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Lockwood and Davis (1996) present a concise description of magnetopause reconnection pulses, with the claimed support of three types of observations: (1) flux transfer events (FTE), (2) poleward-moving auroral forms on the dayside, and (3) steps in cusp ion dispersion characteristics. However, there are a number of errors and misconceptions in the paper that make their conclusions untenable. They do not properly take account of the fact that the relevant processes operate in the presence of a plasma. They fail to notice that the source of energy (a dynamo with E < J<0) must be close to the region of dissipation (the electrical load with E < J0) in transient phenomena, since energy (or information) cannot travel faster than the group velocity of waves in the medium (here the Alfvén velocity VA). In short, Lockwood and Davis use the wrong contour in their attempt to evaluate the electromotive force (emf). This criticism goes beyond their article: a dynamo is not included in the usual definition of reconnection, only the reconnection load. Without an explicit source of energy in the assumed model, the idea of magnetic reconnection is improperly posed. Recent research has carried out a superposed epoch analysis of conditions near the dayside magnetopause and has found the dynamo and the load, both within the magnetopause current sheet. Since the magnetopause current is from dawn to dusk, the sign of E c J reflects the sign of the electric field. The electric field reverses, within the magnetopause; this can be discovered by an application of Lenz’s law using the concept of erosion of the magnetopause. The net result is plasma transfer across the magnetopause to feed the low latitude boundary layer, at least partly on closed field lines, and viscous interaction as the mechanism by which solar wind plasma couples to the magnetosphere. more...

Hemodynamical changes in coarctation were studied with an experimental model. Coarctation of the thoracic aorta was induced in seven puppies at the age of 8 wk. After a 7-month follow-up period a corrective operation with a venous patch was performed. Two dogs were lost a few hours after the correction operation. The remaining five dogs were followed for 12 months postoperatively. Renal perfusion was measured with a 133Xenon washout method just prior to the operation, 1 h, 6 and 12 months postoperatively. The glomerular filtration rate was measured using the slCr-EDTA method 1 wk before the operation, 3 wk, 2, 6, and 12 months after it. Six healthy adult dogs were used as controls for glomerular filtration rate measurements. Peripheral renin activity was measured at operation, just before the correction of aortic coarctation, Vi, 1 h, 1, 3, 7 days, 2 and 6 months after the correction operation. Renal perfusion decreased significantly (p < 0.05) immediately after the correction operation and rose again during the follow-up. Peripheral renin activity rose significantly (p < 0.01) from the preoperative values and was at its greatest 1 day after the operation. Later on, peripheral renin activity values returned to normal. Coarctated dogs had significantly (p < 0.01) lower glomerular filtration rate values than controls in each measurement except at the 2 months postoperative measurement. These results support decreased renal perfusion with resultant increased peripheral renin activity as part of the pathomechanism of the paradoxical hypertension observed after correction of coarctation. more...

Two ideas were advanced for the process of solar wind-magnetospheric interaction in the same year 1961. Dungey suggested that the interplanetary magnetic field (IMF), although weak, might determine the nature of this process by magnetic reconnection as the solar wind plasma flows across the separatrix surface which divides the IMF from the geomagnetic field. Axford and Hines pointed out that the flow inside the magnetopause is in the same sense as the magnetosheath flow and appears to be viscously coupled. Within a few years the dependence of geomagnetic activity on the IMF predicted by Dungey's mechanism was observed, and reconnection began to dominate current theories. One difficulty, that of the implied dissipation at the magnetopause, was troublesome; however, the ISEE-1/2 observations of the predicted high speed flows on several occasions was enough to convince many persons that reconnection ideas were basically correct. Several investigators found some evidence in the ISEE-3 data in the distant magnetotail for the steady-state reconnection line, as demanded by the Dungey model, in the form of a southward sense of the magnetic field through the current sheet. Here, again, there is some hard contrary evidence when the data are analyzed exactly at the cross-tail current sheet: the instantaneous values show a northward sense, even at high values of auroral activity. Coupled with the anti-Sunward plasma flow, this repudiates the steady-state Dungey model. On the other hand, it lends strong support to some kind of viscous effect through the medium of the magnetospheric boundary layer. This is not a semantic problem, as the sense of the electric field (as well as the magnetic field) is opposite for the two cases. The downfall of the reconnection model is its implicit use of frozen-field convection; this problem is obvious when the problem is viewed in three dimensions. Instead, the view is taken that the relevant process must be essentially time-dependent, three-dimensional, and localized. It is proposed that the term merging be used for this generalized timedependent form of reconnection. The merging process (whatever it is) must permit solar wind plasma to cross the magnetopause onto closed field lines of the boundary layer. Once it is there, it provides the viscous-like effect that Axford and Hines had envisaged. more...

The Bryggen Papers. Main Series, vol. 1. Oslo, (1985). ISBN 82-00-07289-4. 280 pp.Saari, Heikki: Re-enactment: A Study in R. G. Collingwood's Philosophy of History. (Acta Academia Aboensis. Ser. A, vol. 63,2. 1984). 141 pp.Suomen taloushistoria 3. Historiallinen tilas to (The economic history of Finland 3. Historical statistics). Ed. by Kaarina Vattula. Helsinki, (1983). ISBN 951-30-5089-0. 470 pp.Paasivirta, Juhani, Suomi ja Eurooppa 1914-1939 (Finland and Europe 1914-1939). Helsinki, (1984). ISBN 951-26-2588-1. 548 pp. more...

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a potent dopaminergic neurotoxin that causes biochemical, pharmacological, and pathological deficits in experimental animals similar to those seen in human parkinsonian patients. All of the deficits can be prevented by treating mice with selective inhibitors of monoamine oxidase B (MAO-B), including deprenyl, prior to MPTP administration. We now report that the dopaminergic neurotoxicity of two potent MPTP analogs, namely the 2'-methyl and 2'-ethyl derivatives (2'-MeMPTP and 2'-EtMPTP), cannot be prevented by deprenyl pretreatment. However, the neurotoxicity of these two analogs can be prevented by pretreatment with a combination of deprenyl and the selective MAO-A inhibitor clorgyline at doses that are sufficient to almost completely inhibit both MAO-B and MAO-A activities. Moreover, the neurotoxicity of 2'-EtMPTP (but not of 2'-MeMPTP and MPTP) can be significantly attenuated by clorgyline alone. There was a parallel between the capacity of the MAO inhibitors to decrease the brain content of the pyridinium species after administration of the tetrahydropyridines and the capacity of the MAO inhibitors to protect against the neurotoxic action of the tetrahydropyridines. The data support the conclusion that both 2'-MeMPTP and 2'-EtMPTP are bioactivated to pyridinium species to a significant extent by MAO-A. Further, it appears that the formation of the pyridinium species plays an important role in the neurotoxic process. more...

In this study, we have examined whether members of the small heat shock protein family, hsp30, were capable of forming heat-induced aggregates in Xenopus laevisA6 kidney epithelial cells. Rate-zonal centrifugation coupled with immunoblot analysis demonstrated the presence of hsp30 aggregates with an estimated sedimentation coefficient of 10-16S. Also, pore exclusion limit electrophoretic analysis of labeled protein from heat-shocked A6 cells revealed four heat-induced aggregates, including a prominent 510 kDa aggregate, as well as weaker 350, 290, and 240 kDa aggregates. Immunoblot analysis of the aggregates employing an hsp30C antibody suggested that the 510 and 350 kDa aggregates were comprised of hsp30 protein. One- and two-dimensional SDS–PAGE analysis of the proteins isolated from the 510 kDa region of the pore exclusion limit electrophoretic gel confirmed the presence of 30 kDa heat-induced protein. A total of eight small hsps were present in this aggregate, suggesting that virtually all of the major small hsps in XenopusA6 cells were involved in aggregate formation. This study also detected the presence of heat-inducible hsp70 in the 510 kDa gel fraction containing the small hsps, but it could not be determined whether it was part of the multimer complex. more...

In rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal system we compared the behavioral effects of pergolide with those of L-dopa, bromocriptine, and lergotrile. In this animal model of parkinsonism, doses of 0.25 mg per kilogram pergolide (free base) induced vigorous circling for 24 hours. Pergolide was more potent than bromocriptine or lergotrile. Pretreatment with alpha-methylparatyrosine nearly abolished the effects of bromocriptine, markedly diminished the effects of lergotrile, and only partially diminished the effects of pergolide. These findings suggest that pergolide should be more effective than bromocriptine in the treatment of parkinsonism. more...

Fifty-one infants with limited abduction of the hip and acetabular dysplasia were, between 1969 and 1975, treated with abduction-adduction exercises, administered by the parents; no abduction devices were used. In 1983 a follow-up examination was carried out on 41 of these patients. Although at birth these children had characteristics similar to patients with congenital dislocation of the hip, none of their hips dislocated. At birth acetabular measurements showed that half the children had severe dysplasia and the other half slight dysplasia; the difference between the affected and the healthy hips was significant. At follow-up the gait was normal in all the patients. Movements at the hips were symmetrical and within normal limits in all but one patient. The acetabular angle, the centre-edge angle, the shaft-neck angle, the hip ratio, and the size of the femoral head were the same on the previously affected side as on the normal side. Nineteen of the children followed up had preferred lying on one side and dysplasia of the upper hip had developed. The significance of the sleeping position on the development of acetabular dysplasia is discussed. more...

Five common misconceptions are discussed relative to the disabled learner and higher education.

We have isolated a full-length cDNA clone encoding a Xenopus laevisimmunoglobulin binding protein (BiP; also called glucose-regulated protein or grp78). The BiP cDNA sequence includes an open reading frame of 1,965 bp encoding a 655 amino acid protein with an N-terminal hydrophobic leader sequence and a C-terminal KDEL tetrapeptide which has been found in other lumenal proteins of the endoplasmic reticulum. The 3′untranslated region contains a polyadenylation and an adenylation control element (ACE) as well as a putative mRNA instability sequence. The XenopusBiP amino acid sequence displayed high identity with BiP from other vertebrates including chicken (91.3%), rat (90.7%), and human (89.9%). Northern hybridization analysis demonstrated that BiP mRNA was present constitutively in the XenopusA6 kidney epithelial cell line and that BiP mRNA levels could be enhanced by treatment of the cells with galactose-free media, 2-deoxyglucose, 2-deoxygalactose, glucosamine, tunicamycin, heat shock, dithiothreitol, and the calcium ionophore, A23187. Finally, while BiP mRNA was detected in all of the adult tissues examined, the relative level of BiP mRNA differed dramatically between organs. For example, relatively high levels of BiP mRNA were detected in liver with moderate levels in testis, ovary and heart and reduced levels in eye and muscle tissue. more...

Hydrogen peroxide, superoxide radical, and hydroxyl radical were all formed during the autoxidation of four cytotoxic agents, namely, 6-hydroxydopamine, 6-aminodopamine, 6,7-dihydroxytryptamine, and dialuric acid. Ascorbic acid and 5-hydroxydopamine, two autoxidizable agents of biological interest but without similar cytotoxic actions, were used as negative controls. The results tend to implicate O2-and ·OH, as well as H2O2, in the molecular mechanisms for cytotoxicity. more...

The 24-hour rest-activity pattern and the amount of motor activity was studied in a patient with fatal familial insomnia (FFI) by means of wrist actigraphy. During the study, the patient underwent indirect calorimetry. The 52-day recording showed severe disruption of the 24-hour rest-activity pattern with increased motor activity up to 80%. The 24-hour energy expenditure, assayed in a respiration chamber, was strikingly elevated by 60%. Chronic motor overactivity and loss of circadian rest-activity rhythm may play a role in the progressive metabolic exhaustion leading to death in FFI patients. more...

We investigated the prevalence of sleepwalking using a well defined population previously used for epidemiologic investigations:the Finnish Twin Cohort. The study population consisted of 11,220 subjects aged 33 to 60 years, and it included 1,045 monozygotic and 1,899 dizygotic twin pairs. Questions on the frequency of sleepwalking were asked separately for occurrence in childhood and adulthood. Childhood sleepwalking was significantly more frequent in women ("often" in 2.8% of women and 2.0% of men and "sometimes" in 6.9% of women and 5.7% of men). As adults, sleepwalking had occurred in 3.9% of men and in 3.1% of women, and it was reported "weekly" in 0.4% for both genders. There was no significant difference in frequency between monozygotic and dizygotic twin individuals, either in childhood or adulthood. For sleepwalking in childhood the probandwise concordance rate was 0.55 for monozygotic and 0.35 for dizygotic pairs, and for adults, 0.32 for monozygotic, and 0.06 for dizygotic pairs. Those who reported never having walked in their sleep in childhood did so as adults rarely (0.6%), both men and women. Those who reported walking in their sleep often or sometimes in childhood did so as adults for 24.6% of men and for 18.3% of women. Of adult men sleepwalkers 88.9% had a positive history of sleepwalking in childhood, and in women, 84.5%. The proportion of total phenotypic variance attributed to genetic influences was 66% in men and 57% in women in childhood sleepwalking, and 80% in men and 36% in women in adult sleepwalking. Our results show that there are substantial genetic effects in sleepwalking in both childhood and adulthood. more...

Several analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were synthesized and compared to MPTP for their ability to be oxidized by monoamine oxidase (MAO) and for their ability to cause nigrostriatal dopaminergic neurotoxicity in mice. Most of the compounds were oxidized by mouse brain MAO, either predominantly by the B-form or by both the A- and B-forms. The MAO-catalyzed oxidation of all of the MAO substrates resulted in the formation of dihydropyridinium intermediates which, in turn, except for the dihydropyridinium of 1-methyl-4-benzyl-1,2,3,6-tetrahydropyridine, formed pyridinium species as the final oxidation product. Nine analogs were found to be neurotoxic; all were oxidized by MAO to pyridinium compounds. However, some non-neurotoxic MPTP analogs were also oxidized by MAO. Neither 1-methyl-4-benzyl-1,2,3,6-tetrahydropyridine nor the compounds which were not substrates for MAO were neurotoxic. Also, the neurotoxicity of all of the compounds tested was blocked by inhibiting either MAO-B, MAO-A or both MAO-B and MAO-A together, indicating that MAO activity was necessary for the neurotoxicity of the compounds to be manifested. The capacity of an MPTP analog to be oxidized by MAO to a pyridinium appears to be a necessary, but not sufficient, parameter in determining the neurotoxic potential of the compound. more...

In the accompanying paper, several tetrahydropyridine analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were screened for their abilities to be oxidized by monoamine oxidase (MAO) to pyridiniums and to produce neurotoxicity in mice. We reported that most of the analogs were oxidized by MAO to pyridiniums and some of the analogs were neurotoxic. We concluded that the capacity of a tetrahydropyridine MPTP analog to be oxidized by MAO to a pyridinium was a necessary, but not sufficient, condition for the compound to be a neurotoxin. In the present paper we attempt to explain further the neurotoxicity or lack of neurotoxicity of these analogs by evaluating the abilities of the pyridinium compounds to serve as substrates for the neostriatal dopamine (DA) transport system and as inhibitors of mitochondrial respiration. We now report that all of the neurotoxic MPTP analogs are oxidized to pyridiniums that are good substrates for the neostriatal DA carrier and good inhibitors of mitochondrial respiration. The results are consistent with an important role for both uptake of the pyridiniums by the DA carrier and inhibition by the pyridiniums of mitochondrial respiration in the neurotoxicity induced by MPTP and its analogs. more...

OBJECTIVE: The outcome of patients with acute myocardial infarction who received thrombolytic therapy was assessed in relation to the size and comprehensiveness of cardiovascular services in the admitting hospitals. METHODS: Two characteristics were obtained for each of the 438 hospitals: number of beds and in-house availability of cardiovascular services (coronary catheterization laboratory and coronary angioplasty or bypass surgery). Hospitals were grouped into four categories on the basis of size (≤300 vs >300 beds) and availability of cardiovascular services. Baseline and outcome variables were compared by χ2 analysis and logistic regression. Patients were followed up for 6 months. RESULTS: Baseline variables were comparable among hospital categories except for significant differences in the distribution of antecedent angina and time to treatment. Significantly more coronary angioplasties and bypass surgeries were performed in patients first treated in hospitals with coronary revascularization services (4.1% and 4.2% vs 1.0% and 1.9%, P&lt;.0001). Rates of strokes (1.9% vs 1.3% and 1.6%, P=.54 hospital mortality (11.9% vs 8.5%, (P=.11), and 6-month mortality (17.0% vs 11.8% and 12.3%, P=.03) were highest among patients treated in small hospitals that had coronary revascularization facilities. The rate of invasive procedures was higher in the smaller hospitals (odds ratio [OR], 1.44; 95% confidence limits [CL], 1.11 and 1.87; P=.006) and in hospitals with coronary revascularization services (OR, 4.05; 95% CL, 3.14 and 5.22; P&lt;.0001); hemorrhage was more frequent in centers with coronary revascularization facilities (OR, 1.39; 95% CL, 1.13 and 1.71; P=.002). Rates of hospital mortality and 6-month mortality were similar. CONCLUSIONS: Patients with acute myocardial infarction treated with thrombolytic therapy have the same mortality in small centers without in-house coronary revascularization services as in larger centers with such services.(Arch Intern Med. 1994;154:2237-2242) more...

SH-SY5Y human neuroblastoma cells can be induced to differentiate by phorbol esters but not by bryostatins although both agents increase protein kinase C (PKC) activity in these cells to a similar extent. We examined whether this difference could be explained by differences in the responses of specific PKC isoenzymes. Both TPA and bryostatin 1 at 10 nM induced a rapid increase in membrane-associated PKC-α immunoreactivity which was sustained for 72 hours in TPA-treated cells, but was down-regulated within 24 hours in bryostatin-treated cells. TDA likewise induced a sustained phosphorylation of an 80 kDa PKC substrate whereas in bryostatin-treated cells the 80 kDa substrate was rapidly phosphorylated reaching a maximum at 6 hours followed by a decline to basal level within 48 hours. A higher concentration of TPA (300 nM), which results in a less differentiated phenotype, induced down-regulation of PKC-α within 24 hours. In contrast, both TPA and bryostatin 1 stimulated translocation and a partial down-regulation of PKC-ε with similar kinetics. These results suggest that the divergent actions of bryostatin I and TPA in SH-SY5Y cells are at least partially due to differential modulation of PKC-α but not PKC-ε by these two agents.Copyright 1993, 1999 Academic Press more...

Elevation of the incubation temperature of Chinook salmon embryo cells from 20 to 24 degrees C or exposure to heavy metals such as CdCl2 (5 microM) or ZnCl2 (100 to 500 microM) induces the reversible expression of a set of heat shock or stress proteins. Continuous exposure of the cells to either metal ions or heat shock results in recovery of protein synthesis to a control-like pattern. Treatment of these cells with either ZnCl2 or CdCl2 also induces the protein metallothionein. Heat shock, however, does not induce metallothionein, suggesting that it does not belong to the common group of heat shock or stress proteins. The induction of these stress proteins can be inhibited by pretreatment with actinomycin D, suggesting that their expression is regulated at the transcriptional level. The major stress proteins are detectable in the products of an in vitro translation system programmed with RNA isolated from heat shock- or metal ion-treated cells. A recombinant DNA probe complementary to Drosophila mRNA coding for the 70,000-dalton heat shock protein was found to hybridize to RNA isolated from heat shock-or metal ion-treated cells but not from control cells. The fish mRNA coding for the heat shock protein with a molecular weight of 70,000 appears to be of similar size to the corresponding Drosophila mRNA. more...

We have examined the activity of the Xenopus heat-shock transcription factor (HSF) in extracts from stressed and unstressed embryos at various stages of development using DNA mobility shift analysis. A specific interaction between HSF and a synthetic oligonucleotide corresponding to the proximal heat-shock element (HSE) of the Xenopus HSP70B gene was greatly enhanced in heat-shocked embryos compared to controls. HSF binding was inducible at all developmental stages examined including pre-midblastula transition (MBT) stages which are incapable of expressing HSP genes. In time-course experiments with both cleavage and neurula stage embryos, the activation of HSF binding was rapid and transient. Removal of cleavage and neurula stage embryos from heat stress resulted in a rapid loss of binding activity. The molecular mass of HSF, as determined by comparative gel electrophoresis of photoaffinity-labeled factor was 88X103 in both heat-shocked cleavage and neurula stage embryos. These experiments suggest that maternally derived HSF is stored in pre-MBT embryos in a heat-activatable form and may function in the regulation of heat-shock genes immediately after the MBT. more...

This paper outlines a method for assessing experts' evaluation of how municipal revenues and expenditures are allocated across land use categories. The method includes selection of experts, the nature of their interactions, and the process by which their diverse opinions may be meaningfully aggregated. This method is implemented for the City of Vancouver, using two distinct groups of experts. The results from these two groups' efforts are strikingly similar, suggesting that vacant and commercial land uses are net fiscal contributors, while residential and industrial uses do not on average contribute revenues that cover the cost of services rendered by the municipality. more...

In the present study we observed pronounced differences in the capacity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce dopaminergic neurotoxicity in several strains of mice. For example, there was no MPTP-induced decrement in neostriatal dopamine content in Ace Swiss-Webster mice and a 92% decrement in Taconic Farms C57 bl mice. Several parameters which could possibly explain this differential sensitivity to MPTP were studied. These include: 1) neostriatal monoamine oxidase-B (MAO-B) activity; 2) the capacity of neostriatal synaptosomes prepared from the mouse strains to accumulate 1-methyl-4-phenylpyridinium (MPP+), the major metabolite of MPTP formed via oxidation by MAO-B; and 3) the neostriatal MPP+ content after MPTP administration to the mice. There were no significant differences in the Km values for MAO-B in the neostriatum among the strains of mice examined. Neostriatal Vmax values for MAO-B differed somewhat among the strains, with a low of 2915 +/- 172 nmol/g of tissue per hr (CD-1 mice from Charles River) and a high of 3884 +/- 203 nmol/g of tissue per hr (C57 bl mice from Taconic Farms). However, Vmax values for MAO-B in the mouse strains did not correlate significantly with the relative sensitivity of the strains to MPTP. There were no significant differences in the capacity of neostriatal synaptosomes prepared from the mouse strains to accumulate MPP+. Studies on the metabolism of MPTP after peripheral administration revealed that there was a significant (P less than .01) positive correlation between the relative sensitivity of the mouse strains to MPTP and their neostriatal MPP+ content after MPTP administration.(ABSTRACT TRUNCATED AT 250 WORDS) more...

The administration of methamphetamine (METH) to experimental animals results in damage to nigrostriatal dopaminergic neurons. We have demonstrated previously that the excitatory amino acids may be involved in this neurotoxicity. For example, several compounds which bind to the phenyclidine site within the ion channel linked to the N-methyl-D-aspartate (NMDA) receptor protected mice from the METH-induced loss of neostriatal tyrosine hydroxylase activity and dopamine content. The present study was conducted to characterize further the role of the excitatory amino acids in mediating the neurotoxic effects of METH. The administration of three or four injections of METH (10 mg/kg) every 2 hr to mice produced large decrements in neostriatal dopamine content (80-84%) and in tyrosine hydroxylase activity (65-74%). A dose-dependent protection against these METH-induced decreases was seen with two noncompetitive NMDA antagonists, ifenprodil and SL 82.0715 (25-50 mg/kg/injection), both of which are thought to bind to a polyamine or sigma site associated with the NMDA receptor complex, and with two competitive NMDA antagonists, CGS 19755 (25-50 mg/kg/injection) and NPC 12626 (150-300 mg/kg/injection). Moreover, an intrastriatal infusion of NMDA (0.1 mumol) produced a slight but significant loss of neostriatal dopamine which was potentiated in mice that also received a systemic injection of METH. The results of these studies strengthen the hypothesis that the excitatory amino acids play a critical role in the nigrostriatal dopaminergic damage induced by METH. more...

In previous studies it was shown that the pyridinium species formed by the monoamine-oxidase-catalyzed conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-(2'methylphenyl)-1,2,3,6-tetrahydropyridine (2'Me-MPTP) inhibited mitochondrial electron transport at Complex I. In addition, these substances, when incubated with mouse neostriatal slices, caused an increased lactate accumulation. However, it was not clear whether this inhibition could occur within dopamine nerve terminals. In the present study we investigated if dopamine uptake blockers, shown previously to protect against tetrahydropyridine-induced dopaminergic neurotoxicity, would attenuate MPTP- and 2'Me-MPTP-promoted lactate formation in neostriatal slices. 2'Me-MPTP-induced lactate accumulation in neostriatal slices from mice or rats with a lesion of the nigrostriatal pathway was also studied. The dopamine uptake blocker, Win 35,428 [8-azabicyclo[3.2.1]octane-2-carboxylic acid, 3-(4-fluorophenyl)-8-methyl-, methylester [1R-(exo, exol)]), attenuated the increased lactate formation caused by MPTP and 2'Me-MPTP. At low concentrations of 2'Me-MPTP (5 microM), the increased lactate production was inhibited completely by Win 35,428. These latter data suggest that at low concentrations of 2'Me-MPTP, the increased lactate accumulation was associated primarily with dopaminergic nerve terminals. Two other dopamine uptake inhibitors, McN 5908 [trans-4-(1,2,3,5,6,10b-hexahydropyrrolo[2,1-alpha]isoquinolin+ ++-6-yl) benzenamine hydrobromide methanolate (4:4:1)] and mazindol [5-(4-chlorophenyl)-2,5-dihydro-3H-imidazo- [2,1-alpha]isoindol-5-ol], also attenuated tetrahydropyridine-induced lactate formation. At concentrations selective for their respective uptake systems, norepinephrine- and serotonin-uptake inhibitors did not attenuate 2'Me-MPTP-induced lactate accumulation.(ABSTRACT TRUNCATED AT 250 WORDS) more...

1-Phenyl-3-(2-thiazolyl)-2-thiourea (PTTU) administered i.p. to mice prevented the neurodegenerative actions of subsequently injected (1 hour later) 6-hydroxydopamine (6-OHDA) or 6-aminodopamine on peripheral adrenergic nerve terminals. Destruction of nerve terminals was studied in vitro in the left atrium by measuring the accumulation of 3H-norepinephrine (3H-HE), and in the iris by both 3H-NE accumulation and fluorescence microscopy methods. Strong protection was observed at 4, 24 and 72 hours after 6-OHDA. The degree of protection was dose-dependent and showed step-wise decrements for concentrations of PTTU below 200 mg/kg (viz., 100, 50 and 20 mg/kg) or concentrations of 6-OHDA-HBr above 7.5 mg/kg (viz., 10, 20 and 50 mg/kg). Protection also fell off at time intervals greater than 1 hour after administration of PTTU (viz., 3 and 5 hours). The appearance (fluorescence microscopy) of the nerve plexus of fully protected mice and the remaining plexus in partially protected mice was essentially normal at 24 hours, except for infrequent large swellings. PTTU proved to be a very effective scavenger of hydroxyl radicals; the formation and scavenging of these radicals was studied by gas chromatography in a system in which the hydroxyl radicals (which were generated during the autoxidation of 6-aminodopamine) gave rise to ethylene, a hydrocarbon gas. Other hydroxyl radical scavengers, namely diethyldithiocarbamate and methimazole, exhibited a protective action on sympathetic nerves in the left atrium; PTTU, diethyldithiocarbamate and methimazole are also recognized as copper chelating compounds. Ethanol, n-butanol and cysteamine, which are well known hydroxyl radical scavengers, also exhibited some degree of protection against 6-OHDA. Blockade of transport of 6-OHDA into sympathetic nerves was ruled out as a protective mechanism by the observation that none of the protective compounds inhibited the accumulation of tritium by the left atrium when 3H-NE was injected in place of 6-OHDA. The mechanism of action for these protective agents has not been definitively established, but scavenging of cytotoxic hydroxyl radicals within neurons may play a significant role. more...

Mazindol and two homologs of mazindol were tested for their effects as uptake inhibitors in rat tissue slices for [3H]dopamine in the neostriatum, for [3H]norepinephrine in occipital cortex and for [3H]serotonin in whole brain. All three drugs were potent inhibitors of [3H]dopamine uptake (ED50 values between 57 and 280 nM), [3H]norepinephrine uptake (ED50 values less than 19 nM) and were somewhat weaker against [3H]serotonin uptake (ED50 values between 550 and 4100 nM). All three drugs were in contrast very weak as releasing agents for previously accumulated 3H-biogenic amines. Mazindol injection resulted in a large increase in locomotor activity in mice, but its two homologs were without effect. Mazindol was able to counteract amphetamine-induced increases in activity in reserpinized mice, but its homologs were inactive. Mazindol also caused a vigorous ipsilateral rotation in rats with an unilateral 6-hydroxydopamine lesion of the nigrostriatal system, but again the homologs had no such effect. However, all three drugs were potent inhibitors of prolactin secretion in rats (ID50 values 1-2 mg/kg orally). Correlations between the capacities of the drugs to inhibit 3H-biogenic amine uptake and the various in vivo responses are made. more...

Sundrehagen E, Benestad HB, Heikkila R, Hersleth IB, Siebke M, Strøm-Gundersen I. A new method for rapid technetium-99m labelling of leucocytes: functional cell studies in vitro. Scand J Clin Lab Invest 1985; 45: 717-724.The aim of this study was to assess the cytotoxicity of a new leucocyte-labelling method, which may be used clinically to localize inflammatory and immune reactions. Human blood leucocytes, their mononuclear sub-population, and mouse mononuclear bone marrow cells were labelled with 99mTc for 30-45 min, washed once, and then evaluated in various functional assays. The new procedure includes [99mTc]-labelling with a bisalt method, in the presence of dihydroxybenzoic acid as an intermediate antioxidant-complexing stabilizer, and a carboxylic acid salt of stannous ions as a reducing agent. To challenge the method, cells were labelled about two orders of magnitude more heavily in these initial methodological studies than in on-going clinical trials. Labelled leucocytes ingested latex beads as readily as the controls, but migrated chemotactical-ly and randomly somewhat slower than the control cells. The lymphocytes were triggered by PHA and Con A in a normal way. However, lymphocytes and haemopoietic progenitor cells exposed to radiation for several days, were killed by the isotope doses used, of which about 2% (i.e. 20 MBq) were bound per million cells. All deleterious effects were apparently due to irradiation, and the labelling procedure itself did not damage the cells. more...

The structure of TiO2 hydrates is studied by X-ray diffraction, atomic force microscopy (AFM), and transmission electron microscopy (TEM). The samples prepared by NH4OH precipitation from an aqueous TiCl4 solution are amorphous or partially crystalline. They consist of a mixture of distorted anatase and brookite crystallites, each having a diameter of 20 nm. The sample prepared by thermal hydrolysis from a titanium oxide sulfate solution was totally crystalline, composed only of distorted anatase crystallites with a diameter of 15 nm. Primary particles can be oriented in chainlike structures. The crystallinity and the crystal shape reveal the sample history. The applicability of the AFM and TEM measurements for structural investigations of the powder specimens concerned is briefly discussed. more...

To examine the biochemical basis for growth factor-induced responses in human lung cancer cells, we used the quin2 technique to study the effect of the amphibian peptide bombesin and its congeners including mammalian gastrin-releasing peptide (GRP) on the intracellular free calcium level [Ca2+]i in small cell lung cancer cell lines. In five of eleven cell lines tested, Tyr4-bombesin or GRP elicited a rapid and transient increase in [Ca2+]i. The response was seen with as little as 1 nM ligand, was not affected by membrane depolarization, and derived in part from internal calcium stores. Desensitization to a second addition of active bombesin congeners occurs subsequent to initial addition of Tyr4-bombesin. Structure-activity analysis showed the carboxyl-terminal octapeptide was the active portion of the peptide. Analogs in which the carboxyl terminus was oxidized or deamidated were inactive. Ranatensin, litorin, alytesin, and GRP, but not physalaemin, were as active as Tyr4-bombesin. A monoclonal antibody to the carboxyl terminus of bombesin selectively blocked the increased [Ca2+]i elicited by Tyr4-bombesin. These studies suggest that bombesin congeners can act on some small cell lung cancer cell lines by a pathway utilizing increased [Ca2+]i. more...

Nineteen structural analogs of 1-methyl-4-phenylpyridinium (MPP+) were studied for their capacity to inhibit the mitochondrial oxidation of NAD+-linked substrates and the aerobic oxidation of NADH in inner membrane preparations from cardiac mitochondria. In the majority of cases, a good correlation was found between the two inhibition effects monitored. A few compounds were effective inhibitors of NADH oxidase but had only marginal effects on mitochondrial respiration. From studies of their accumulation by mitochondria, it appears likely that the latter compounds are not effectively concentrated by intact mitochondria by the electrical gradient and, in part for this reason, cannot reach sufficiently high concentrations at the appropriate binding site of NADH dehydrogenase. In addition, evidence is presented that the penetration of pyridinium analogs to the inhibition site in the NADH dehydrogenase complex may also be rate limiting. The data support the thesis that, for a substituted tetrahydropyridine to be acutely neurotoxic, its pyridinium oxidation product must be actively accumulated in the mitochondria and must inhibit NADH-ubiquinone oxidoreductase in its membrane environment. more...

We report the clinical spectrum of 3 patients with Parkinson's disease who experienced complex patterns of levodopa-related dystonia. Dystonia was unrelieved by multiple medication regimens but responded well to continuous, duodenal levodopa infusions. Patients were able to remain mobile without severe dystonia despite a very narrow window of benefit between the levodopa concentration necessary to achieve the “on” state and that which caused the onset of dystonic spasms. more...

Objective. To examine the prevalence, underlying diseases, abnormalities of left ventricular function and prognosis in congestive heart failure (CHF) of old age.
Design. A population-based clinical and echocardiographic study with a 4-year mortality follow-up.
Setting. University hospital.
Subjects. Five hundred and one individuals born in 1904, 1909 and 1914 (367 women).
Main outcome measures. Presence of CHF by clinical and chest radiograph criteria; left ventricular size and systolic function by echocardiography; grade of aortic and mitral valve lesions by Doppler echocardiography; 4-year total and cardiovascular mortality.
Results. Forty-one of 501 participants (8.2%) had CHF. Ischaemic heart disease (54%), hypertension (54%) and moderate-to-severe mitral or aortic valve disease (51%) were the main underlying conditions; 90% of patients had one or more of these diseases. Most individuals with CHF (28 of 39 patients, 72%) had normal left ventricular contractions at echocardiography. `Diastolic CHF', defined as CHF with normal systolic left ventricular function and no regurgitant valve disease, was found in 51% (20 of 39 patients). The relative 4-year risk for death associated with CHF, adjusted for age and sex, was 2.1 (95% confidence interval 1.3-3.4) for all-cause mortality and 4.2 (CI 1.9-5.6) for cardiovascular mortality.
Conclusions. The prevalence of CHF in a population aged 75-86 years is approximately 8%. Ischaemic or valvular heart disease and hypertension are the main underlying conditions. At echocardiography, about 50% of the elderly with CHF have normal left ventricular systolic contractions in the absence of valve disease and an additional 20% have normal systolic function with mitral regurgitation. The presence of CHF doubles the age- and sex-adjusted risk of death from all causes, and quadruples the risk of cardiovascular death during 4-year follow-up. more...

Objectives. To examine associations of N-terminal and C-terminal components of the proatrial natriuretic peptide [ANP (1-98) and ANP (99-126), respectively], with echocardiographic measurements of left ventricular structure and performance and with the function of the aortic and mitral valves in old age. To compare the predictive value of the atrial peptides and echocardiographic data for short-term mortality.
Design. A population-based survey with 1.5-year mortality follow-up.
Setting. University hospital.
Subjects. Three-hundred and thirty-three people aged 78-88 years.
Main outcome measures. (i) Plasma ANP (1-98) and ANP (99-126); (ii) M-mode and Doppler echocardiographic measurements of left atrial diameter; left ventricular diameters, mass and fractional shortening; peak transmitral velocities; aortic valve area, aortic regurgitation jet length and mitral regurgitant jet area; (iii) total and cardiovascular 1.5-year mortality.
Results. ANP (1-98) correlated with left atrial diameter (r=0.33; P&lt;0.001), left ventricular mass (r=0.19; P&lt;0.001), fractional shortening (r=-0.16; P&lt;0.01) and the early-to-atrial peak transmitral velocity ratio (r=0.23; P&lt;0.001). Also, ANP (1-98) predicted the degree of aortic valve obstruction and the severity of aortic and mitral regurgitation. Associations of ANP (99-126) with echocardiographic data were much weaker. Aortic valve stenosis and ANP (1-98) were independent predictors of age-and sex-adjusted total and cardiovascular mortality at 1.5 years of entry.
Conclusions. Circulating ANP (1-98) correlates with left atrial size, with left ventricular mass and performance and with the severity of aortic and mitral valve dysfunction in persons representing the general elderly population. ANP (1-98) also predicts both total and cardiovascular mortality. more...

Bombesin is an amphibian tetradecapeptide whose mammalian homologue, gastrin-releasing peptide (GRP), is produced by many small-cell lung-cancer (SCLC) cells, and which can function in an autocrine growth-promoting manner in SCLC. Studies reported here show that [Tyr4]bombesin and its congeners increase inositol 1,4,5-trisphosphate within seconds in NCI-H345, a SCLC cell line that constitutively produces GRP. After 30 min in the presence of 0.01 M-Li+ and [Tyr4]bombesin, there is marked accumulation of inositol monophosphates and inositol tetrakisphosphate. Pretreatment with phorbol 12-myristate 13-acetate (PMA) for 20 min inhibited the ability of [Tyr4]bombesin to induce phosphatidylinositol (PtdIns) turnover and to increase intracellular free Ca2+ ([Ca2+]i). Pretreatment with PMA for 48 h attenuated the ability of subsequently added PMA to decrease the response to [Tyr4]bombesin. Pretreatment with pertussis toxin (PT; 1 microgram/ml for 18-24 h) decreased by less than 30% [Tyr4]bombesin-induced increases in [Ca2+]i and PtdIns metabolites. However, interpretation of this result is complicated by the inability of PT to ADP-ribosylate completely its substrates in intact NCI-H345 cells. In contrast, pretreatment with cholera toxin (1 microgram/ml for 18-24 h) lowered basal [Ca2+]i and basal inositol phosphate concentrations, attenuated the response of NCI-H345 to subsequently added [Tyr4]bombesin, and was not mimicked by treatments that increase cellular cyclic AMP. These data demonstrate the activation of phospholipase C in SCLC by bombesin congeners. In addition, the results suggest a regulatory role for protein kinase C, a cholera-toxin substrate, and perhaps a pertussis-toxin substrate in the response of SCLC to bombesin. more...

We report a patient with Meige syndrome (segmental cranial dystonia) who had neuropathology changes of Parkinson's disease on postmortem examination. Neuropathologic examination showed typical and atypical Lewy bodies in the pigmented nuclei of the brainstem (substantia nigra, locus ceruleus), the nucleus basalis of Meynert, and the nucleus ambiguus. Neurochemical analysis of postmortem brain tissue showed evidence for decreased dopamine turnover in the substantia nigra, striatum, and nucleus accumbens. We propose that some cases of Meige syndrome may be included in the spectrum of Lewy body disease. more...

According to the classification scheme of Kebabian and Calne,2there are two types of dopamine (DA) receptors: D1(activation of which causes increased cyclic AMP formation) and D2(activation of which causes no increment in cyclic AMP). It is not clear what role the different receptors play in mediating motor behavior. Using drugs that act selectively at only one receptor site, we studied the effects of D1and D2receptor activation in two different models of parkinsonism—the rotating rat and the reserpinized mouse. Neither the D1agonist nor the D2agonist, given alone, could overcome reserpine akinesia, but together they restored locomotor activity. In rats with unilateral nigrostriatal lesions, both drugs induced a rotational response, each with a distinct temporal pattern. Pretreatment with alpha-methyl-paratyrosine (an inhibitor of DA synthesis) led to decrements in the rotational response induced by D2agonists, but not that induced by D1agonists. The mechanism by which these DA agonists induce motor activity is different; activation of both types of DA receptors seems to be necessary for normal motor behavior. more...

Can brain metabolize ethanol? We present data demonstrating that brain catalase in conjunction with endogenous H2O2will oxidize ethanol in vivo. The method is based on an H2O2‐dependent inhibition of brain catalase in vivo by 3‐amino‐1,2.4‐triazole and its prevention by ethanol. The irreversible inhibition of catalase by aminotriazole is known to proceed via the reaction of (catalase‐H2O2) compound I with aminotriazole. Inhibition can be prevented by compounds that are oxidized by compound I. Ethanol is one such compound. Prevention of the inhibition of brain catalase in vivo by prior administration of ethanol constitutes indirect evidence for the oxidation of ethanol to acetalde‐hyde in rat brain. The catalase content of the tissues represented catalase in the brain parenchyma, from which erythrocytes and capillaries had been excluded. Ethanol did not alter the levels of aminotriazole in brain. These results constitute the first demonstration of ethanol oxidation by living brain. more...

Hedonic regression methods are used to assess the impact of dwelling and structure characteristics, neighborhood effects, and multiple locations on a sample of almost 11000 residential property sales in Los Angeles County in 1980. Correction for the dwelling characteristic permits the analysis to be interpreted in terms of land values rather than property values per unit area. The selected equation explains more than 93% of the variation in the dependent variable (house price per unit of lot area). All the independent variables (five property or transaction characteristics, four neighborhood effects, and ten locational nodes) are statistically significant, with one major exception: distance from the CBD, which has a very low /-value and an unexpected sign. This result should be considered in the context of many superficial references, based largely on visual symbols such as new office buildings, to a revival of downtown Los Angeles. The authors interpret the finding that eight subcenters have a statistically significant influence on metropolitan residential land values in Los Angeles as yet another indication of the demise of the monocentric model and the need to discuss VSmetropolitan areas in policentric terms. more...

There are marked species differences in susceptibility to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mice are sensitive, whereas rats are relatively insensitive to MPTP. In these two species, the effects of peripherally administered MPTP or intrastriatally infused 1-methyl-4-phenylpyridinium (MPP+) were examined to identify potential underlying mechanisms responsible for their difference in susceptibility to MPTP. In vivo intrastriatal microdialysis and an MPP+ 2-day test/challenge paradigm were used to monitor dopamine efflux as an indicator of the neurotoxic effects of MPTP or MPP+. By using this method, the EC50 for neurotoxicity by an intrastriatal infusion of MPP+ in mice was 0.4 mM, whereas it was 10-fold higher in rats (4.3 mM). In addition, by using the traditional postmortem examination, neostriatal dopamine was depleted markedly in mice (> or = 80%), but only depleted marginally in rats in which MPP+ was infused into the neostriatum. These data indicate that rats are relatively insensitive to MPTP as compared to mice, because they are less sensitive to MPP+ whether it is formed in vivo from MPTP administered systemically or administered directly into neostriata. Thus, there appears to be a fundamental difference in the susceptibility of the nigrostriatal systems in these two species to the neurotoxic consequences of MPP+ exposure. more...

Several parameters necessary for the expression of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity to dopaminergic neurons were examined in both mice and rats in order to determine if differences in these processes might underlie the marked differences in the sensitivity of the two species to the neurotoxic effects of MPTP. Monoamine oxidase-B activity was greater in brain tissues from rats than from mice. The kinetics of 1-methyl-4-phenylpyridinium (MPP+) uptake into neostriatal synaptosomal preparations from the two species were similar. Brain and neostriatal levels of MPP+ were 2-fold higher in rats after the administration of MPTP at 60 mg/kg and were 10 to 20 times higher in rats than in mice after MPTP treatment which produced similar decrements in the content of neostriatal dopamine. MPP+ concentrations in the extracellular fluid of the neostriatum of the two species were similar after the administration of the same dose of MPTP (40 mg/kg). However, this dose induced a 40-fold increase in neostriatal dopamine efflux in mice, whereas in rats only a 3-fold increase was observed. In addition, pretreatment of rats with guanethidine, a ganglionic blocking agent, permitted the use of high doses of MPTP which resulted in substantial damage to the striatal dopaminergic nerve terminals. It is concluded that nigrostriatal dopaminergic neurons in the rat require exposure to a much higher concentration of MPP+ than do those in mice for the induction of toxicity. more...

In rats with a unilateral lesion of the nigrostriatal dopaminergic pathway, the ipsilateral rotation produced by the enhanced actions of endogenous dopamine (DA) on the nonlesioned side, induced by either the DA-releasing drug amphetamine or the DA uptake inhibitor GBR 13069, was blocked effectively by pretreatment with either the selective D1 DA receptor antagonist, SCH 23390, or the D2 selective antagonist, haloperidol. In contrast, contralateral rotation produced by apomorphine or I-dihydroxyphenylalanine, which lead to the preferential activation of D1 and D2 receptors on the lesioned side, was effectively prevented only when both receptor subtypes were inhibited. The results of these experiments demonstrate that the interaction between D1 and D2 receptors in the lesioned side differs from that in the nonlesioned side. Whereas the simultaneous stimulation of both DA receptor subtypes in the normally innervated basal ganglia is required for the production of turning behavior, the stimulation of either subtype alone in the dopaminergic denervated side can produce rotation. However, the concurrent administration of the D1 agonist, SKF 38393, with the D2 agonist, LY 171555, produced a synergistic effect on contralateral rotation. These results suggest that there is preservation of at least some functional interaction between D1 and D2 receptors in the lesioned basal ganglia but that there may be in addition a mechanism by which the two receptor subtypes can function independently of each other. The unilaterally lesioned rat appears to be a very good model in which to study the interaction between D1 and D2 receptors under conditions of both normal innervation and of DA denervation.(ABSTRACT TRUNCATED AT 250 WORDS) more...

1-Methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'CH3-MPTP) was shown previously to be a more potent neurotoxicant than 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. The present investigation was conducted to determine possible reasons for the greater potency of 2'CH3-MPTP and to determine if its neurotoxic action might be similar to that of MPTP. 2'CH3-MPTP was a much better substrate for monoamine oxidase than was MPTP (Km values of 66 and 114 microM and Vmax values of 3433 and 1389 nmol/g of tissue per hr for 2'CH3-MPTP and MPTP, respectively) and it is likely that this is an important feature which contributes to its greater potency. In addition, its pyridinium metabolite, 1-methyl-4-(2'-methylphenyl)pyridinium was found to be an excellent substrate for the dopamine carrier with Km and Vmax values (513 nM and 4.1 nmol/g of tissue per min, respectively) similar to those of 1-methyl-4-phenylpyridinium (872 nM and 5.2 nmol/g of tissue per min, respectively). In vivo, 2'CH3-MPTP-induced neurotoxicity, like MPTP-induced neurotoxicity, was attenuated by the pretreatment of mice with a dopamine uptake inhibitor (mazindol or GBR 13069). However, selective doses of the monoamine oxidase (MAO)-B inhibitors, deprenyl or MDL 72145, failed to prevent in vivo neurotoxicity induced by 2'CH3-MPTP although these doses effectively blocked MPTP-induced neurotoxicity. Protection against 2'CH3-MPTP-induced neurotoxicity was observed only at a nonselective dose of MDL 72145 which blocked both MAO-B and MAO-A activities.(ABSTRACT TRUNCATED AT 250 WORDS) more...

In previous studies and in the accompanying paper, 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'CH3-MPTP) was found to be more potent than MPTP in producing dopaminergic neurotoxicity in mice. One purpose of the present study was to determine whether 1-methyl-4-(2'-methylphenyl)pyridinium (2'CH3-MPP+), the primary oxidation product of 2'CH3-MPTP both in vivo and in vitro, inhibits mitochondrial respiration as does 1-methyl-4-phenylpyridinium (MPP+), the primary oxidation product of MPTP. Another aim was to determine whether treatments which modify MPTP- and 2'CH3-MPTP-induced neurotoxicity in vivo also cause parallel changes in the metabolic toxicity of these compounds. It was found that 2'CH3-MPP+, like MPP+, inhibited the oxidation of NAD(H)-linked substrates by isolated brain mitochondria in a concentration- and time-dependent manner, whereas succinate oxidation was not affected. Thus, the effect was on Complex I in the electron transport chain. Furthermore, 2'CH3-MPP+, like MPP+, enhanced lactate formation by neostriatal tissue slices as would be expected if Complex respiration were inhibited. MPP+ was slightly more potent than 2'CH3-MPP+ in both of these studies. However, 2'CH3-MPTP was several-fold more potent than MPTP in increasing lactate accumulation by the neostriatal slices. This difference in potency correlated with the differing capacities of 2'CH3-MPTP and MPTP to be oxidized by monoamine oxidase (MAO).(ABSTRACT TRUNCATED AT 250 WORDS) more...

Release of 3H-doapamine or of 3H-norepinephrine and inhibition of accumulation of 3H-dopamine or 3H-norepinephrine by d- and l-amphetamine were studied in slices of rat neostriatum and in slices of rat cerebral cortex. The two stereoisomers of amphetamine were equally potent as inhibitors of accumulation in the cortex, whereas d-amphetamine was approximately 3-fold more potent than l-amphetamine in the neostriatum. A similar relationship was observed between the two stereoisomers in release experiments. Some spontaneous efflux of 3H-dopamine from tissue slices was evident in absence of added drug in release experiments. When cocaine (2 X 10(-5) M), a known inhibitor of biogenic amine uptake, was added to the medium, there was very little increment in spontaneous efflux of 3H-dopamine in neostriatal slices, but cocaine blocked the release caused by d-amphetamine. This showed that the apparent releasing action of d-amphetamine in the neostriatum was not due to blockade of reuptake of spontaneously released material and that d-amphetamine itself must be taken up to evoke a releasing action. Experiments were designed to compare directly the releasing and uptake inhibiting actions of d-amphetamine. In the cortex, uptake inhibition of 3H-norepinephrine was greater than release over a wide concentration range, while in the neostriatum the two actions were essentially identical in magnitude for 3H-dopamine. We conclude that in the cortex, d-amphetamine can act both to release and to block uptake of 3H-norepinephrine. In the neostriatum, on the other hand, there is releasing action of 3H-dopamine by d-amphetamine (which is stronger than that in the cortex), but the apparent blockade of "uptake" is of questionable significance and appears to result from the release of previously accumulated 3H-dopamine more...