Laterality and 3H-imipramine binding: studies in the frontal cortex of normal controls and suicide victims.

Serotonin [5-hydroxytryptamine (5-HT)]-sensitive imipramine binding (IB) was determined in the left and right hemisphere of frontal cortex of suicide victims and nonpsychiatric controls who died due to myocardial infarction or accident. The Kd (an inverse measure of affinity of 3H-imipramine to its binding sites) was significantly higher in left hemisphere than right hemisphere in normal controls. There were no differences in Bmax and Kd or Bmax between left hemisphere and right hemisphere in normals and suicides, respectively. These results do not support the finding of hemispheric asymmetry of 5-HT uptake as measured by IB (Bmax) in postmortem tissue from controls and suicide victims.     

Abnormal platelet 5-hydroxytryptamine uptake and imipramine binding in postnatal dysphoria.

Platelet 14C-5-hydroxytryptamine (14C-5-HT) uptake, 3H-imipramine binding and monoamine oxidase (MAO) activity were measured in women 5 days postpartum and compared with depression scores (Edinburgh Postnatal Depression Scale) at that time and 6 weeks later. Mean Km of 14C-5-HT uptake was significantly reduced in the group showing dysphoria at 5 days (p less than 0.01). Mean Kd of 3H-imipramine binding was significantly increased in the group who later went on to become depressed at 6 weeks postpartum (p less than 0.03). Vmax for 14C-5-HT uptake, Bmax for 3H-imipramine binding and MAO activity did not differ between depressed and non-depressed patients on either occasion. Although the observed changes manifested in a system known to be disturbed in other forms of depression, they were in affinity rather than Bmax or Vmax. Even though probably not of direct physiological significance, such results, if confirmed, together with other pointers in the literature, suggest biochemical abnormalities specific to the puerperal period.     

Reduced 3H-imipramine binding but unaltered 3H-serotonin uptake in platelets of adolescent enuretics

High affinity 3H-imipramine binding and 3H-serotonin uptake to platelets was evaluated in nine untreated adolescent enuretics (ages 13-18) and nine age- and sex-matched controls. A significant decrease in the maximal binding of 3H-imipramine (Bmax) was observed in the enuretics as compared to the controls. No alteration in the affinity of 3H-imipramine to its binding sites (Kd) or in serotonin uptake kinetic parameters (Vmax, Km) was detected. The lack of correlation between Bmax and Vmax values might indicate that the binding sites for imipramine and the sites for serotonin uptake are not identical.     

Serotonergic markers in platelets of patients with major depression: upregulation of 5-HT2 receptors.

The uptake of [3H]5-HT and the density (Bmax) as well as affinity (Kd) of 5-HT uptake sites labelled with [3H]paroxetine and of 5-HT2 receptors labelled by [3H]LSD were determined in platelets from 25 medication-free patients with major depression and 20 normal controls. The density (Bmax) of 5-HT2 receptors was found to be significantly increased (by 52%) in platelets from depressed patients, particularly females. No changes were found in the affinity (Kd) of 5-HT2 receptors and in 5-HT uptake or [3H]paroxetine binding parameters. Density of 5-HT2 receptors positively correlated with that of [3H]paroxetine sites in control but not in depressed subjects. No correlation was found between the HAMD scores and Bmax of [3H]LSD binding. The results suggest that upregulation of platelet 5-HT2 receptors is a useful biological marker in major depression, particularly in females.     

Seasonal variation of platelet serotonin uptake and 3H-imipramine binding in normal and depressed subjects

Density of 3H-imipramine binding sites and serotonin (5-HT) uptake in blood platelets were repeatedly recorded in normal controls (n = 9) and depressed patients (n = 7 for the imipramine binding assay and n = 4 for the serotonin uptake) over a 1-year period. The study demonstrated a striking seasonal variation of both parameters in both groups, with lower values in winter and spring than in summer and fall. No difference in the density of 3H-imipramine binding sites was found between the two populations throughout the year, but serotonin uptake was significantly decreased in depressed patients in May and September. These results underscore the importance of studying controls and patients at the same time of the year.     

Platelet 3H-imipramine binding sites in obsessive-compulsive behavior.

Several studies indicate a serotonergic dysfunction in patients with obsessive-compulsive disorder (OCD). We examined serotonergic function in OCD by determining platelet 3H-impiramine binding sites in patients with OCD during a drug-free baseline period as well as normal control volunteers. The maximum number of binding sites (Bmax) and apparent dissociation constant (Kd) was determined using 3H-imipramine (IMI) as the binding ligand. We observed that the mean 3H-IMI binding Bmax (fmol/mg protein) determined in 24 patients with OCD was not significantly different from that in 23 normal control subjects. There were no significant differences in the Kd between patients with OCD and normal control subjects. Our results are thus similar to those reported by Insel et al (1985) and Black et al (1990), who observed no significant differences in platelet 3H-IMI binding between OCD patients and controls; but different from those reported by Weizmann et al (1986), who observed decreased 3H-IMI Bmax in OCD patients. The discrepancy in the results is not clear, but may be related to several factors. Our results thus indicate that any abnormality in serotonergic function present in patients with OCD is not related to imipramine binding sites in the platelets. However, the possibility that there may be an abnormal platelet serotonin uptake or other serotonergic function in OCD cannot be ruled out.     

Platelet imipramine binding in autistic subjects

Previous reports of elevated platelet serotonin (5-HT) concentrations in autistic subjects suggest that platelet 5-HT uptake might be altered in autism. Parameters of 3H-imipramine (IMI) binding were measured in 11 drug-free autistic subjects and 10 normal volunteers. Similar means (+/- SD) for Bmax (autistics, 1350 +/- fmole/mg protein; normals, 1590 +/- 206 fmole/mg protein) and Kd (autistics, 0.98 +/- 0.10 nM; normals, 0.94 +/- 0.13 nM) were found in the two groups. The normal number (Bmax) and affinity (Kd) of the IMI binding site in autistic subjects suggest that the regulation of 5-HT uptake is not different in autism.     

Serotonin uptake in blood platelets of Duchenne muscular dystrophy patients

Serotonin (5-HT) uptake was studied in the blood platelets of 10 patients with Duchenne-type muscular dystrophy (DMD) and 7 age-matched controls. Vmax (maximum number of uptake sites) of platelet 5-HT uptake in the DMD patients was significantly less than that of the normal controls. There was no difference in the affinity for 5-HT (Km) between the two groups. There was a significant negative correlation between serum creatine kinase activity and Km of 5-HT uptake in blood platelets of these patients. However, no correlation was found between Km or Vmax and ambulatory status of DMD.     

Variation in human platelet 3H-imipramine binding

Platelet 3H-imipramine binding values from 45 normal controls and 20 depressed subjects were collected over a 2-year period. During this time, wide inter-individual variations in the affinity constant (Kd) and maximal number of binding sites (Bmax) were observed in the control population; however, we failed to observe a seasonal change in platelet 3H-imipramine binding. The Kd and Bmax values of depressed subjects were not significantly different from those of controls.     

High-affinity 3H-imipramine binding sites: a possible state-dependent marker for major depression

Ten patients with DSM-III diagnoses of nonbipolar recurrent major depression were studied in an attempt to assess the relationship between 3H-imipramine binding site density and clinical depressive state. They were compared with eight healthy controls who had no past or family history of affective disorders. Evaluations with the Hamilton Rating Scale for Depression and the Self-Rated Scale for Depression were done on the same day as platelet collection at baseline, and also at 2 and 5 weeks after the beginning of treatment with tricyclic antidepressants. The number (Bmax) and the affinity (Kd) of platelet 3H-imipramine binding sites were highly correlated with the improvement of the clinical depression. These results raise the interesting possibility that a decrease in 3H-imipramine binding sites may be a state-dependent marker in patients suffering from nonbipolar recurrent major depression.     

Decreased platelet 3H-imipramine binding in Down's syndrome

Platelet 3H-imipramine binding in 12 subjects with Down's syndrome showed a significantly lower maximal number of binding sites (Bmax) as compared to both unrelated normal and parental controls. No difference in the affinity constant (Kd) was observed. The results support the value of the platelet 3H-imipramine binding assay in the investigation of defects in serotonin metabolism in humans.     

3H-imipramine platelet binding sites in unipolar depression

High-affinity 3H-imipramine binding to platelets was determined in 15 drug-free unipolar depressed women and 15 normal controls. The maximum number of binding sites (Bmax) was lower in the depressed population, but the difference fell short of statistical significance (p = 0.07). The dissociation constant for imipramine binding (Kd) was found to be significantly lower among patients than in controls (p = 0.02). The various factors that can affect the in vitro platelet assay, and the implications for affective disorder research, were discussed.     

Influence of age, sex and diurnal variability on imipramine receptor binding and serotonin uptake in platelets of normal subjects.

Imipramine (IMI) binding and serotonin (5-HT) uptake were determined in platelets of 98 healthy volunteers; and their association with age, sex and circadian rhythm were evaluated. A large interindividual variability was found for both IMI and 5-HT parameters. There was a negative correlation of IMI affinity constant (Kd) and binding (Bmax) with age, but no such correlation of 5-HT affinity constant (Km) or uptake (Vmax). Significant age-related diurnal variability was found for 5-HT Km in the whole group as well as for IMI Kd in males, but not in females. There was no significant correlation between 5-HT Vmax and IMI Bmax. Our results underscore a cautious approach to the interpretation of platelet serotonergic studies. In light of the multiple variables influencing the results, the usefulness of IMI or 5-HT as clinical markers should be re-evaluated.     

Serotonin uptake in the blood platelets of Alzheimer's disease patients

We determined serotonin (5-HT) uptake in the blood platelets of Alzheimer's disease (AD) patients and comparable age-matched normal controls. The maximum number of 5-HT uptake sites (Vmax) was significantly increased in mild and moderate AD patients, and a trend toward decreased V max was observed in severe AD patients as compared with normal controls. The Km of 5-HT uptake was negatively correlated with the Face-Hand Test (FHT) score of severely ill AD patients, whereas Vmax was correlated with the FHT score and the Mental Status Questionnaire score in the entire AD sample.     

Effects of chlorpromazine on serotonin uptake in blood platelets

Platelet serotonin (5-HT) uptake was studied in schizophrenic patients before and after treatment with chlorpromazine (CPZ) for 2-3 weeks. No difference was noted in the affinity of 5-HT (Km) or maximum velocity of 5-HT uptake (Vmax) of unmedicated schizophrenic patients and normal controls. Administration of CPZ was associated with a significant increase in Km and Vmax. Specific uptake of 5-HT, at 0.5 microM, was significantly decreased in most subjects. Chlorpromazine inhibited 5-HT uptake into platelets from normal controls in vitro (IC50, 1.8 +/- 0.1 microM) in a competitive manner.     

Peripheral markers of serotonin and dopamine function in obsessive-compulsive disorder.

In an attempt to clarify the possible role of a serotonergic and dopaminergic dysfunction in obsessive-compulsive disorder (OCD), we measured platelet 3H-imipramine (3H-IMI) binding, serotonin uptake, and platelet sulfotransferase activity in 17 drug-free OCD patients and an equal number of healthy controls. Serotonin uptake and 3H-IMI binding sites in platelets have been shown to constitute peripheral markers of those present in presynaptic serotonergic neurons. Sulfotransferase, an enzyme involved in the catabolism of phenolic compounds and of cathecholamines such as dopamine, has similar kinetic characteristics in brain and platelets. Our results showed a lower number of 3H-IMI binding sites and a higher level of sulfotransferase activity in OCD patients compared with those in controls. These preliminary results suggest involvement of both the serotonin and dopamine systems in OCD.     

Relationship between seasonal patterns of platelet serotonin uptake and 3H-imipramine binding in depressed patients and normal controls

1. Significant seasonal variations were found in the velocity of serotonin (Vmax) uptake and the density of 3H-imipramine binding sites (Bmax) in blood platelets from normal controls. 2. Peak 3H-imipramine (3H-IMI) binding was found in February whereas peak serotonin (5HT) uptake was found in June and these measures were not correlated in paired comparisons. 3. Both Vmax and Bmax values of depressed patients deviated from the normal seasonal pattern with lower uptake and binding in the patient group. 4. A comparison of Vmax and Bmax deviations from the normal patterns of uptake and binding revealed a significant correlation between these measures such that patients with low Vmax values were the same as those with low Bmax values. 5. The results support previous claims that the 3H-IMI binding site may be closely associated with, or identical to, a 5HT transport carrier. 6. A significant correlation between uptake and binding further suggests that a common defect may be responsible for observed decreases in Vmax and Bmax values of depressed patients.     

3H-imipramine binding in the blood platelets of normal twins

3H-Imipramine binding (IB) was studied in the blood platelets of 13 pairs of monozygotic (MZ) and dizygotic (DZ) twins, and 15 pairs of unrelated normal volunteers, to determine if IB is under genetic control. The intrapair variance of Bmax (the maximum number of 3H-IB sites) was significantly smaller in MZ twins and unrelated control pairs than in DZ twins. The intraclass correlations (ICC) of Bmax were significant for all the pairs with no difference between these correlations. The ICC of the Kd (inversely related to the affinity for 3H-imipramine) of IB was significant only for the normal control pairs and the DZ twins. These results suggest that the kinetic constants of IB in blood platelets are not under genetic control and that interassay variance significantly affects the absolute values for Kd and Bmax of 3H-IB. The environmental and assay factors that influence 3H-IB may account for the numerous discrepancies in platelet 3H-IB between various research reports.     

Aggression, hyperactivity and platelet imipramine binding.

We measured platelet 3H-imipramine binding parameters in 16 subjects affected by different types of mental deficiency, all characterized by hyperactive and/or aggressive behaviour, and in 16 healthy controls. The patients had a lower maximum binding capacity than the controls, with no difference in Kd, irrespectively of the type of mental disorder. These findings suggest a link between 5-HT disturbances, reflected by reduced imipramine binding sites, and behavioural dyscontrol, expressed as hyperactivity and aggression.     

Decreased high affinity 3H-imipramine binding in platelets of enuretic children and adolescents

High affinity 3H-imipramine binding sites have been demonstrated in human brain and platelet membranes. It has been suggested that these binding sites selectively label serotonin transporter or uptake sites. Since imipramine has a beneficial effect in the treatment of nocturnal enuresis, the present study was carried out to investigate a possible association between alteration in 3H-imipramine binding parameters in enuretics in comparison to nonenuretic control subjects. 3H-Imipramine binding to platelets was examined in 16 enuretic children and adolescents and compared to that in 22 healthy subjects of similar ages. A significant reduction was observed in the number of 3H-imipramine binding sites, while the dissociation constants (Kd) did not differ significantly in the platelets of enuretics as compared to controls. 3H-Imipramine binding values did not discriminate between familial and nonfamilial enuresis. These results may indicate that an alteration in the serotonin transporter in peripheral or central neuronal levels might be involved in the pathophysiology of nocturnal enuresis.