large unilamellar phospholipid vesicles (LUVs) has been measured. Micromolar squalamine causes leakage of carboxyfluorescein (CF) from vesicles prepared from the anionic phospholipids phosphatidylglycerol (PG), phosphatidylserine (PS), and cardiolipin. Binding analyses based on the leakage data show that squalamine has its highest affinity to phosphatidylglycerol membranes, followed by phosphatidylserine and cardiolipin membranes. Squalamine will also induce the leakage of CF from phosphatidylcholine (PC) LUVs at low phospholipid concentrations. At high phospholipid concentrations, the leakage of CF from PC LUVs deviates from a simple dose-response relationship, and it appears that some of the squalamine can no longer cause leakage. Fluorescent dye leakage generated by squalamine is graded, suggesting the formation of a discrete membrane pore rather than a generalized disruption of vesicular membranes. By using fluorescently labeled dextrans of different molecular weight, material with molecular weight </=4000 g/mol is released from vesicles by squalamine, but material with molecular weight >/=10,000 is retained. Negative stain electron microscopy of squalamine-treated LUVs shows that squalamine decreases the average vesicular size in a concentration-dependent manner. Squalamine decreases the size of vesicles containing anionic phospholipid at a lower squalamine/lipid molar ratio than pure PC LUVs. In a centrifugation assay, squalamine solubilizes phospholipid, but only at significantly higher squalamine/phospholipid ratios than required for either dye leakage or vesicle size reduction. Squalamine solubilizes PC at lower squalamine/phospholipid ratios than PG. We suggest that squalamine complexes with phospholipid to form a discrete structure within the bilayers of LUVs, resulting in the transient leakage of small encapsulated molecules. At higher squalamine/phospholipid ratios, these structures release from the bilayers and aggregate to form either new vesicles or squalamine/phospholipid mixed micelles.

Animals↗
PubMed1998

Re-evaluation of the role of the dopamine transporter in dopamine system homeostasis.

Mice with a genetic deletion of the dopamine transporter (DAT) were used to assess its role in the function of dopamine (DA) neurons. Profound alterations in the homeostasis of the nigrostriatal DA system were induced by the absence of the DAT. Extracellular levels of DA were elevated and clearance of released DA was 300-times slower than in control mice. This was accompanied by a 20-fold decrease in tissue DA levels and a paradoxical doubling of the rate of DA synthesis. A crucial role is indicated for the DAT in maintenance of DA neuron presynaptic function, particularly in the control of storage mechanisms.

Animals↗
PubMed1998

Cocaine self-administration in dopamine-transporter knockout mice.

The plasma membrane dopamine transporter (DAT) is responsible for clearing dopamine from the synapse. Cocaine blockade of DAT leads to increased extracellular dopamine, an effect widely considered to be the primary cause of the reinforcing and addictive properties of cocaine. In this study we tested whether these properties are limited to the dopaminergic system in mice lacking DAT. In the absence of DAT, these mice exhibit high levels of extracellular dopamine, but paradoxically still self-administer cocaine. Mapping of the sites of cocaine binding and neuronal activation suggests an involvement of serotonergic brain regions in this response. These results demonstrate that the interaction of cocaine with targets other than DAT, possibly the serotonin transporter, can initiate and sustain cocaine self-administration in these mice.

Animals↗
PubMed1998

Increased MPTP neurotoxicity in vesicular monoamine transporter 2 heterozygote knockout mice.

The neurotoxic action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been proposed to be attenuated by sequestration into intracellular vesicles by the vesicular monoamine transporter (VMAT2). The purpose of this study was to determine if mice with genetically reduced levels of VMAT2 (heterozygote knockout; VMAT2 +/-) were more vulnerable to MPTP. Striatal dopamine (DA) content, the levels of DA transporter (DAT) protein, and the expression of glial fibrillary acidic protein (GFAP) mRNA, a marker of gliosis, were assessed as markers of MPTP neurotoxicity. In all parameters measured VMAT2 +/- mice were more sensitive than their wild-type littermates (VMAT2 +/+). Administration of MPTP (7.5, 15, or 30 mg/kg, b.i.d.) resulted in dose-dependent reductions in striatal DA levels in both VMAT2 +/- and VMAT2 +/+ animals, but the neurotoxic potency of MPTP was approximately doubled in the VMAT2 +/- mice: 59 versus 23% DA loss 7 days after 7.5 mg/kg dose for VMAT2 +/- and VMAT2 +/+ mice, respectively. Dopaminergic nerve terminal integrity, as assessed by DAT protein expression, also revealed more drastic reductions in the VMAT2 +/- mice: 59 versus 35% loss at 7.5 mg/kg and 95 versus 58% loss at 15 mg/kg for VMAT2 +/- and VMAT2 +/+ mice, respectively. Expression of GFAP mRNA 2 days after MPTP was higher in the VMAT2 +/- mice than in the wild-type: 15.8- versus 7.8-fold increase at 7.5 mg/kg and 20.1- versus 9.6-fold at 15 mg/kg for VMAT2 +/- and VMAT2 +/+ mice, respectively. These observations clearly demonstrate that VMAT2 +/- mice are more susceptible to the neurotoxic effects of MPTP, suggesting that VMAT2-mediated sequestration of the neurotoxin into vesicles may play an important role in attenuating MPTP toxicity in vivo.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Effects of cold stress on survival and reproduction of Haematobia irritans (Diptera: Muscidae).

Adult horn fly, Haematobia irritans (L.), survival, mating success, and ovarian development were measured following exposure of pupae to 4 degrees C for 2, 3, and 4 wk, and were compared with an untreated control group held at 29 degrees C. Survival varied inversely with duration of low-temperature exposure, and ranged from 92.1% in the control to 7.0% following a 4-wk exposure. Mating success also varied inversely with duration of low-temperature exposure, and ovarian development was delayed, especially in the week 4 group. Reproductive and population parameters were measured in a 2nd cohort of horn flies following exposure of pupae to 1-4 wk at 4 degrees C, and in a control. Adult longevity varied inversely with duration of exposure. Mean longevity was greatest in the week 1 group at 17.6 d, followed by the control at 14.7 d. Week 4 flies lived an average of 2.2 d and produced no eggs. The preoviposition period was longest in the week 3 group at 7.3 d. In cohort 2, control and week 1 flies produced the highest number of eggs, eggs per female, and eggs per day compared with other groups. Eggs were produced over a mean of 6.8 d by week 3 flies compared with 25.4 d by week 1 flies. Reproductive rates varied inversely with low-temperature exposure duration, as did F1 generation egg hatch, larval development, and adult emergence. Survivorship and fecundity schedules are discussed with respect to the effects of low-temperature exposure duration. The effects of low-temperature exposure duration on horn fly reproduction and life-history patterns are discussed with respect to rearing, storage, and ecology.

Animals↗
PubMed1997

Movement in the normal visual hemifield induces a percept in the 'blind' hemifield of a human hemianope.

We have investigated visual responses to moving stimuli presented to the normal hemifield of a hemianope, GY, who exhibits residual visual function in his right, 'blind' hemifield. Preliminary experiments established that his perception of moving stimuli localized in his 'blind' hemifield is retained when a similar stimulus is presented simultaneously in the normal hemifield. In response to a grating stimulus moving horizontally towards fixation in the non-foveal region of the normal, left hemifield, he perceives in addition to a normal motion percept in the left hemifield, a sensation of movement localized in the right hemifield. Qualitatively, this latter is indistinguishable from responses elicited by direct stimulation localized within his 'blind' hemifield by moving stimuli. We have investigated the characteristics of the mechanisms which induce the 'blind' field component of GY's responses to stimulation of the normal hemifield. We show that GY's sensitivity for detection of movement localized within his 'blind' hemifield is dependent on the direction of movement, the contrast and the velocity of a grating presented to the normal hemifield. No induced effects were recorded in response to colour or to non-moving, flickering stimuli. We examine the possible contribution of scattered light to our observations, and eliminate this factor by consideration of our experimental results. We discuss the neural mechanisms which may be involved in this response.

Humans↗
PubMed1997

Knockout of the vesicular monoamine transporter 2 gene results in neonatal death and supersensitivity to cocaine and amphetamine.

Vesicular monoamine transporters are known to transport monoamines from the cytoplasm into secretory vesicles. We have used homologous recombination to generate mutant mice lacking the vesicular monoamine transporter 2 (VMAT2), the predominant form expressed in the brain. Newborn homozygotes die within a few days after birth, manifesting severely impaired monoamine storage and vesicular release. In heterozygous adult mice, extracellular striatal dopamine levels, as well as K+- and amphetamine-evoked dopamine release, are diminished. The observed changes in presynaptic homeostasis are accompanied by a pronounced supersensitivity of the mice to the locomotor effects of the dopamine agonist apomorphine, the psychostimulants cocaine and amphetamine, and ethanol. Importantly, VMAT2 heterozygous mice do not develop further sensitization to repeated cocaine administration. These observations stress the importance of VMAT2 in the maintenance of presynaptic function and suggest that these mice may provide an animal model for delineating the mechanisms of vesicular release, monoamine function, and postsynaptic sensitization associated with drug abuse.

Amphetamine↗
PubMed1997

Dopamine transporter is required for in vivo MPTP neurotoxicity: evidence from mice lacking the transporter.

The neurotoxic effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was tested on mice lacking the dopamine (DA) transporter (DAT-/- mice). Striatal tissue DA content and glial fibrillary acidic protein (GFAP) mRNA expression were assessed as markers of MPTP neurotoxicity. MPTP (30 mg/kg, s.c., b.i.d.) produced an 87% decrease in tissue DA levels and a 29-fold increase in the level of GFAP mRNA in the striatum of wild-type animals 48 h after administration. Conversely, there were no significant changes in either parameter in DAT-/- mice. Heterozygotes demonstrated partial sensitivity to MPTP administration as shown by an intermediate value (48%) of tissue DA loss. Direct intrastriatal infusion of the active metabolite of MPTP, 1-methyl-4-phenylpyridinium (MPP+; 10 mM), via a microdialysis probe produced a massive efflux of DA in wild-type mice (>320-fold). In the DAT-/- mice the same treatment produced a much smaller increase in extracellular DA (sixfold), which is likely secondary to tissue damage due to the implantation of the dialysis probe. These observations show that the DAT is a mandatory component for expression of MPTP toxicity in vivo.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

Importance of supercooling points in the overwintering of the horn fly and stable fly (Diptera:Muscidae).

Supercooling points were determined for eggs, 3rd instars, pupae, newly emerged unfed adults and 3-d-old engorged laboratory reared adults of Haematobia irritans (L.) and Stomoxys calcitrans (L.). Wild nondiapausing and diapausing pupae of H. irritans also were tested. Mean supercooling points ranged from -28.0 degrees C for H. irritans eggs to -6.8 degrees C for H. irritans larvae. Mean supercooling points of all H. irritans developmental stages were lower than those of comparable S. calcitrans developmental stages, with the exception of larvae where the reverse was true. The mean supercooling point of diapausing H. irritans pupae (-23.5 degrees C) was significantly lower than those of nondiapausing laboratory pupae (-20.8 degrees C) or nondiapausing wild pupae (-20.2 degrees C). Developmental stages of both species were freeze intolerant, with no survival following exposures to temperatures below the supercooling points. Results are discussed with respect to the disparate overwintering strategies of these species and in relation to typical climatic minima experienced in south central Texas. The cold tolerance of H. irritans and S. calcitrans pupae was compared at 4 degrees C, a temperature below their developmental threshold of 11.5 degrees C and above their mean supercooling points. The survival of H. irritans pupae was significantly greater than the survival of S. calcitrans pupae. Cold injury was a significant mortality factor for both species.

Animals↗
PubMed1997

Upper thermal limits for Hypoderma lineatum (Diptera: Oestridae) egg hatching and development.

During periods of Hypoderma lineatum (De Villers) oviposition activity, ambient temperatures reached 28 degrees C and dorsal bovine dermal temperatures exceeded 45 degrees C. Egg hatch decreased linearly with increased constant temperatures from 79% at 35 degrees C to 0% at 39 degrees C. Egg hatch varied from 58 to 80% after 1-, 3-, or 5-h exposures to 40 or 45 degrees C. Exposures of 3 h or more at 50 degrees C were lethal, whereas 66% of all eggs survived 1-h exposures to 50 degrees C. The upper thermal limit for survival at constant temperatures lies between 38 and 39 degrees C, with approximately 53% survival at 37 degrees C. H. lineatum eggs are well adapted to typical temperatures occurring in their natural habitat; however, these temperatures can at times exceed the eggs' upper developmental threshold. This limitation of the host environment may have led to the evolution of adult oviposition preferences for the lower parts of the host animal, shielded from incident solar radiation.

Animals↗
PubMed1997

In vitro infection of a cell line from Ictalurus nebulosus with Piscirickettsia salmonis.

Piscirickettsia salmonis, the etiologic agent of salmonid rickettsial septicemia (SRS), affects several species of salmonids. Previous reports using the appearance of cytopathic effect (CPE) as the criterion for susceptibility, showed that Piscirickettsia salmonis (ATCC strain) can be grown in vitro in some cells lines derived from salmonid fish, but not in BB cells from brown bullhead (Ictalurus nebulosus) and BF-2 cells from bluegill (Lepomis macrochirus). In this study we describe growth of P. salmonis (ATCC strain VR 1361) in a cell line previously believed to be nonpermissive for this organism. CPE was first detected in chinook salmon embryo (CHSE-214) and epithelioma papulosum ciprini (EPC) cell lines at 6 d postinfection (dpi). In contrast, using BB cell line, CPE was first detected 45 dpi and the monolayer completed CPE by 78 dpi. Electron microscopic examination of BB cells 78 dpi revealed free, intracytoplasmic and extracellular localization of the agent. P. salmonis was also observed within membrane-bounded vacuoles in BB cells, similar to that described in CHSE 214 cells. Contrary to earlier reports, results from the present study show that the BB cell line, is susceptible to Piscirickettsia salmonis infection. The delayed onset of CPE in BB cells in comparison to other permissive cell lines suggests that BB cells are not ideal hosts for P. salmonis. Interestingly, however, these results demonstrate that P. salmonis can infect non-salmonid cell lines, and raises the possibility that non-salmonid fish may play a role in the persistence and transmission of SRS in the natural environment.

Animals↗
PubMed1996

Expression of mRNA coding for the serotonin transporter in aged vs. young rat brain: differential effects of glucocorticoids.

Serotonin transporter mRNA expression in midbrain of young and aged rats was measured after long-term infusion of dexamethasone (0.01 and 0.05 mg/kg/day). Aging alone had no effect. Dexamethasone significantly decreased expression in both young and old rats but the effect was greater in the aged group. Adrenocortical dysregulation is common in elderly depression; our results suggest that glucocorticoids interact with aging to exacerbate abnormalities of serotonergic function, contributing to reduced antidepressant effectiveness.

Animals↗
PubMed1996

Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter.

Disruption of the mouse dopamine transporter gene results in spontaneous hyperlocomotion despite major adaptive changes, such as decreases in neurotransmitter and receptor levels. In homozygote mice, dopamine persists at least 100 times longer in the extracellular space, explaining the biochemical basis of the hyperdopaminergic phenotype and demonstrating the critical role of the transporter in regulating neurotransmission. The dopamine transporter is an obligatory target of cocaine and amphetamine, as these psychostimulants have no effect on locomotor activity or dopamine release and uptake in mice lacking the transporter.

Amphetamine↗
PubMed1996

Functional and anatomical evidence for different dopamine dynamics in the core and shell of the nucleus accumbens in slices of rat brain.

The characteristics of dopamine (DA) uptake and release were compared in the core and shell of the nucleus accumbens (NAc). DA release was elicited from rat brain slices by local electrical stimulation, and its extracellular concentration was monitored with fast-scan cyclic voltammetry using Nafion-coated, carbon-fiber microelectrodes. The voltammetric results show that the values of DA release and uptake in the shell NAc are approximately one-third of those measured in the core region, and DA uptake in the shell was less sensitive than the core to inhibition by either cocaine or nomifensine. The density of [3H]mazindol binding sites in the NAc was examined by autoradiography and the shell was found to have an average of half the number of DA uptake sites measured in the core region. This combination of anatomical and functional results shows that DA neurotransmission in the shell NAc is distinct from that in the core region. These data are consistent with the view that multiple functional forms of the DA transporter, exhibiting disparate kinetics and pharmacology, exist in different brain regions that exhibit disparate kinetics and pharmacology. Different forms of the transporter, combined with different release kinetics and auto- and heteroreceptor activity, give a vast range of possibilities for regional variation in DA neurotransmission.

Animals↗
PubMed1996

Effects of intermittent and continuous cocaine administration on dopamine release and uptake regulation in the striatum: in vitro voltammetric assessment.

Chronic daily injections of cocaine induce behavioral sensitization to subsequent cocaine challenge, while continuous infusion induces tolerance. Following a 7-day withdrawal period, we examined the effects of these two dosing regimens on: (1) baseline dopamine efflux and uptake following single-pulse electrical stimulation, (2) inhibition of uptake by cocaine; and (3) inhibition of efflux by autoreceptor activation. Cocaine (40 mg/kg per day) was administered to rats for 14 days either continuously by osmotic minipumps or intermittently by once-a-day injections. Minipumps containing saline were implanted in the control group. After 7 days of withdrawal, dopamine kinetics in the caudate was examined using in vitro fast-scan cyclic voltammetry. This technique provides very rapid measurements of dopamine in the extracellular space. Thus, when combined with endogenous dopamine efflux evoked by single-pulse, electrical stimulations, it was possible directly to measure the release and uptake components of the efflux. In the absence of pharmacological agents, no group differences were found in the amount of baseline dopamine released or in the uptake kinetics; the potency of bath-applied cocaine (0.03-60 microM) in inhibiting the uptake was also unaltered in either group. In contrast, the potency of quinpirole (an autoreceptor agonist, 5-250 nM) was significantly decreased and increased in the cocaine injection and pump groups, respectively. Thus, the cocaine administration regimen which produces sensitization results in a functional subsensitivity of release-modulating autoreceptors, while the tolerance-producing regimen results in autoreceptor supersensitivity.

Animals↗
PubMed1996

The synthesis and characterization of analogs of the antimicrobial compound squalamine: 6 beta-hydroxy-3-aminosterols synthesized from hyodeoxycholic acid.

Analogs of the aminosterol antimicrobial agent squalamine have been synthesized beginning from hyodeoxycholic acid. After carboxylic acid esterification and oxidation of both alcohol functions to ketones, the A/B ring junction was converted from cis to trans by acid-catalyzed isomerization. Different polyamines were added to the 3-keto group by reductive amination, yielding both the 3 alpha and 3 beta addition products. The synthetic products exhibited potent, broad-spectrum antimicrobial activity similar to that of the parent compound. Changing the identity of the polyamine or the stereochemistry of addition has little effect upon antimicrobial activity but appears to change the selectivity of the agents. The analogs are synthesized with high yield from inexpensive starting materials and are promising alternatives to squalamine as potential antibiotics.

Anti-Bacterial Agents↗