I. Masala

Latest advancements on serotonin and dopamine transporters in lymphocytes.

Different data show that circulating lymphocytes possess functional serotonin and dopamine transporters (SERT and DAT, respectively). This papers aims to review most of the available literature on this topic, while highlighting the possible role of SERT and DAT, as well as that of their substrates including antidepressants on the immune system.

Platelet [3H]paroxetine binding in patients with OCD-related disorders

The recently introduced notion of clinical conditions being related one to another, the spectrum concept, permits the testing of the involvement of serotonergic systems in a broad range of disorders tentatively linked to obsessive-compulsive disorder (OCD) for which no pathophysiological hypotheses yet exist. We therefore compared the binding of [3H]paroxetine ([3H]Par), a ligand that specifically labels the serotonin (5-HT) transporter, in platelets of drug-free outpatients suffering from various OCD-related disorders with binding in platelets of OCD patients and healthy subjects. Diagnoses were made according to DSM-IV criteria. The most frequent diagnosis was that of body dysmorphic disorder, followed by impulse control disorder, kleptomania, Tourettes syndrome and trichotillomania. Platelet membranes and [3H]Par binding were studied according to standardized protocols. The results, showing a similarly decreased density of [3H]Par binding sites in both patient groups as compared with healthy subjects, suggest the presence of a shared abnormality at the level of the presynaptic 5-HT transporter, probably linked to a common dimension yet to be identified.

Increased Inhibitory Activity of Protein Kinase C on the Serotonin Transporter in OCD

Different observations show a reduced functionality of the serotonin (5-HT) transporter in obsessive-compulsive disorder (OCD) that might be due to a disturbance of its regulation at intracellular level. Protein kinase C (PKC) has been reported to provoke a decrease in the number of the 5-HT transporter proteins. Therefore, we investigated whether OCD patients differed from control subjects in the effect of PKC upon the 5-HT transporter, after stimulation of this enzyme with 4β-12-tetradecanoylphorbol 13-acetate (β-TPA). Fifteen patients affected by OCD, according to DSM-IV criteria, were compared with a similar group of healthy subjects. The determination of 5-HT uptake was carried out according to the method of Arora and Meltzer with slight modifications. At baseline, OCD patients showed a significant decrease in the maximal velocity (Vmax) of 5-HT uptake, as compared with control subjects, with no change in the Michaelis-Menten constant (Km). The activation of PKC with β-TPA provoked a significant decrease in Vmax values in both groups, but the effect was significantly more robust in OCD patients who, in turn, also showed also an increase in Km values. These findings could indicate the presence of hyperactivity of PKC in OCD that could be the result of increased activity of the phosphatidylinositol pathway. In addition, this suggests new potential therapeutic targets in OCD.

Distribution of [3H]GR65630 binding in human brain postmortem.

We investigated the distribution of serotonin (5-HT) receptors of type 3 (5-HT3) in human brain areas, by means of the the specific binding of [3H]GR65630. The brains were obtained during autoptic sessions from 6 subjects. Human brain membranes and the binding of [3H]GR65630 were carried out according to standardized methods. The highest density (Bmax ± 6 SD, fmol/mg protein) of [3H]GR65630 binding sites was found in area postrema (13.1 ± 9.7), followed at a statistically lower level, by nucleus tractus solitarius (6.7 ± 3.4), nervus vagus (5.5 ± 2.1), striatum (4.8 ± 2.4) with a progressive decrease in amygdala, olivar nuclei, hippocampus, olfactory bulbus and prefrontal cortex, and then by the other cortical areas and the cerebellum, where no binding was detected. These observations extend previous findings on the distribution of 5-HT3 receptors and confirm interspecies variations that might explain the heterogeneous properties of 5-HT3 receptors in different animals.

Impulsivity, gender, and the platelet serotonin transporter in healthy subjects

The present study explored the possible relationships between impulsivity, gender, and a peripheral serotonergic marker, the platelet serotonin (5-HT) transporter (SERT), in a group of 32 healthy subjects. The impulsivity was measured by means of the Barratt Impulsivity Scale, version 11 (BIS-11), a widely used self-report questionnaire, and the platelet SERT was evaluated by means of the specific binding of 3H-paroxetine (3H-Par) to platelet membranes, according to standardized protocols. The results showed that women had a higher BIS-11 total score than men, and also higher scores of two factors of the same scale: the motor impulsivity and the cognitive complexity. The analysis of the correlations revealed that the density of the SERT proteins, as measured by the maximum binding capacity (Bmax) of 3H-Par, was significantly and positively related to the cognitive complexity factor, but only in men. Men showed also a significant and negative correlation with the dissociation constant, Kd, of (3H-Par) binding, and the motor impulsivity factor. These findings suggest that women are generally more impulsive than men, but that the 5-HT system is more involved in the impulsivity of men than in that of women.

Jealousy and Subthreshold Psychopathology: A Serotonergic Link

Background: A few studies suggest that different neurotransmitters may play a role in the expression of jealousy. Our study aimed to explore the serotonergic system by means of the specific binding of 3H-paroxetine (3H-Par) to platelet membranes of healthy subjects with and without excessive jealousy concerns, according to a specific self-administered questionnaire [Questionnaire for affective relationships (QAR)]. Subjects and Methods: The study sample includes 21 subjects concerned by jealousy thoughts and 21 control subjects without jealousy concerns, as shown by their QAR scores. Subjects of the first group were administered a battery of self-report instruments designed to detect the presence of typical, atypical and subthreshold psychopathology. Platelet membranes and 3H-Par binding were carried out according to standardized protocols. Results: Subjects with excessive jealousy concerns had a reduced density of 3H-Par binding as compared with control subjects without jealousy concerns and had one or more psychiatric spectrum conditions. Conclusions: Our findings suggest that excessive jealousy is associated with various forms of psychopathology and may be underlain by alteration of the serotonergic system, as reflected by the lower density of the platelet serotonin transporter.

Regulation of the platelet serotonin transporter by protein kinase C in the young and elderly.

BACKGROUND Some data show that different factors may influence the serotonin (5-HT) uptake rate. Our study aimed at evaluating the possible role of a protein kinase C (PKC) activator, i.e., 4-beta-12-tetradecanoylphorbol-13-acetate (beta-TPA) on the platelet 5-HT uptake of young and elderly subjects, through the measurement of the 5-HT uptake itself and 3H-paroxetine ([3H]PAR) binding sites, which correspond to the transporter protein. METHODS Human platelets and 5-HT uptake were evaluated according to the method of Arora and Meltzer, while [3H]PAR binding was performed following the Marazziti et al method. RESULTS The results showed that beta-TPA reduced significantly the maximal velocity (Vmax) of 5-HT uptake, with no change in the Michaelis constant or in [3H]PAR binding parameters, in platelets of both young and elderly subjects. Although this last group of subjects had a significantly lower Vmax than the other, the degree of inhibition was almost the same (75%) in both. CONCLUSIONS These findings indicate that PKC decreases the 5-HT uptake rate by modifying the phosphorylation state of the transporter and with no change in the number of [3H]PAR binding sites. The responsiveness of this pathway is identical in both young and elderly subjects.

Presence and Characterization of the Dopamine Transporter in Human Resting Lymphocytes

The paucity of information on the presence of the dopamine transporter (DAT) in blood cells, prompted us to explore it in human resting lymphocytes by means of the binding of 3H-WIN 35,428, a compound which is currently considered the most selective ligand for labelling this protein, and by means of the specific reuptake of 3H-dopamine (3H-DA). Lymphocytes were obtained by 15 healthy subjects. The results showed the presence of a specific and saturable binding of 3H-WIN 35,428, which labelled one site only. A specific 3H-DA reuptake was also measured. The pharmacological characterization of both binding and reuptake was overlapping. These findings would indicate that human resting lymphocytes carry the DAT, whose functions in periphery are still unknown.

Decreased platelet [3H]paroxetine binding sites in suicide attempters.

Research to date would suggest the possible involvement of the serotonin (5-HT) system in the pathophysiology of suicide. With this study, we aimed to investigate the platelet 5-HT transporter, by means of the specific binding of tritiated paroxetine ([3H]Par), in a sample of 20 suicide attempters recruited at a first-aid service, as compared with healthy control subjects and psychiatric patients with no current or previous history of suicide attempt. The results, showing a decreased number of [3H]Par binding sites in suicide attempters, would suggest the involvement of the presynaptic 5-HT transporter in self-aggressive behavior.

Alterations of the dopamine transporter in resting lymphocytes of patients with different psychotic disorders

The aim of our study was to investigate and compare the dopamine (DA) transporter (DAT) in resting lymphocytes of 20 psychotic patients and 20 healthy control subjects, by means of both the binding parameters (Bmax and Kd) of 3H-WIN 35,428, and the reuptake parameters (Vmax and Km) of 3H-DA. The results showed that both the Bmax of 3H-WIN 35,428 binding and the Vmax of 3H-DA reuptake of the patients were significantly lower than those of healthy subjects, while the Kd or Km did not show any change. These findings, while indicating a reduced density of the lymphocyte DAT proteins, provide further support of the role of DA in psychoses and suggest that DA alterations may not be limited to brain structures.