Biomedical subjects

R Jeanningros

Publications and source records attributed to R Jeanningros.

At least 19 recordsLinked to original sources

PubMed2001

Chronic effects of triiodothyronine in combination with imipramine on 5-HT transporter, 5-HT(1A) and 5-HT(2A) receptors in adult rat brain.

Triiodothyronine (T3) has been shown to accelerate and potentiate the clinical response to tricyclic antidepressant (TCA) treatment in depressive disorders. The neurobiological mechanisms underlying these therapeutic effects of T3 are still unknown. Since brain serotonin (5-HT) changes have been implicated in the mode of action of TCA drugs, the effects of a chronic (7 or 21 days) administration of imipramine (10 mg/kg/day) and of a low dose of T3 (4 microg/kg/day), given alone or in combination, were investigated on the density of midbrain 5-HT transporters and of hippocampal 5-HT(1A) and cortical 5-HT(2A) receptors in adult Wistar rats. Neither single nor combined administration of imipramine and T3 for 7 days modified the density of 5-HT transporters and of 5-HT(1A) receptors. On day 21, the combination did not change imipramine- or T3-induced decrease in 5-HT transporter density whereas it prevented imipramine-induced increase in 5-HT(1A) receptor density. Whatever the treatment duration, imipramine-T3 combination potentiated imipramine-induced decrease in 5-HT(2A) receptor density. On both day 7 and day 21, T3 given alone had no effects on the density of 5-HT(1A) and 5-HT(2A) receptors. These data indicate that T3 is able to modulate the long-term adaptive changes which occur at the postsynaptic level of 5-HT neurotransmission after antidepressant treatment.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2000

Red blood cell triiodothyronine uptake in unipolar major depression: effect of a chronic antidepressant treatment.

The evolution of kinetic parameters (Vmax, maximal velocity, and Km, Michaelis constant) of red blood cell (RBC) triiodothyronine (L-T3) initial uptake was followed in 19 inpatients suffering from unipolar depression after 1 week (D7) and 4 weeks (D28) of a chronic administration of fluvoxamine, in relation with the clinical efficacy of the drug. In a drug-free state (DO), Vmax (in pmol/min/10(8) cells) and Km (in nM) were significantly increased in depressed patients (Vmax +/- S.D.= 1.02 +/- 0.29, p< 0.01 and Km +/- S.D.= 68.8 +/-15.4, p< 0.05; n=19) compared to healthy volunteers matched for age and sex (Vmax +/- S.D.= 0.82 +/- 0.15 and Km S.D.= 58.8 +/- 9.0; n= 19). When patients were dichotomized on the basis of their treatment response, responders had kinetic parameters significantly increased (Vmax +/-S.D.= 1.03 +/- 0.26, p< 0.01 and Km +/- S.D.= 71.7 +/- 18.7, p< 0.05, n= 10) compared to controls, whereas non-responders had not (Vmax +/- S.D.= 1.00 +/- 0.33, NS and Km +/- S.D.= 65.7 +/- 10.9, NS, n= 9). At D7, Vmax differed from the one of controls only in the responders (Vmax +/- S.D.= 1.03 +/-0.26, p< 0.01). In addition, the percentage of variation of the individual Vmax values during the first week of treatment was significantly lower in responders than in non-responders (deltaVmax(D7-D0) +/- S.D. in % = 10.7 +/- 6.0 and 22.0 +/- 11. 1, p< 0.05, respectively). At D28, kinetics of L-T3 uptake normalized only in the responders (Vmax +/- S.D.= 0.91 +/- 0.13, NS; Km+/-S.D.= 65.7 +/- 7.4, NS). The results indicate that both RBC L-T3 uptake at the pretreatment level and its change during the first week of fluvoxamine treatment were related to the further clinical response to the antidepressant. RBC L-T3 uptake seems to be a biological correlate of the depressive symptomatology since the disturbances disappear only with the clinical remission.

Adult↗

PubMed1999

Kinetics of red blood cell T3 uptake in hypothyroidism with or without hormonal replacement, in the rat.

L-triiodothyronine (L-T3) is taken up and accumulated into red blood cells (RBC) by means of a specific carrier-mediated system. The aim of this study was to evaluate the reactivity of this system in relation to induced alterations in thyroid hormone (TH) supply. We investigated the kinetic parameters (Vmax, maximal velocity and Km, Michaelis constant) of washed-RBC L-T3 uptake 1) in thyroidectomized (TXT) rats, 2) in TXT rats administered with low doses of L-T4 (15 microg/kg/day x 14) to restore normal serum TH levels (REPL), 3) in TXT rats administered with high doses of L-T4 (200 microg/kg/day x 14) to achieve a large increase in serum TH levels (HIGH). Serum free T3 and T4 levels were significantly decreased in TXT rats (2.4 and 8.8 fold, respectively), not different in REPL rats and significantly increased in HIGH rats (2.4 and 3 fold, respectively) compared to sham-operated rats (SHAM). Both kinetics of RBC L-T3 uptake were significantly increased in TXT rats (Vmax+/-SE in pmol/min/10(8) cells=235.1+/-11.1, p<0.05 and Km+/-SE in nM=190.1+/-9.0, p<0.05), not different in REPL rats (Vmax=1 84.8+/-7.6 and Km=151.9+/-7.1) and significantly decreased in HIGH rats (Vmax=168.0+/-4.1, p<0.01 and Km=131.9+/-4.6, p<0.01) compared to SHAM rats (Vmax=197.7+/-5.8 and Km=160.9+/-6.1). These results show that kinetics of RBC L-T3 uptake are modified in response to defect or excess in circulating TH levels. Since RBC play likely a role of a buffer system, the changes in carrier-mediated influx of L-T3 could be seen as a compensatory mechanism that counteract the disturbances in the TH availability for the target tissues.

Animals↗

PubMed1999

Evidence for an increase in functional platelet 5-HT2A receptors in depressed patients using the new ligand [125I]-DOI.

Abnormalities in the serotonergic system have been implicated in the pathophysiology of depressive disorders. Human platelets possess serotonin-2A (5-HT(2A)) receptors, and previous research using LSD or ketanserin as ligands have indicated that their number is increased in depressed patients. Compared to other ligands previously used in platelet studies, DOI is highly selective for the 5-HT(2A) receptor and binds to its high-affinity state, therefore labeling only the receptors that are biologically coupled to the G-protein. We determined the density (Bmax) and the affinity (Kd) of 5-HT(2A) receptors labeled by [(125)I]-DOI in platelets from 21 untreated patients with major depression and 21 healthy volunteers. The density of the 5-HT(2A) binding sites was found to be increased in platelets from female depressed patients as compared to controls. No changes were observed in the Kd. We did not find any relationship between the binding parameters and either the severity of the depressive episode or the suicidal tendencies of the patients. Our results show that the number of coupled platelet 5-HT(2A) receptors is increased in depressed patients, indicating that platelet 5-HT(2A) receptor function is enhanced in depression.

Adult↗

PubMed1999

Effects of experimental hypothyroidism on 5-HT1A, 5-HT2A receptors, 5-HT uptake sites and tryptophan hydroxylase activity in mature rat brain1.

The study was aimed at investigating the repercussions of deficiency in thyroid function with and without thyroid hormone (TH) replacement on the neurochemical entities which underly serotonin (5-HT) neutrotransmission, namely 5-HT1A, 5-HT2A receptors, 5-HT transporter and tryptophan hydroxylase (TPH) in the mature brain. Surgically thyroidectomized male Wistar rats received: (1) an iodine-free diet to produce severe hypothyroidism; (2) hormonal replacement with 15 microgram/kg/day of thyroxine (T4) for 21 days to normalize serum TH levels, or (3) hormonal replacement with 200 microgram/kg/day of T4 for 14 days to produce an excess of circulating THs. Sham-operated rats were used as controls. Neither hypothyroidism nor an excess in serum TH levels affected 3H-8-OH-DPAT binding to 5-HT1A receptors, 3H-citalopram binding to 5-HT transporter and TPH activity in various brain structures indicating that, in the mature brain, the presynaptic entities of 5-HT neurotransmission are resistant to large variations in TH levels. By contrast, hypothyroid rats had a significant decrease in Bmax of 3H-ketanserin binding to cortical 5-HT2A receptors compared to controls. Cortical 3H-ketanserin binding in thyroidectomized rats was normalized after replacement with low-dose T4. Excess serum TH levels in thyroidectomized rats did not produce any changes in cortical 5-HT2A receptors when compared to thyroidectomized rats with normalized TH levels. The present data suggest that the decrease in cortical 5-HT2A receptors is the main neurochemical event underlying the impairing effect of hypothyroidism on 5-HT neurotransmission.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1998

Increase in red blood cell triiodothyronine uptake in untreated unipolar major depressed patients compared to healthy volunteers.

1. Kinetic parameters of red blood cell (RBC) L-triiodothyronine (T3) initial uptake (Vmax, maximal velocity and Km, Michaelis constant) were determined in 34 untreated inpatients suffering from unipolar depression and in 40 healthy volunteers. 2. Both Vmax and Km were significantly increased in depressed patients as compared to controls. The alterations in kinetic parameters were not associated with the severity of depression. 3. Out of the 19 depressed patients who were submitted to TRH test, 7 of them (36%) showed a blunted TRH-induced TSH response associated with a Vmax situated outside the control mean value +/- 1 S.D. 4. The authors found a significant positive correlation between Vmax of RBC L-T3 and L-tryptophan (TRP) uptakes which is in agreement with the assumption that L-T3 and L-TRP share a common carrier system at the erythrocyte level. 5. The results indicate that the uptake of L-T3 by RBC is increased in major depression. These transport perturbations might reflect alterations in the plasmatic metabolism of L-T3. Evaluation of RBC L-T3 uptake could be useful in a best biological characterization of the depressed patients with regard to their thyroid function.

Adult↗

PubMed1998

[Plasma tryptophan bioavailability during chronic urticaria].

OBJECTIVES: Chronic idiopathic urticaria is known to have psychogenic component with a triggering or favoring effect. Different tests or evaluation scales have been unable to identify a specific psychological profile. Erythrocyte-specific membrane transport of tyrptophan (TRP), the main plasma precursor of cerebral serotonin synthesis, controls, by a erythrocyte-specific storage and release mechanism, circulating TRP homeostasis. Bioavailability of circulating TRP is a factor controlling serotonin synthesis in the brain. An evaluation of the rate of TRP transfer could be a biochemical approach to chronic urticaria more informative than psychological tests. PATIENTS AND METHODS: A kinetic study of L-TRP influx into circulating erythrocytes was conducted in 17 patients with chronic urticaria with no detectable cause and in 35 healthy controls. Blood samples were marked with 3H-TRP. Maximum L-TRP-specific influx (Vmax) was expressed in mumol/cell/min. The urticaria patients also underwent psychological testing to determine anxiety and depression scores using standardized scales (Hamilton). RESULTS: Mean Vmax was not significantly difference between the two groups. Vmax values were quite similar in all the control subjects but showed wide dispersion in the urticaria group. Three subgroups were found in the urticaria patients depending on Vmax: those with Vmax equivalent in control levels (+2 SD), those with Vmax less then 2 SD (29% of the patients) and those with Vmax greater than 2 SD of control levels (23% of the patients). Thus more than 50% of the urticaria patients had perturbed erythrocyte-specific L-TRP influx. The anxiety and depression scores obtained from the psychological evaluation were not correlated with Vmax. DISCUSSION: Erythrocyte-specific TRP membrane transport, evaluated by Vmax. Would not appear to be perturbed in chronic urticaria. Even though the urticaria patients could be divided into three groups according to their Vmax, the mean value was not significantly different from that in controls. These findings do not allow a conclusion concerning a perturbation of bioavailability of plasmatic TRP and any possible central serotoninergic dysfunction in chronic urticaria.

Adolescent↗

PubMed1997

Experimental hypothyroidism increases immobility in rats in the forced swim paradigm.

Effects of severe and mild hypothyroidism on the immobile response to inescapable stress were examined in male Wistar rats using the forced swim paradigm. Rats were exposed to two sessions of inescapable swim stress: pretest (for 15 min) followed by test (for 5 min) 24 h later. Surgically thyroidectomized rats showed a significant increase (by 90%) in immobility during test compared to sham rats. Chronic administration of high (200 micrograms/kg per day) but not low (15 micrograms/kg per day) dose of T4 prevented the increase in immobility in thyroidectomized rats. Normal rats submitted to iodine-free diet for 2 weeks in order to produce a mild hypothyroidism showed a significant increase (by 60%) in immobility time during test compared to control rats. The results indicate that hypothyroid rats are more vulnerable to inescapable stress than normothyroid rats.

Animals↗

PubMed1997

Red blood cell L-tryptophan uptake in depression. II. Effect of an antidepressant treatment.

The evolution of the kinetic parameters, maximal velocity (Vmax) and Michaelis constant (Km), of L-tryptophan (L-TRP) uptake into red blood cells (RBC) was studied in 30 depressed patients in a drug-free state (D0) and after 1 week (D7) and 4 weeks (D28) of a treatment involving a variety of antidepressant drugs, including SSRIs and tricyclics. At D0, 76% of patients exhibited abnormal values of Vmax, which were either higher (36%) or lower (40%) than the control range (control Vmax mean +/- 1 S.D.). High and low Km values were observed in parallel with high and low Vmax values. At D7, individual values of Vmax varied drastically compared to their corresponding value at D0, whatever the pretreatment value of the parameter. The magnitude of the Vmax variation during the first week of treatment was found to be significantly larger in the treatment responders than in the non-responders. At D28, Vmax values of all the responders to treatment were within the control range, whatever their pretreatment Vmax value. On the contrary, non-responders had Vmax values that were significantly lower than those of the controls. Changes in Km followed changes in Vmax during antidepressant treatment. In conclusion, normalization of L-TRP transport kinetics was concomitant with a clear alleviation of depressive symptoms, indicating that RBC L-TRP uptake is dependent on clinical state. Moreover, early reactivity of the Vmax as soon as the first week of treatment may be useful as a predictive index of clinical outcome at D28.

Adolescent↗

PubMed1996

Red blood cell L-tryptophan uptake in depression: kinetic analysis in untreated depressed patients and healthy volunteers.

Kinetic parameters (Vmax and K(m)) of L-tryptophan (TRP) uptake into red blood cells (RBC) were measured in 72 drug-free depressed inpatients and 35 healthy volunteers. Mean Vmax and K(m) values were not significantly different between patients and volunteers. The frequency distributions of Vmax values, however, largely differed in the two groups: Vmax values were homogeneous in the volunteers while they were widely scattered in the depressed patients. Only 15 out of the 72 depressed patients (21%) had Vmax values within 1 SD from the mean control value. Forty-four percent of the patients (n = 32) had Vmax values above the control mean + 1 SD in 11 patients and above the control mean + 2 SD in 21 patients. Thirty-five depressed patients (n = 25) had Vmax values below the control mean - 1 SD in 8 patients and below the control mean - 2 SD in 17 patients. High and low K(m) values were observed in combination with high and low Vmax values. The alterations in kinetic parameters were neither associated with severity of depression nor with a specific diagnostic subtype of depression. The data show abnormalities in RBC L-TRP uptake in most depressed patients that likely reflect a disturbance in peripheral availability of TRP on which central serotonin synthesis closely depends.

Adolescent↗

PubMed1995

Decrease in red blood cell L-tryptophan uptake in schizophrenic patients: possible link with loss of impulse control.

1. Kinetic parameters of erythrocyte L-tryptophan (TRP) uptake (Vmax, maximal velocity and Km, Michaelis constant) were determined in 19 neuroleptic-free schizophrenic patients and in 19 healthy volunteers. Both Vmax and Km values were significantly lower in schizophrenic patients than in controls. 2. Mean Vmax value was found to be lower in patients who had attempted suicide than in patients who had not. No difference was observed when patients were subdivided on the basis of the violence of suicide attempts. 3. A significant negative correlation was observed between Vmax and scores on the loss of impulse control item as assessed on the PANS scale. 4. Decrease in red blood cell L-TRP uptake reflects a disturbance in the peripheral metabolism of TRP that may result in a deficiency of the plasma L-TRP availability on which the central serotonin (5HT) synthesis closely depends. 5. In addition, the results suggest that the alteration in RBC L-TRP uptake is associated with loss of impulse control in schizophrenic patients.

Adult↗

PubMed1995

Kinetic characterization of a carrier-mediated transport system for L-tryptophan in human blood platelets.

We have characterized a membrane transport system on washed human blood platelets for tritiated L-tryptophan (L-TRP). This transport was extremely rapid, temperature dependent and markedly reduced by disruption of the platelet membranes. Kinetic studies within a large range of L-TRP concentrations have revealed the presence of a high affinity saturable transport system which follows simple Michaelis-Menten kinetics, with an apparent Km value of 10 microM and a Vmax of 200 pmol/min/10(8) cells. Platelet L-TRP accumulation was insensitive to changes in sodium concentrations and to the inclusion of ouabain in the incubation medium. Furthermore, uptake was unmodified by the presence of the metabolic inhibitor dinitrophenol, suggesting that it is mediated by facilitated diffusion. D-Tryptophan was a very poor inhibitor of L-TRP uptake. Transport was insensitive to serotonin and imipramine but was inhibited in a dose-dependent manner by L-tyrosine, L-phenylalanine and L-leucine, implying that it may be mediated by a system that is specific for aromatic and long chain amino acids. The results were compared to reports examining the L-TRP transport in other cell types.

Biological Transport↗

PubMed1994

Relation between lymphocyte beta-adrenergic responsivity and the severity of depressive disorders.

Basal level and isoproterenol-induced response of cyclic adenosine monophosphate (cAMP) were determined in mononuclear leucocytes from 17 drug-free patients with major depressive (n = 9) or dysthymic disorders (n = 8) and 20 normal controls. No significant difference was observed between basal cAMP levels from depressed and control subjects. The cAMP production in response to maximal stimulation by isoproterenol (ISO), a beta-agonist, was significantly lower (-34.7%) in depressed patients than in controls, and was significantly negatively correlated to the severity of the depression as assessed by the Hamilton depression rating scale score (r = -0.62; p < 0.003). When the depressed group was subdivided on the basis of the DSM-III-R (APA 1987) diagnosis criteria into major depressive and dysthymic disorders, the ISO-stimulated cAMP levels in the two groups were indistinguishable. When evaluated at the same time than the density of beta-adrenoreceptors in eight depressed patients, the ISO-stimulated cAMP levels were highly significantly correlated with the Bmax values (r = 0.89; p < 0.003). The results indicate that the decrease in beta-adrenergic responsiveness of mononuclear leukocytes can be present in depressed patients whatever the nosographical subtype of the depressive disorder and is quantitatively related to the depression severity. Based on these data, it seems that the blunted beta-adrenergic sensitivity observed in mononuclear leukocytes (MNL) cells of depressed patients is closely associated with a loss of beta-adrenoceptors.

Adult↗

PubMed1994

Lack of association between platelet tritiated imipramine binding and clinical status of depressed patients on chronic antidepressant treatment.

Platelet tritiated imipramine binding (Bmax) was studied in 33 depressed patients, before and after 1 and 4 weeks of antidepressant treatment, and in 34 healthy volunteers. The Bmax was significantly lower (-21%) in drug-free depressed patients than in controls and increased significantly as early as the first week of treatment to reach the control value, in parallel with a 38% decrease in the Hamilton depression rating scale (HDRS) score. After 4 weeks of treatment, the Bmax was still normal and remained significantly higher than the baseline value, while the clinical state of the patients had greatly improved (a 63% decrease in the HDRS score). However, an increase in the Bmax also occurred in non-responders to treatment. In addition, we observed that the ability of the treatment to increase the Bmax depended on the pharmacological profile of the drug used. The present results show that, in patients on antidepressant medication, platelet tritiated imipramine binding normalization cannot be considered as a marker of clinical remission.

Adult↗

PubMed1993

Evidence for a defective platelet L-tryptophan transport in depressed patients.

The kinetic characteristics of platelet L-tryptophan uptake were investigated in 23 untreated depressed patients and 18 healthy volunteers. A significant increase of 50% in the apparent Michaelis constant (Km) was observed in depressed patients compared with controls, without significant change in the maximal velocity (Vmax). After 1 month of successful antidepressant treatment the mean Km value decreased significantly and reached the control value. This result raises the possibility that the decrease in platelet tryptophan uptake affinity is a state-dependent marker for depression. It is likely that the transport alteration results in a decrease in platelet tryptophan accumulation. The effect of this peripheral membrane defect on brain serotonin function is discussed.

Administration, Oral↗

PubMed1992

Rapid changes in 3H-imipramine platelet binding after chronic treatment with amineptine, a selective dopamine uptake blocker, in major depressed patients.

The effect of chronic treatment with amineptine (200 mg daily), a tricyclic antidepressant drug selectively blocking dopamine uptake, on 3H-imipramine binding, was investigated in platelets of major depressed patients in conjunction with changes in clinical state. Before treatment, depressed patients had a significantly lower Bmax (P less than 0.01) than age- and gender-matched healthy controls. After only 1 week of amineptine administration, Bmax values increased significantly (P less than 0.01) and reached the control value concomitantly with a large and significant clinical improvement (P less than 0.01). After 1 month, Bmax was still significantly different from the pretreatment value (P less than 0.05), and not significantly different from the control value, while the improvement in clinical status persisted. No significant changes in Kd values were observed during treatment. We also verified that amineptine did not displace 3H-imipramine binding from platelets either in depressed or in control subjects. The results show that the successful treatment with amineptine, an antidepressant drug devoid of affinity for the tritiated imipramine platelet binding site, can rapidly lead to its density normalization.

Adult↗

PubMed1991

Beta-adrenoceptor density of intact mononuclear leukocytes in subgroups of depressive disorders.

Binding parameters of (-)-iodopindolol to beta 2-adrenoceptors were determined on intact mononuclear cells in 41 untreated patients with different DSM-III subtypes of depression. Both maximal beta-receptor density (Bmax) and dissociation constant (Kd) were not significantly different between control and all depressed subjects. However, Bmax was significantly decreased in unipolar patients as compared to controls (p less than 0.001) whereas no significant difference was found in bipolar or dysthymic patients. In unipolar patients, a very strong association was found between Bmax values and the severity of the depression as assessed by the Hamilton Depression Rating Scale score (r = -0.75; p less than 0.005). This correlation was also highly significant in the entire depressed population (r = -0.58; p less than 0.0009). These results suggest that the lower number of beta-adrenoceptors in intact leukocyte cells of depressed patients is related to the depression severity.

Adrenergic beta-Antagonists↗

PubMed1991

Early decrease in density of mononuclear leukocyte beta-adrenoceptors in depressed patients following amineptine treatment: possible relation to clinical efficiency.

1. The effect of chronic amineptine treatment (200mg/day) on beta-adrenoceptor density of intact mononuclear leukocytes (MNL) was examined in unmedicated major unipolar depressed patients. 2. Pretreatment parameters of (-)-[125I]-iodopindolol specific binding did not differ significantly from age- and sex-matched healthy controls as the patients were only moderately depressed. 3. All patients showed a highly significant clinical improvement as assessed by the AMDP-depression scale after one week of amineptine (D7), while 2 patients relapsed after one month of treatment (D28) and were considered to be non-responders. 4. The maximal density of beta-adrenoceptors (Bmax) was significantly decreased at D7 (by 33%) compared to pretreatment level (D0) in the treatment responders and remained lower at D28, although the difference was no longer significant. No alteration in beta-receptor affinity (Kd) was detected during the treatment. 5. These results indicate that treatment with amineptine, an antidepressant drug known to selectively inhibit the dopamine uptake system, can rapidly affect MNL beta-adrenoceptors. 6. Moreover, the present findings show that the reduction in MNL beta-adrenoceptor density, which is associated with a stable clinical improvement, may provide a predictive index for successful antidepressant treatment.

Adult↗