[The role of the general practitioner seen from a perspective of family medicine. Competence about dementia should be developed].
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Caregivers↗
Biomedical subjects
J Marcusson
Publications and source records attributed to J Marcusson.
GABA uptake sites in frontal cortex from suicide victims and in aging.
The binding of [3H]nipecotic acid to GABA uptake sites was studied in post mortem human frontal cortex from 17 suicide victims and 21 controls without known neurological or psychiatric disorder. The suicide victims were subclassified according to the use of violent or non-violent methods and to the presence or absence of a known history of a depressive disorder. No difference was found between the suicide victims and the controls with regard to [3H]nipecotic acid binding to GABA uptake sites (Bmax) and apparent affinity (Kd). No differences were found either with regard to method of suicide or whether a depressive symptom existed or not. The binding of [3H]nipecotic acid to GABA uptake sites was also studied in post mortem human frontal cortex with regard to aging. The age of the subjects ranged from 16 to 84 years. No significant difference in either Bmax or Kd was found. The present findings suggest that the GABA uptake sites in the human frontal cortex are not subjected to regulation or degenerative changes in conditions investigated.
Aged↗
[A balanced debate on tacrine is necessary].
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Alzheimer Disease↗
Brain monoaminergic and neuropeptidergic variations in human aging.
The effect of age on the monoamines 5-hydroxytryptamine (5-HT), noradrenaline (NA) and dopamine (DA), their metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), 3,4-dihydroxphenylacetic acid (DOPAC), and the 5-HT precursor 5-hydroxy-L-tryptophan (5-HTP), together with the peptides neuropeptide Y (NPY), somatostatin (SOM), and corticotropin-releasing factor (CRF), was studied in frontal cortex, gyrus cinguli and hypothalamus from 23 healthy control subjects, aged 16-75 years. After correcting for postmortem interval, significant decreases in gyrus cinguli NA, NPY and CRF, and hypothalamic DA, HVA, and 5-HIAA concentrations were obtained with advancing age. The involvement of the monoaminergic system in several functional abnormalities appearing in senescence is suggested. Furthermore, evidence is given of the participation of the peptidergic systems in the aging process.
Adolescent↗
Diagnosis of dementia at the primary care level.
In Sweden, as in many other industrial countries, the majority of patients with symptoms of dementia are initially evaluated by a general practitioner (GP), and many do not receive a follow-up assessment by a specialist. Accordingly, GPs play a vital role in identifying patients with possible dementia and undertaking additional diagnostic procedures. Currently, however, the ability of most GPs to perform assessments for dementia is limited. It is important that tests to confirm the presence of dementia be performed uniformly, irrespective of the specialty of the examining physician. Once a diagnosis of dementia has been established and appropriate living arrangements for the patient have been made, the GP should continue to monitor the patient's health status. In Sweden, "dementia teams" of health care professionals have been successful in providing a consistently high level of care to patients with dementia, reducing the incidence of hospitalization for acute illness.
Dementia↗
Brain 5-HT1A, 5-HT1D, and 5-HT2 receptors in suicide victims.
We report on 5-HT1A, 5-HT1D, and 5-HT2 binding sites in 23 control subjects and 18 suicide victims subdivided according to the method of death and the previous existence of depressive symptoms. No difference in maximum binding (Bmax) or binding affinity (Kd) was found between the control and overall suicide groups for the binding sites studied. The drug overdose subgroup showed, however, a significant decrease in the 5-HT1A binding affinity, probably explained by the higher sensitivity of this binding site to the acute administration of tricyclic antidepressants. A significant decrease in 5-HT1D binding affinity was also found in the depressed suicides, together with a significant decrease in the number of 5-HT1D binding sites in the nondepressed suicides. Further studies should be carried out on the 5-HT1D binding site as it might represent a new tool in the understanding of the depressive illness.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
[3H]paroxetine and [3H]citalopram as markers of the human brain 5-HT uptake site: a comparison study.
The binding of [3H]paroxetine and [3H]citalopram to the human brain serotonin (5-HT) uptake site has been characterized and compared. Our results reveal that the binding exclusively involved with the 5-HT uptake site is identical for both [3H]ligands. The selective 5-HT uptake inhibitor citalopram displays the highest affinity for this uptake site, as compared with the affinities obtained for desipramine and norzimeldine, which is in accordance with their respective blockage of 5-HT uptake. Similar Bmax values were obtained for both radioligands in the brain regions studied, indicating their binding to the same presynaptic membrane protein. Together these findings suggest that both [3H]paroxetine and [3H]citalopram are good markers of the 5-HT transporter as both bind selectively and with high affinity to the serotonin uptake sites. However, the higher affinity of [3H]paroxetine confirms that this compound is the best radioligand for the 5-HT uptake site available today.
Adult↗
Effect of aging in human cortical pre- and postsynaptic serotonin binding sites.
5-HT1A, 5-HT1D, 5-HT2 binding sites and affinity and 5-HT uptake sites were simultaneously determined in frontal cortex samples from 23 control subjects, aged 16-75 years. A significant reduction in the number of 5-HT1D and 5-HT2 binding sites was found with regard to age, together with a significant decrease in the 5-HT2 binding affinity. It is suggested that the total 5-HT1 age-related loss described in previous studies could be ascribed to the 5-HT2 subtype. Furthermore, aging does not seem to be associated with a reduced cortical serotonergic innervation, as indicated by the stability of the [3H]paroxetine-labeled 5-HT uptake sites.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
[3H]nipecotic acid binding to GABA uptake sites in human brain.
The binding of [3H]nipecotic acid to frozen post-mortem human brain tissue has been characterized. Competition experiments with gamma-aminobutyric acid (GABA), GABA uptake inhibitors, ligands active at post-synaptic GABA receptors and receptors for other neurotransmitter systems, suggest that [3H]nipecotic acid binds to the neuronal (but not glial) GABA uptake site. Competition and kinetic experiments suggest that 85% of the binding is to a high affinity site. The dissociation constants (Kd) measured in kinetic and equilibrium experiments were in the same range (0.5-0.6 microM). The regional distribution was studied in 19 brain regions and the binding was relatively homogenous. It is concluded that [3H]nipecotic acid binding can be used as a marker for neuronal GABA uptake sites in post-mortem human brain tissue.
Aged↗
Alterations in brain cholecystokinin receptors in suicide victims.
Cholecystokinin (CCK) and benzodiazepine receptor binding characteristics were analyzed in the brain tissue samples from 19 suicide victims and 23 control cases. In the frontal cortex, significantly higher apparent number of CCK receptors and affinity constants were found in the series of suicide victims. These differences between suicides and controls were present in similar proportions when the suicide cases with depressive syndrome or violent or non-violent means of self-killing were compared to matched controls. However, when the samples were split into subgroups consisting of persons either below or over the age of 60 years, significant differences in the CCK receptor characteristics in the frontal cortex were observed only between younger suicides and controls. Furthermore, the younger suicide victims had a higher density of CCK receptors in the cingulate cortex, whereas in older suicides the value was lower as compared to age-matched controls. No difference in benzodiazepine receptor binding was found between control and suicide groups. The results of this investigation suggest that CCK-ergic neurotransmission is linked to self-destructive behaviour, probably through its impact on anxiety and adaptational deficits.
Adolescent↗
Gamma-aminobutyric acid-B (GABAB) binding sites in postmortem suicide brains.
Gamma-aminobutyric acid-B (GABAB) binding sites labelled with [3H]GABA were determined in postmortem frontal cortex samples of 20 control subjects and 16 suicides. The suicide group was further subdivided according to the method of suicide and the existence of depressive symptoms prior to death. No significant differences in GABAB binding were found either between overall suicide and control groups or between the control group and the other subgroups (violent suicide, nonviolent suicide, nondepressed and depressed suicide victims). A significant increase in GABAB binding was observed in those individuals dying from carbon monoxide poisoning. It is concluded that although GABAB binding sites are not altered in our suicide group, a presynaptic dysfunction might account for the increased GABAB binding found in the carbon monoxide subgroup.
Adult↗
Age stability of human brain 5-HT terminals studied with [3H]paroxetine binding.
The effect of age on serotonin uptake sites labeled with [3H]paroxetine was studied in two sets of brains. The first set included 28 subjects (19 males and 9 females) between the ages 0 and 100 years. The cortex of cingulate gyrus and the amygdala were studied. No age-related changes in binding capacity (Bmax) or binding affinity (Kd) were noted. In the second set, the frontal cortex and hypothalamus from 22 subjects (18 males and 4 females) between 16 and 75 years were studied. No age-related changes in the binding were observed. The interval between death and freezing of the tissue did not influence the binding. Regarding the [3H]paroxetine binding as an indirect marker for 5-HT terminals, the data suggest a stability of 5-HT terminals with increasing age in the human brain.
Adolescent↗
Brain gamma-aminobutyrate transaminase and monoamine oxidase activities in suicide victims.
The activity of gamma-aminobutyrate amino-transferase (GABA-T) and monoamine oxidase (MAO-A and -B) was measured in 42 postmortem human brains. Three brain regions (frontal cortex, cingulate cortex and hypothalamus) from 23 controls without known neurological or psychiatric disorder and from 19 suicide victims were analysed. The suicide victims were classified according to the use of violent and non-violent methods and to the presence or absence of a known history of depressive disorder. No difference was found between the series of suicide victims and the control subjects with regard to GABA-T activity. Carbon monoxide poisoning and death by drug overdose, however, were found to reduce the activity. The MAO-B activity did not differ between the groups. With MAO-A, however, a significant elevation (t = 2.01; P less than 0.05) was found in the hypothalamic region of the suicide victims. The difference seemed to be confined to the subgroup of suicides with a record of depressive disorder.
4-Aminobutyrate Transaminase↗
High affinity [3H]paroxetine binding to serotonin uptake sites in human brain tissue.
[3H]Paroxetine binding to human brain tissue was characterized. Competition studies in the putamen and frontal cortex revealed single-site binding models for binding sensitive to 5-hydroxytryptamine (5-HT) (Ki 1-3 microM) and citalopram (Ki 0.6 nM), which displaced the same amount of binding. However, desipramine, norzimeldine and fluoxetine displaced additional binding (10-20%) and these competitors fitted two-site binding models with high affinity components in the nanomolar range and low affinity components in the micromolar range. The high affinity components approximated the 5-HT- and citalopram-sensitive binding fraction. Most of the [3H]paroxetine binding sites were protease-sensitive, but the low-affinity (microM) sites appeared to be protease-resistant. Based on these findings, only the [3H]paroxetine binding representing the fraction sensitive to 30 microM 5-HT (or e.g. 0.3 microM norzimeldine), was regarded as specific binding. This binding fraction was saturable with an apparent binding affinity (Kd) of 0.03-0.05 nM throughout the brain. The highest binding densities were obtained in the hypothalamus and substantia nigra (Bmax 500 fmol/mg protein). The basal ganglia reached intermediate densities (Bmax 200 fmol/mg protein), whereas cortical areas had low Bmax values (less than 100 fmol/mg protein). The lowest B max value was noted in cerebellar cortex (30 fmol/mg protein). The [3H]paroxetine binding was competitively inhibited by low concentrations of 5-HT, imipramine and norzimeldine, suggesting that the substrate recognition site for 5-HT uptake was labeled. Compounds active at dopaminergic, noradrenergic, histaminergic, 5-HT1, 5-HT2 and cholinergic muscarinic sites did not affect the binding at 100 microM concentrations. It is concluded that [3H]paroxetine is a marker for the 5-HT uptake site in the human brain, provided that an adequate pharmacological definition of specific binding is performed.
Aged↗
Inhibition and dissociation of [3H]-paroxetine binding to human platelets.
Previous data on dissociation studies of [3H]-imipramine and [3H]-paroxetine binding to the human platelet 5-hydroxytryptamine (5-HT, serotonin) transporter have suggested that the binding is heterogeneous in nature and/or is subject to allosteric modifications through a separate low affinity site. The platelet 5-HT transporter is often used as a biological marker in psychiatric conditions. Therefore, it was of interest to further characterize the 5-HT uptake site by using [3H]-paroxetine. The 5-HT uptake inhibitors tested (citalopram, clomipramine, imipramine, norzimeldine and paroxetine) and 5-HT itself produced competitive inhibition patterns in saturation experiments, suggesting that these agents bind to the same site. In dissociation experiments in the presence of the 5-HT uptake inhibitors, the half-time values for dissociation were the same, whereas 5-HT slowed the dissociation. These data suggest that with the concentrations used of the 5-HT uptake inhibitors, they do not modify the 5-HT transporter. However, in the presence of 5-HT, the [3H]-paroxetine dissociation is decreased, suggesting an allosteric modification of the [3H]-paroxetine binding site.
Antidepressive Agents↗
[3H]GBR-12935 binding to dopamine uptake sites in the human brain.
The binding of the selective dopamine uptake inhibitor [3H]GBR-12935 to post-mortem human brain membranes was studied. Competition experiments indicated the presence of multiple binding sites, but when a binding fraction that could be discriminated by either 0.3 microM mazindol or 1 mM dopamine was regarded as specific binding, a single-site binding model was obtained. The [3H]GBR-12935 binding was of protein nature since it was abolished after protease treatment and the binding appeared to label the dopamine uptake site. This was supported by the findings that dopamine uptake inhibitors inhibited the binding with high affinity (Ki 30-130 nM), whereas substances active at dopamine D1, D2 or autoreceptor sites revealed much lower affinities (Ki greater than 10 microM or inactive). Moreover, dopamine was the neurotransmitter with the highest affinity for the [3H]GBR-12935 binding site (Ki 30 microM). The dopaminergic nature of the [3H]GBR-12935 binding was further indicated by its regional distribution, which largely corresponds the known distribution of the dopamine system in the rat brain. The highest binding densities were obtained in the caudate nucleus and putamen (Bmax 1500-2000 fmol/mg protein), followed by the olfactory tubercle (Bmax 900 fmol/mg protein) and the substantia nigra (Bmax 300 fmol/mg protein). The apparent binding affinity (Kd) was the same in all brain regions (Kd 1-1.5 nM). Detectable specific [3H]GBR-12935 binding was obtained also in the globus pallidus, amygdala and cortices of orbital/rectus and cingulate gyri. Drug inhibition studies with the addition of low concentrations of dopamine and mazindol produced only alterations in the apparent Kd values, suggesting a competitive inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Unaltered 5-HT- and desipramine-sensitive [3H]imipramine binding and [3H]5-HT uptake in rat brain after chronic imipramine and norzimeldine treatment.
Several reports have shown heterogeneity of [3H]imipramine binding to brain membranes. Recently, a high affinity and 5-HT sensitive [3H]imipramine binding site of protein nature, that was suggested to be identical to the substrate recognition site for 5-HT uptake, was demonstrated. Since most studies on the regulation of the [3H]imipramine binding sites by antidepressants have used desipramine displaceable binding, which is heterogenous in nature and contains binding not related to 5-HT uptake sites, the present report studies the possible effects of chronic (3 weeks) administration of imipramine or norzimeldine (10 mg/kg intraperitoneally twice daily) on 5-HT sensitive [3H]imipramine binding sites. For comparison, desipramine sensitive binding was also studied, as well as the physiological correlate 5-HT uptake. There were no changes in either [3H]imipramine binding or 5-HT uptake after the antidepressant treatment.
Animals↗
Dissociation kinetics of [3H]paroxetine binding to rat brain consistent with a single-site model of the antidepressant binding/5-hydroxytryptamine uptake site.
The effects of 5-hydroxytryptamine (5-HT) and 5-HT uptake inhibitors on the dissociation of [3H]paroxetine from rat brain membrane binding sites have been investigated. The dissociation induced by 5-HT (100 microM), paroxetine (0.15 microM), clomipramine (1 microM), citalopram (1 microM), imipramine (1 microM), or norzimeldine (1 microM) was consistent with first-order dissociation kinetics with half-life values of dissociation (t1/2) between 130 and 140 min. The dissociation induced by the combination of 5-HT (100 microM) with either citalopram (1 microM) or imipramine (1 microM) was not different from that initiated by either agent alone. These dissociation data, which are at variance with previous data on the 5-HT transporter labeled with [3H]imipramine, support a single-site model of the antidepressant binding/5-HT uptake site.
Animals↗