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Biomedical subjects

P Plenge

Publications and source records attributed to P Plenge.

At least 19 recordsLinked to original sources
PubMed1995

Lithium prophylaxis of manic-depressive disorder: daily lithium dosing schedule versus every second day.

The prophylactic efficacy of lithium carbonate given every second day versus daily intake was compared in a double-blind study including 50 manic-depressive patients. The patients met the DSM-III-R criteria for bipolar disorder or depressive disorder; according to ICD-8 the patients fulfilled criteria for manic-depressive disorder: All patients had experienced at least 3 episodes of mania or major depression, and all had been euthymic for at least 4 months. The median doses of lithium carbonate given were 800 mg/day or 1200 mg/every second day corresponding to median 12-h serum lithium concentrations of 0.6 mmol/l or 0.7 mmol/l, respectively. Manic or depressive relapse was defined as DSM-III-R criteria for mania or major depression, and a score > or = 10 on the Bech-Rafaelsen Mania Scale or the Bech-Rafaelsen Melancholia Scale, respectively. The two treatment schedules were allocated at random. Using the Cox proportional hazard model for statistical analysis, the lithium dosing schedule of every second day did not maintain its prophylactic efficacy against recurrent episodes of manic-depressive disorder. The risk of relapse increased 3 times when the interval between intake of lithium was extended from 1 to 2 days.

Adult↗
PubMed1995

Differences in brain 5-HT transporter dissociation rates among animal species.

The potential of using receptor-ligand dissociation rates as a model for investigating molecular changes in receptors was tested using the dissociation of [3H]citalopram, [3H]paroxetine and [3H]imipramine from the brain 5-HT transporter of four different species (mouse, rat, pig and man). Since the dissociation rates of each of the three ligands differed in most of the species investigated, receptor-ligand dissociation rate constants would seem to be a sensitive measure of receptor conformation. The model could be useful in the search of structural variation in receptors whether attributable to genetic factors or to posttranslational modification.

Adrenergic Uptake Inhibitors↗
PubMed1994

24-hour lithium concentration in human brain studied by Li-7 magnetic resonance spectroscopy.

Brain and serum lithium concentrations were measured every second hour during a 24-hr period following lithium intake, and again 48-hr later in two normal subjects in steady state lithium treatment receiving lithium carbonate (Priadel Synthelabo) once every evening. The brain-lithium concentration was measured by 7Li magnetic resonance spectroscopy (MRS). The brain lithium level was found to undulate in a peak-trough pattern that followed the serum lithium profile, although in an attenuated form. The brain/serum lithium concentration ratio varied considerably during the 48-hr period, ranging from 0.5 to 1.3, but the ratio was independent of the serum-lithium concentration. The median half-life for lithium was 28 hr in the brain, and 16 hr in serum. The brain lithium concentration in the morning was about 75% of the clinically relevant standard 12-hr serum lithium concentration. The finding that brain lithium undulates during the day means that MRS measurements of brain lithium can only be compared if carried out under standard conditions that include a fixed interval following lithium intake and an identical treatment regimen.

Adult↗
PubMed1992

Lithium treatment regimens induce different changes in [3H]paroxetine binding protein and other rat brain proteins.

Rats were treated with lithium administered either via the food or by intraperitoneal injection. Lithium administration via the food results in a rather stable serum lithium concentration, whereas lithium injection results in a varying serum lithium concentration whereby a sharp increase shortly after the injection is followed by an exponential decline until the next injection (Plenge et al. 1981). After 5 months of lithium treatment the 5HT transport protein, the beta-adrenergic receptor and several other brain proteins were determined. The 5HT transport protein, labelled with [3H]paroxetine, was found to be decreased in the lithium-injected rats (Bmax = 347 fmol/mg protein) but was unchanged in the lithium-fed rats (Bmax = 389 fmol/mg protein), as compared with control rats (Bmax = 396 fmol/mg protein), and therefore probably is a specific effect only seen with varying lithium concentration. In contrast, the neuronal membrane marker protein D3 was decreased in the lithium-fed rats (88% of the control value), and showed a trend towards decrease in the lithium-injected rats. The decrease in D3 in the lithium-fed rats may indicate some neuronal damage due to the continuous presence of lithium. This damage may be more pronounced than in rats, where periods of low lithium concentration enable repair to take place. The beta-adrenergic receptor and the neural cell adhesion molecule NCAM were unaffected by the different lithium treatment regimens. Lithium has been reported to inhibit the 5HT1B receptor (the serotonin autoreceptor).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
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↗