Analysis of exposure-time-response relationships using a spline weight function.

To examine the time-dependent effects of exposure histories on disease, we estimate a weight function within a generalized linear model. The shape of the weight function, which is modeled as a cubic B-spline, gives information about the impact of exposure increments at different times on disease risk. The method is evaluated in a simulation study and is applied to data on smoking histories and lung cancer from a recent case-control study in Germany.

Mortality among radiologic technologists in the united states (1926-1997). 2(nd) Follow up.

PURPOSE: To evaluate risk for all-cause and cause-specific mortality in a large, primarily female (73%) cohort of radiologic technologists.METHODS: The study consists of 145,915 radiation technologists, certified in the American Registry of Radiologic Technologists (1926-1982) and followed through 1997. Causes of death were obtained from death certificates or, more recently, through NDI Plus.

The use of sliding time windows for the exploratory analysis of temporal effects of smoking histories on lung cancer risk.

To examine the time-dependent effects of exposure histories on disease we use sliding time windows as an exploratory alternative to the analysis of variables like time since last exposure and duration of exposure. The method fits a series of risk models which contain total cumulative exposure and an additional covariate for exposures received during fixed time intervals. Characteristics of the fitted models provide insight into the influence of exposure increments at different times on disease risk.

Effects of high-dose methamphetamine on monoamine uptake sites in rat brain measured by quantitative autoradiography.

The neurotoxicity of methamphetamine to monoaminergic neurons was examined. Neurotoxicity was assessed by quantitative autoradiography using radioligands specific for binding to norepinephrine, dopamine, and serotonin uptake sites. High-dose administration of methamphetamine led to decreases in binding to uptake sites for the three monoamines.

Lack of effect of high-dose cocaine on monoamine uptake sites in rat brain measured by quantitative autoradiography.

There have been a number of claims that high-dose administration of cocaine to rats leads to neurotoxic effects on dopamine neurons. In this study possible neurotoxic effects on monoamine neurons were examined by measuring the effects of cocaine (35 mg/kg daily for 10 days) on the binding of radioligands to uptake sites for dopamine, serotonin and norepinephrine using qualitative autoradiography. No effects of cocaine on any of the binding sites were observed and therefore, it is concluded that cocaine, unlike amphetamine derivatives which have similar pharmacologic properties, does not produce neurotoxic effects on monoamine neurons.

Central administration of 1-isoproterenol in vivo induces a preferential regulation of beta 2-adrenoceptors in the central nervous system of the rat.

1-Isoproterenol has equal affinity for beta 1- and beta 2-adrenoceptors and is a full agonist at both subtypes. However, when infused in vivo into the rat brain, it has been shown to induce a preferential reduction of central beta 2-adrenoceptors. To investigate this phenomenon further, in the present study rats were infused centrally with higher doses of 1-isoproterenol (15 or 45 micrograms/h).

Preferential reduction of binding of 125I-iodopindolol to beta-1 adrenoceptors in the amygdala of rat after antidepressant treatments.

This study utilized quantitative receptor autoradiography to examine the effects of repeated administration of antidepressants to rats on the binding of the beta adrenoceptor antagonist, 125I-iodopindolol (125I-IPIN) to either beta-1 or beta-2 adrenoceptors in various regions of brain. Antidepressants were selected to represent various chemical and pharmacological classes including tricyclic compounds (desipramine and protriptyline), monoamine oxidase inhibitors (clorgyline, phenelzine and tranylcypromine), atypical antidepressants (mianserin and trazodone) and selective inhibitors of the uptake of serotonin (citalopram and sertraline). Additionally, rats were treated with various psychotropic drugs that lack antidepressant efficacy (cocaine, deprenyl, diazepam and haloperidol).

[Blood MAO/DBH index and the results of the treatment of endogenous depression].

In the group of 115 endogenous depression patients 84 responded to tricyclic antidepressant medication and 31 remained drug-resistance. The changes of platelet MAO activity and serum DBH activity in the latter group were found. Among drug-resistant patients, 40% showed low MAO/DBH index (.

The role of brain serotonin in the electroconvulsive shock-induced changes in behavioural effects of intra-hippocampally injected clonidine.

The influence of central serotonin depletion upon behavioural effects of intra-hippocampally injected clonidine in the electroconvulsive shock-treated rats (ECS), was studied. Repeated ECS significantly attenuated the depressive influence of clonidine upon the locomotor activity of the rats in the open field test. Chemical lesions to the median raphe nucleus (MR) did not significantly affect ECS-induced changes in clonidine activity in this test.

Are ascending noradrenergic and serotonergic pathways necessary for effects of electroconvulsive treatment? Clonidine hypothermia and forced swim study.

Are ascending noradrenergic and serotonergic pathways necessary for effects of electroconvulsive treatment? Clonidine hypothermia and forced swim study. W. DANYSZ , W.

Evaluation of mono- and dibenzoyl esters of dopamine as potential pro-drugs for dopamine in the central nervous system.

In this study, two ester pro-drugs of dopamine (DA) were synthesized and evaluated. These derivatives were the monobenzoyl (MBDA) and dibenzoyl (DBDA) esters of DA. MBDA was 300-fold and DBDA was 20,000-fold more lipophilic than DA itself.

Brain neurotransmitter systems mediating behavioral deficits produced by inescapable shock treatment in rats.

The effect of inescapable footshock (IS) upon rats' motor activity (the open field and forced swim tests) was studied in rats subjected to drugs, and neurotoxin treatments, affecting their central neurotransmitter systems. The agonists of GABA-receptor complex, dopamine, noradrenaline and serotonin neuronal systems, as well as the cholinergic antagonist, partially reversed motor suppression induced by IS, while the dopamine agonist, chlorpromazine, and the cholinergic antagonist, physostigmine, potentiated it. The effects of chemical lesions of the brain monoaminergic neurons with p-chlorophenylalanine (pCPA), N-chloro-ethyl-2,2-bromo-benzylamine (DSP-4), 6-hydroxydopamine (6-OHDA) and 5,7-dihydroxytryptamine (5,7-DHT) were more complex, depending upon the extent of monoamine depletion, and the kind of test applied.

The effect of 5,7-DHT-induced lesions of the median raphe nucleus and chronic desipramine administration upon motor behaviour of rats given intrahippocampal clonidine injection.

The role of serotonergic (5-HT) innervation of rat hippocampus in clonidine- induced behavioural effects was studied in naive and desipramine-pretreated animals. 5,7- DHT-lesions of the median raphe nucleus (MR) produced about 50 per cent decrease of serotonin and 5-hydroxyindoloacetic acid (5-HIAA) content in the rat cortex and hippocampus. Lesions of the MR also accelerated the attenuating effect of desipramine upon locomotor inhibition produced by intrahippocampal clonidine injections.

Suppression of ethanol tolerance and dependence in rats treated with DSP-4, a noradrenergic neurotoxin.

The formation of tolerance to the hypothermic effect of ethanol was inhibited in rats after intraperitoneal injection of the neurotoxin DSP-4 50 mg/kg. The neurotoxin also significantly suppressed the ethanol withdrawal syndrome; hyperlocomotion, audiogenic seizures and spasticity. These behavioural changes were accompanied by a 52% decrease of the brain norepinephrine (NE) content, with no alterations in the dopamine or serotonin levels.

On the role of noradrenergic neurotransmission in the action of desipramine and amitriptyline in animal models of depression.

Three weeks of treatment with desipramine (DMI) and amitriptyline (AMI) reduced the hypothermic action of clonidine in rats. Both electrolytic and 6-hydroxydopamine lesions of the locus coeruleus (LC) and administration of DSP-4 counteracted the reduction of clonidine hypothermia produced by antidepressants. Lesions of the LC and DSP-4 administration also antagonized the anti-immobility action of single doses of DMI but failed to modulate the action of AMI in the forced swim test.

Evidence for the locus coeruleus involvement in desipramine action in animal models of depression.

Desipramine (DMI) effectively antagonized hypothermia induced by reserpine and clonidine in rats. DMI effects were attenuated or even abolished after electrolytic or 6-hydroxydopamine-induced lesion of the locus coeruleus (LC) as well as by administration of DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine), a selective noradrenergic neurotoxin. Contrary to the LC lesions, electrolytic destruction of the ventral noradrenergic bundle did not change DMI action but antagonized reserpine-induced hypothermia by itself.

Effects of ATP gamma S in isolated rat brain synaptosomes.

The effects of ATP gamma S, a slowly hydrolyzable analogue of ATP, were investigated in the preparation of synaptosomes isolated from rat cerebral cortex. It was found that addition of [35S]ATP gamma S resulted in substantial magnesium-dependent incorporation of 35S into synaptosomal proteins which was prevented completely by ATP. The most prominently labeled polypeptides were those with apparent molecular weights of 100,000; 84,000; 74,000; 62,000; 55,000; 48,000; and 41,000.

High affinity proline uptake in rat brain synaptosomes.

The uptake of L-proline by synaptosomes isolated from different regions of the brain was investigated. The highest rates of transport and the largest accumulation ratios were found in synaptosomes from the midbrain, striatum, hippocampus and hypothalamus, with lower activity in the cortex and medulla (+ pons) and lowest in the cerebellum. The high affinity, Na+-dependent proline uptake had a Km of 12 microM, a Vmax of 0.

Interaction between noradrenergic and serotonergic brain systems as evidenced by behavioral and biochemical effects of microinjections of adrenergic agonists and antagonists into the median raphe nucleus.

The effects of microinjections of adrenergic receptors agonists and antagonists into the median raphe nucleus (MR) on behavior and serotonin (5HT) metabolism was examined in rats. Administration of adrenergic alpha 1 and alpha 2 receptor agonists (noradrenaline, phenylephrine, clonidine) produced behavioral excitation in the open field test and a tendency to decrease the forebrain 5-hydroxyindolo-acetic acid (5HIAA) concentration. Opposite effects were seen after microinjection of adrenergic alpha receptor antagonists (phenoxybenzamine, phentolamine but not yohimbine).

Studies on biogenic amine metabolizing enzymes (DBH, COMT, MAO) and pathogenesis of affective illness. III. Platelet monoamine oxidase activity in endogenous depression.

Platelet MAO activity was determined in blood from 31 healthy persons and 43 persons with endogenous depressive syndrome. It was found that the enzyme activity is significantly higher in women than in men, both in healthy controls and in affective illness groups. Statistically significant lowering of the enzyme activity was found in the group of women with affective illness as compared with healthy women controls (P less than 0.

Rotational behavior produced by unilateral ventral noradrenergic bundle lesions: evidence for a noradrenergic-dopaminergic interaction in the brain.

In this study the effect of unilateral electrocoagulation of the ventral noradrenergic bundle (VB) on rotational behavior produced by dopaminergic agonists was investigated. Unilateral lesions to the VB produced a decrease in the concentration of noradrenaline but not dopamine, serotonin or 5-hydroxyindoleacetic acid (5-HIAA) in the ipsilateral part of the forebrain. These lesions produced also strong and dose-dependent preference for ipsilateral rotation after systemic injection of apomorphine or amphetamine.

Effect of 6-hydroxydopamine-induced lesions of A10 dopaminergic neurons on aggressive behavior in rats.

The present study evaluated the effects of microinjections of 6-hydroxydopamine into the ventral mesencephalic tegmental area (nucleus A10) on aggressive behavior in rats. This treatment resulted in a reduction in foot-shock-induced fighting but failed to influence muricide (mouse-killing) behavior in chronically isolated rats. The general activity of animals tested in the open field was significantly increased two weeks after lesions.

Lesion of serotonergic neurons antagonizes clonidine induced suppression of avoidance behavior and locomotor activity in rats.

The effects of clonidine on avoidance acquisition and locomotor activity were studied in male Wistar rats with 5,6-dihydroxytryptamine (5,6-DHT) lesions of the median raphe nucleus. Lesioned animals showed marked depletion in forebrain serotonin and 5-hydroxyindole acetic acid concentrations. clonidine (0.