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Biomedical subjects

P Plenge

Publications and source records attributed to P Plenge.

At least 37 records · Page 2Linked to original sources
PubMed1992

Serotonin receptors in the brain of rats treated chronically with imipramine or RU24969: support for the 5-HT1B receptor being a 5-HT autoreceptor.

Rats were treated by intraperitoneal injection for four weeks with either RU24969, a 5-HT1B and 5-HT1A agonist or imipramine, a 5-HT uptake inhibitor. Pre- and postsynaptic 5-HT receptors were measured to compare the effect of direct or indirect stimulation of the 5-HT autoreceptor (5-HT1B receptor). The 5-HT transport protein (5-HT uptake site), labelled with [3H]paroxetine, was unaffected after treatment with either one of the drugs. The density of 5-HT2 receptors, labelled with [3H]ketanserin, we found increased after treatment with RU24969 (Bmax = 161 fmol/mg protein) and decreased after treatment with imipramine (Bmax = 109 fmol/mg protein) as compared with control rats (Bmax = 134 fmol/mg protein). The 5-HT1B receptor was found decreased both by the imipramine treatment (Bmax = 106 fmol/mg protein) and the treatment with RU24969 (Bmax = 105 fmol/mg protein), compared with control rats (Bmax = 130 fmol/mg protein). The 5-HT1A receptor was found to be decreased after treatment with RU24969 (control: Bmax = 62 fmol/mg protein; RU24969-treated: 49 fmol/mg protein), but unchanged after treatment with imipramine (Bmax = 58 fmol/mg protein). These results correspond to what could be expected, if the 5-HT1B receptor is the 5-HT autoreceptor.

Animals↗
PubMed1992

Platelet paroxetine binding in alcoholics.

Platelet paroxetine binding was analysed in 24 abstinent alcoholics and 18 control persons. The alcoholics had significantly more binding sites than the control persons. Most of the alcoholics showed affective symptoms and the increased platelet paroxetine binding was predominantly observed among those who had the lowest Newcastle score, indicating the presence of non-endogenous depression.

Adult↗
PubMed1991

Affinity modulation of [3H]imipramine, [3H]paroxetine and [3H]citalopram binding to the 5-HT transporter from brain and platelets.

The dissociations of [3H]imipramine, [3H]paroxetine and [3H]citalopram from the 5-HT (serotonin 5-hydroxytryptamine) transporter were found to be markedly influenced by several drugs, although concentrations in the microM range were needed. Most of these drugs attenuated the dissociation rate, i.e. increased the affinity between the ligand and the binding site. A few increased the dissociation rate however. The binding of drugs to the affinity-modulating site was specific, although of low affinity and probably changing the conformation of the high-affinity binding site, thereby changing the fit between the ligand and the interacting amino acid side-chains. Although the drugs usually affected the dissociation rates of the three ligands in the same manner, there were some which had different effects on [3H]imipramine, [3H]paroxetine and [3H]citalopram. For example, 5-HT markedly attenuated the dissociation of [3H]imipramine, had a moderate effect on [3H]paroxetine and very little effect on [3H]citalopram dissociation. This indicates that the three ligands are bound to different domains on the 5-HT transporter. [3H]Citalopram dissociation from human brain and rat brain were differently affected by several drugs. Indalpine augmented the dissociation rate of the [3H]citalopram 5-HT transport complex in human brain but attenuated it in rat brain, thus revealing a species difference of the 5-HT transporter.

Animals↗
PubMed1991

[3H]citalopram binding to brain and platelet membranes of human and rat.

Citalopram, a selective serotonin (5-HT) uptake inhibitor with antidepressant properties, was found to bind with high affinity to the 5-HT transporter from human neuronal and platelet membranes. At 20 degrees C, KD was about 1.5 nM in both tissues. [3H]Citalopram bound to rat neuronal membranes with higher affinity than to human neuronal and platelet membranes; at 20 degrees C KD was about 0.7 nM. The Bmax value for the binding of [3H]citalopram to platelet membranes was close to that found using the 5-HT uptake inhibitors [3H]imipramine and [3H]paroxetine, suggesting that all three 5-HT uptake inhibitors bind to the 5-HT transporter. The dissociation rate of [3H]citalopram increased twofold with each 4-5 degree C increase in temperature in both human and rat membranes, although at any given temperature, the dissociation rate was about four times faster in the human neuronal and platelet membranes than in rat neuronal membranes.

Animals↗
PubMed1990

Inhibitory and regulatory binding sites on the rat brain serotonin transporter: molecular weight of the [3H]paroxetine and [3H]citalopram binding proteins.

Citalopram binds with high affinity to a specific binding site located on the serotonin (5-HT) transporter in 5-HT neurons. The binding affinity of [3H]citalopram was found to increase with increasing concentration of citalopram. This may be a homotropic positive allosteric effect, thus indicating the presence of an allosteric binding site for citalopram. The molecular weight of the proteins containing the high-affinity binding sites for citalopram and paroxetine, as well as the allosteric binding site for citalopram were determined by the irradiation method. The molecular weights of the three binding site proteins were found to be the same, suggesting that all three binding sites are located on the same protein molecule in the 5-HT transporter. The results support a hypothesis that the binding area for [3H]citalopram is located deeper in the transport channel than the [3H]paroxetine binding area. Thus the two high-affinity binding sites probably cover different, but overlapping, parts of the protein molecule. The allosteric binding site may be located elsewhere on the protein where it induces conformational changes of the 5-HT transporter with the result that high-affinity bound ligands get trapped in the transport channel, thereby explaining the increase in affinity.

Animals↗
PubMed1990

Imipramine binding in depressed patients with psychogenic pain.

Imipramine binding to platelet membranes from depressed patients was analyzed. The patients were divided into two groups: one with depression alone, another with depression and psychogenic pain. The depressed patients with psychogenic pain had lower imipramine binding than the depressed patients without pain.

Blood Platelets↗
PubMed1990

Regional distribution of the serotonin transport complex in human brain, identified with 3H-paroxetine, 3H-citalopram and 3H-imipramine.

1. Regional distribution of the serotonin transport complex was studied in 12 different brain areas from human brains. The serotonin uptake complex was measured with 3H-paroxetine, and 3H-imipramine. The binding site density was highest in the nucleus of raphé, medium in the basal ganglia, and lowest in cortical areas. The specific binding measured with 3H-paroxetine and 3H-citalopram was compared with the high affinity 3H-imipramine binding determined with either 100 microM 5HT or 1 microM imipramine as non specific displacers. 3H-paroxetine and 3H-citalopram allowed a more precise determination of Bmax, and are both good ligands for the serotonin uptake site, but the determinations with 3H-imipramine were within the same range. 2. Protease digestion of brain membranes showed that the binding site measured with all three ligands disappeared with the same rate as other membrane proteins, and not faster as might be expected from the literature. 3. Left/right hemisphere distribution was measured in cortical tissue from 6 brains using 3H-paroxetine. No difference between the two hemispheres was found. In one brain from a lithium treated patient a very low binding was measured, possibly indicating that the lithium treatment had decreased the serotonin uptake mechanism.

Adolescent↗
PubMed1990

Why some depressed patients may have low platelet 3H-imipramine binding.

Human platelet membranes were incubated with 3H-imipramine, 3H-paroxetine or 3H-chlorimipramine. It was found that chlorimipramine remained in the membranes, as it was impossible to remove this antidepressant drug by normal washing procedures. Similar results, although to a lesser degree, were found with paroxetine, whereas imipramine could be washed away from the membranes. Treatment of volunteers with chlorimipramine strongly reduced platelet imipramine binding probably due to the presence of chlorimipramine in the membranes during the binding assay. These results suggest that the low imipramine binding reported in depressed patients, at least in some cases, may have been caused by antidepressant drugs or drug metabolites remaining in the platelet membrane preparations.

Antidepressive Agents↗
PubMed1989

[3H]imipramine binding in idiopathic pain syndromes. Basal values and changes after treatment with antidepressants.

The binding affinity (Bmax, Kd) of [3H]imipramine to platelet membranes was investigated in 43 patients with a diagnosis of idiopathic pain syndrome. Measurements were carried out prior to and after 6 weeks' treatment with the antidepressants clomipramine or maprotiline (randomized double-blind trial). Before treatment the Bmax was 11% lower (1109 +/- 237 fmol/mg protein) compared to historical control subjects (n = 21, 1240 +/- 390) and comparable to patients with psychogenic pain with affective symptoms (n = 62, 1110 +/- 360) previously measured at the same laboratory. The Kd was 0.5 +/- 0.3 nM comparable to the Kd of the controls (0.6 +/- 0.2). After 6 weeks of treatment the clomipramine group (n = 11) had significantly lower Bmax = 208.5 +/- 286 (P less than 0.001). In the maprotiline-treated patients (n = 18) the Bmax values (1221 +/- 258) tended to increase towards the values of the controls but without statistical significance. No significant statistical correlation was found between initial Bmax values and clinical outcome.

Antidepressive Agents↗
PubMed1988

Platelet 3H-imipramine binding in psychogenic pain patients.

High-affinity binding of 3H-imipramine was analyzed in platelet membranes from patients with chronic psychogenic pain. The patients who in addition to the pain also showed affective symptoms such as depression and anxiety had lower binding than the pain patients without these symptoms.

Adolescent↗
PubMed1988

Imipramine binding in depressive patients diagnosed according to different criteria.

3H-imipramine binding to platelet membranes, Bmax and KD, was measured in depressed patients, who were divided into endogenous and non-endogenous depression according to three different criteria, the ICD-9, the Newcastle I and the Newcastle II rating scales. Two groups served as controls, a group of healthy volunteers and a group of psychiatric patients suffering from schizophrenia or senile dementia. No significant differences were found in either Bmax or in KD among the different groups of patients and the control groups.

Adolescent↗
PubMed1988

Imipramine binding in depression and other psychiatric conditions.

30 studies of platelet 3H-imipramine binding in depressed patients are reviewed. 19 of these studies found that depressed patients had lower binding than control persons, whereas 11 studies found no difference. This discrepancy is discussed and it is concluded that methodological problems may account for a substantial part of the low imipramine binding in depressed patients.

Blood Platelets↗
PubMed1988

Lithium treatment: are the present schedules optimal?

Lithium treatment is a proven and effective prophylactic treatment of bipolar affective disorders. To day patients receive their lithium in one or two daily doses, and the dosage level in the individual patient is adjusted to the lowest possible level in order to reduce side effects. In the present article we suggest an alternative treatment strategy also aiming at reducing side effects but not involving the slow process of finding the lowest possible effective lithium dose. We suggest prophylaxis may be obtained by giving lithium every second day in a dose producing 12 hour serum lithium concentrations between 0.6 and 0.9 mM, and leading to very low lithium concentrations every second day. This treatment schedule is at present being tested in the clinic.

Bipolar Disorder↗
PubMed1987

The activity of 25 paroxetine/femoxetine structure variants in various reactions, assumed to be important for the effect of antidepressants.

Structure-activity relationships for 25 structural variants around the 5-hydroxytryptamine (5-HT) uptake inhibitors paroxetine and femoxetine have been investigated. Three parameters related to the 5-HT system were investigated: (i) The inhibition of [3H]5-HT uptake into rat brain synaptosomes, (ii) the inhibition of [3H]paroxetine binding to rat neuronal membranes and (iii) the effect of the compounds on the affinity of [3H]imipramine for the human platelet membrane binding site, measured as the dissociation rate of the [3H]imipramine human platelet membrane binding site complex. A highly significant correlation was found for 5-HT uptake inhibition and inhibition of [3H]paroxetine binding for the different substances, indicating that the two parameters are closely connected. However the slope of the regression line was only 0.6 and not 1.0; this may indicate that [3H]paroxetine binding is necessary, but not sufficient for 5-HT uptake inhibition. No correlation was found between the inhibition of [3H]paroxetine binding and the affinity of the compounds for the [3H]imipramine binding site complex. The two binding sites are therefore probably situated on different parts of the 5-HT transport system, the [3H]paroxetine binding site being part of the 5-HT transport mechanism whereas the [3H]imipramine binding site may represent a site modulating the activity of, and affinity for, 5-HT in the 5-HT transport mechanism. Structure-activity relationships among the substances showed that stereochemical changes from (-)- to (+)-trans changed the activity towards both 5-HT uptake inhibition and [3H]paroxetine displacement for most of the (-)-/(+)-pairs. The substitution of -H with -F or -CH3 also affected the activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗