Common Alterations in the Serotonin Transporter in Platelets and Lymphocytes of Psychotic Patients

• Introduction
• Subjects and Methods
• Subjects
• Methods
• Platelets and lymphocyte separation
• [³H]5-HT re-uptake
• [³H]Par binding
• Data Analysis
• Results
• Discussion
• Acknowledgement
• References

Introduction: Given the controversial data concerning the role of the serotonin (5-HT) transporter in psychosis, our study was aimed to investigate this structure by means of the measurements of the re-uptake kinetics and of the protein density, in both platelets and lymphocytes of 25 out- and inpatients with different psychotic disorders. Methods: Diagnoses, according to DSM-IV criteria, were bipolar 1 disorders with mood incongruent psychotic features (14), mixed states (7) and schizophrenia (4). Twenty-five matched healthy subjects were also selected as the control group. Platelet and lymphocyte membranes were prepared according to standardized protocols, as were the [³H]5HT re-uptake and [³H]paroxetine ([³H]Par) binding. Results: The results of this study showed a decreased density of the [³H]Par binding sites coupled with a reduced velocity of [³H]5-HT re-uptake in both platelets and lymphocytes of psychotic patients, as compared with healthy control subjects. Conclusion: These findings would suggest a general abnormality of the 5-HT system in psychotic patients, probably not confined only to the brain.

Introduction

The development and introduction into clinical practice of the so-called atypical antipsychotics, characterized by a pharmacological action including antagonism at the level of serotonin (5-HT) receptors, has provoked a renewed interest in the possible involvement of 5-HT in the pathophysiology of psychosis [6] [11].

The means of exploring neurotransmitter levels or functions in vivo are still limited, except for 5-HT, since blood platelets represent a reliable peripheral model of presynaptic serotonergic neurons [22]. In particular, platelets possess a 5-HT transporter system which practically overlaps that present in the brain where it plays a critical role in regulating the concentrations of 5-HT in the synaptic cleft [12].

Different studies have shown changes of the platelet 5-HT transporter in schizophrenic patients, with heterogenous results. These may be attributed to the different methods used to evaluate the transporter, assessed by means of the re-uptake kinetics [2] [10] [13] [23], or the measurement of tritiated imipramine ([³H]IMI) binding sites, or that of tritiated paroxetine ([³H]Par) binding sites, these last only corresponding to the transporter proteins themselves. Some authors have observed a decreased re-uptake or reduced density of [³H]IMI binding sites in the patients [14] [20], while others have reported either an increase or no difference in healthy control subjects [24]. Again, the patient samples are not entirely comparable in terms of diagnosis or drug intake. Similarly, no conclusion can yet be drawn from studies exploring correlations between platelet 5-HT re-uptake and polymorphism of the 5-HT transporter genes in schizophrenic patients [18].

Given these controversial data, in the present study we carried out an exhaustive exploration of the 5-HT transporter in patients with different psychotic disorders that had been well-characterized from the diagnostic point of view. This structure was evaluated by means of [³H]Par binding sites and [³H]5-HT re-uptake kinetics, in both platelets and lymphocytes where it was recently demonstrated [16].

Subjects and Methods

Subjects

Twenty-five patients (10 women and 15 men, mean age ± SD = 27 ± 7 years) recruited from the out- and inpatient wards of the Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie at Pisa University, were included in the study (Table [1]). Diagnoses, according to DSM IV criteria [1] and assessed by the SCID for DSM-IV [7] were: bipolar 1 disorder with mood incongruent psychotic features (14), mixed states (7) and schizophrenia (4). Nine patients were currently taking drugs, as follows: antipsychotics, namely haloperidol (1), chlorpromazine (1) and olanzapine (2), lithium salts (1) benzodiazepines (3) and valproate (1), while the remaining patients had been drug-free for a period ranging between 2 and 6 months. The severity of the symptoms was assessed by means of the Brief Psychiatric Rating Scale (BPRS) [19]; the total score was 30 ± 4. Fourteen patients had completed the primary school, 8 had completed the high school, and 3 had a doctorate degree. With regards to patients’ occupation, 2 were white collars, 7 blue collars, 8 unemployed, 4 were students and 4 were housewives. Twelve patients were married, while the remaining 13 were single (8) or separated/divorced (5).

Twenty-five healthy drug-free subjects (10 women and 15 men, mean age ± SD = 24 ± 7 years) with neither family nor personal history of any major psychiatric disorder, were included as control subjects. Neither patients nor control subjects suffered from any major physical disorder, as assessed by the normal blood and urine tests and a medical check-up.

All patients or their legal representatives gave their informed written consent to their inclusion in the study, which was approved by the Ethics Committee of Pisa University.

Methods

Platelets and lymphocyte separation

Venous blood (70 ml) was collected from fasting subjects between 8 and 9 a. m. during the months of April-June, in order to avoid the possible interference of circadian or seasonal rhythms, respectively; 30 ml were then gently mixed with 1 ml of anticoagulant (0.15 M EDTA) for platelet preparation, while 40 ml were collected in heparinized (10 UI/ml blood) plastic tubes and processed for lymphocyte preparation.

Platelet-rich plasma was obtained by low-speed centrifugation (200 × g, for 20 min, at 22 °C). Platelets were counted automatically by means of a flux cytometer (Cell-dyn 3500 system, Abbott, Milano, Italy). Lymphocytes were isolated by means of our modification of the Boyum method, as already described [16].

For [³H]5-HT re-uptake, platelets and lymphocytes were used immediately. For [³H]Par binding, platelets and lymphocytes were precipitated by centrifugation at 10,000 × g for 10 min at 4 °C and the ensuing pellets of platelets and lymphocytes were then stored at -80 °C until the assay, which was performed within a week.

[³H]5-HT re-uptake

The [³H]5-HT re-uptake was performed according to the method of Arora and Meltzer [2], with some modifications [16]. Aliquots of platelets or lymphocytes (10⁶ cells) were incubated with [³H]5-HT (specific activity: 30 Ci/mmol, Perkin-Elmer Life Science, Milano, Italy) at six concentrations ranging from 20 nM to 1500 nM in an assay buffer (118 mM NaCl, 4.7 mM KCl, 1.07 mM MgSO₄·7H₂O, 1.17 mM KH₂PO₄, 25 mM NaHCO₃, 11.6 mM glucose, pH 7.4) to a final volume of 0.5 ml and the incubation was carried out for 10 min at 37 °C. Non specific re-uptake was measured in the presence of 10 μM fluoxetine (a gift from Eli Lilly Co, Indianapolis, IN, USA). Specific re-uptake was determined as the difference between total and non-specific re-uptake. All points were performed in duplicate. The reaction was halted by the addition of 5 ml of ice-cold assay buffer which was then followed by rapid filtration through GF/C glass-fibre filters. Filters were then incubated with 200 μl of 0.2 N NaOH to obtain the cell lysis, neutralized by adding 200 μl of 0.2 N glacial acetic acid and then placed in plastic vials with 10 ml of scintillation liquid for radioactivity measurement as above.

[³H]Par binding

The [³H]Par binding was carried out according to the method of Marazziti et al. [15]. The incubation mixture consisted of 100 μl of platelet or lymphocyte membranes (50-100 μg protein/tube), 50 μl of [³H]Par (Perkin-Elmer Life Science, Milano, Italy: 19.1 Ci/mmol) at six concentrations ranging from 0.01 to 1 nM and 1.85 ml of assay buffer. Specific binding was obtained as the binding remaining in the presence of 10 μM fluoxetine as a displacer. All samples were assayed in duplicate and incubated at 22 °C for 1 hour. The incubation was halted while adding 5 ml of cold assay buffer. The content of the tubes was immediately filtered under vacuum through glass fibre filters GF/C and washed 3 times with 5 ml of assay buffer. Filters were then placed in vials with 4 ml of scintillation cocktail, and radioactivity was measured by means of a beta-counter (Packard LS 1600).

Data Analysis

The maximal velocity (V_max, pmol/10⁹cells/min) and the Michaelis-Menten constant (K_m, nM) of the 5-HT re-uptake were calculated by transforming saturation data according to the Lineweaver-Burk plot method with the aid of the GraphPad Prism program. Equilibrium-saturation binding data, the maximum binding capacity (B_max, fmol/mg protein) and the dissociation constant (K_d, nM) were analysed by means of iterative curve-fitting computer programmes EBDA.

The differences in binding parameters between the two groups were analysed by means of Student’s t-test (unpaired, two-tailed). The possible effects of age, sex and diagnosis on biological parameters were investigated by means of analysis of covariance, while the correlations between variables were explored using Pearson’s method, all with the computer software Statview 5 for Macintosh, 1992.

Results

Patients did not differ from control subjects in age or sex and these parameters did not affect B_max and K_d values of [³H]Par binding or V_max and K_m of [³H]5-HT re-uptake to both platelet and lymphocyte membranes.

As far as platelet markers were concerned, B_maxvalues (fmol/mg protein) were statistically lower in patients than in control subjects (951 ± 115 vs 1380 ± 95, respectively, p = 0.016), with no change in the K_d values (nM) (0.10 ± 0.05 vs 0.08 ± 0.02). The V_max values (pmol/10⁹ plt/min, mean ± SD) too, were statistically lower in patients than in control subjects (52 ± 18 vs 133 ± 15, respectively, p = 0.03) while the K_m values (nM) were not different (171.42 ± 62.12 vs 201.53 ± 67.14).

The same results were obtained in lymphocyte membranes, namely the B_max (313 ± 131 vs 600 ± 50, p = 0.008) and V_max (7400 ± 310 vs 9400 ± 350, p = 0.016) values were significantly lower in patients than in the control subjects, with no change in the K_d (0.08 ± 0.02 vs 0.12 ± 0.03) or K_m (195.34 ± 49.11 vs 195.42 ± 49.31) (Table [2]).

No correlation was observed between biological markers and either the BPRS total score or single items.

Discussion

The results of the present study showed that patients with different psychotic disorders presented changes in the 5-HT transporter, as assessed by the specific binding of [³H]Par and re-uptake of [³H]5-HT in both platelet and lymphocyte membranes, as compared with healthy control subjects. All the dysfunctions observed were in the same direction, that is, a decreased density of [³H]Par binding sites coupled with a decreased velocity of 5-HT re-uptake. The decreased density of [³H]Par binding sites, with no change in the dissociation constant, is suggestive of a true decrease in the transporter proteins which, in addition, work at a lower level, not compensated by any change of the Michaelis-Menten constant.

Our findings in platelets are consistent with the results of previous studies showing decreased [³H]IMI binding sites [14] [20], or decreased 5-HT re-uptake [2] [10] in schizophrenic patients. However, some authors have reported either an increase [8] or no difference between patients and healthy control subjects [24]. The main criticism regarding these studies is that the specificity of [³H]IMI in labelling the 5-HT transporter is questionable, since it has been shown that this ligand binds to two sites, only one of which is closely related to the transporter, so that it has been considered advisable to use more specific ligands, such as [³H]Par or [³H]citalopram [17]. Our study may, therefore, be considered one of the first to explore the platelet 5-HT transporter in psychotic patients by means of [³H]Par, since this ligand has to date been employed mostly in PET studies of the brain [5] [9].

Although our sample size was too small for reliable statistical analysis, we did not detect any difference between treated and not-treated patients. It should be underlined, however, that mood stabilizers, benzodiazepines and antipsychotics do not seem to interfere with [³H]Par binding parameters, at least in vitro [3] [21]; however, unmedicated patients have recently been reported to have an up-regulation of the transporter which was unfortunately assessed by means of [³H]IMI [8]. Also, given the small sample size, we could not investigate the effect of single diagnoses on biological parameters.

The most interesting finding in our study was that changes in platelets were parallel and even more significant in lymphocytes. This is not so surprising given the evidence that both cell types belong to the same environment and are subject to similar influences. However, lymphocytes are potentially more interesting as a possible means of investigating a given structure at the level of its transcription processes [16].

In conclusion, our findings would suggest that patients with different psychotic disorders may present a decreased functionality of the 5-HT transporter in presynaptic neurons, which is reflected in blood cells and which involves both the number of the transporter proteins and also their activity. Such a hypofunctionality might be a primary or a secondary phenomenon, representing an adaptation to changes in 5-HT levels in the brain (or possibly in the whole organism). Amongst the functions recently attributed to the 5-HT transporter, it is suggested that it may play a role in brain development and plasticity [4]. A derangement of this process in specific brain areas and at critical ages might constitute some form of vulnerability to the subsequent onset of psychotic symptoms or to psychopathology generally.

Alternatively, the changes observed in the brain and in blood cells, might reflect a general abnormality of the 5-HT metabolism/system involving not only the brain, but also the immune system (lymphocytes) and the circulation (platelets). If this were indeed the case, then similar alterations in the 5-HT transporter might be detected also in other organs rich in it.

Acknowledgement

This study was supported by a grant from the Fondazione IRCCS Santa Lucia, via Ardeatina 306 Roma; convenzione120.3/RF01.166 (to G.B. Cassano, 2001).

References

• 1 American Psychiatric Association. DSM IV, Diagnostic and Statistical Manual of Mental Disorders. 4th Edition 1994 American Psychiatric Press Washington, DC;
• 2 Arora R C, Meltzer H Y. Serotonin uptake by blood platelets of schizophrenic patients.  Psychiatry Res. 1982;  6 327-333
  CrossrefPubMedSearch in Google Scholar
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• 4 Bruening G, Liangos O, Baumgartner H G. Prenatal development of the serotonin transporter in mouse brain.  Cell Tissue Res. 1997;  289 211-221
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• 5 Dean B, Tomaskovic-Crook E, Opeskin K, Keks N, Copolov V. No change in the density of the serotonin-1A receptor, the serotonin- or the serotonin transporter in the dorsolateral prefrontal cortex from subjects with schizophrenia.  Neurochem Int. 1999;  34 109-115
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• 7 First M B, Spitzer R L, Gibbon M, Williams J BW. Structured Clinical interview for DSM-IV Axis I disorders-Patient Edition (SCID-I/P, Version 2.0, 4/97 revision), Biometrics Research Department. New York State Psychiatric Institute 1997
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• 8 Govitrapong P, Mukda S, Turakitwanakan W, Dumrongphol H, Chindaduangratn A, Sanvarinda Y. Platelet serotonin transporter in schizophrenic patients with and without neuroleptic treatment.  Neurochem Int. 2002;  41 209-216
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  CrossrefPubMedSearch in Google Scholar
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  PubMedSearch in Google Scholar
• 12 Lesch K P, Wolozin B L, Murphy D L, Riederer P. Primary structure of the human platelet serotonin uptake site: identity with the brain serotonin transporter.  J Neurochem. 1993;  60 2319-2322
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• 13 Lingjaerde O. Serotonin uptake and efflux in blood platelets from untreated and neuroleptic-treated schizophrenics.  Biol Psychiatry. 1983;  18 1345-1356
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• 14 Marazziti D, Placidi G F, Cassano G B, Akiskal H S. Lack of specificity of reduced platelet imipramine binding in different psychiatric conditions.  Psychiatry Res. 1989;  30 21-29
  CrossrefPubMedSearch in Google Scholar
• 15 Marazziti D, Rossi A, Gemignani A, Giannaccini G, Pfanner C, Milanfranchi A, Presta S, Lucacchini A, Cassano G B. Decreased platelet ³H-paroxetine binding in obsessive-compulsive patients.  Neuropsychobiology. 1996;  34 184-187
  PubMedSearch in Google Scholar
• 16 Marazziti D, Rossi A, Giannaccini G, Baroni S, Lucacchini A, Cassano G B. Presence and characterization of the serotonin transporter in human resting lymphocytes.  Neuropsychopharmacology. 1998;  19 154-159
  CrossrefPubMedSearch in Google Scholar
• 17 Meyerson L R, Ieni J R, Wennogle L P. Allosteric interaction between the site labelled by ³H-imipramine and the serotonin transporter in human platelets.  J Neurochem . 1987;  48 560-565
  PubMedSearch in Google Scholar
• 18 Muller-Oerlinghausen K R, Filler D, Tremblay P B, Berghofer A, Roots I, Brockmoller J. Correlation between serotonin uptake in human blood platelets with the 44-bp polymorphism and the 17-bp variable number of tandem repeat of the serotonin transporter.  Am J Med Genet. 2002;  114 323-328
  CrossrefPubMedSearch in Google Scholar
• 19 Overall G. Brief Psychiatric Rating Scale.  Psychol Rep. 1962;  10 799-812
  CrossrefPubMedSearch in Google Scholar
• 20 Rotman A, Shatz A, Szekely G -A. Correlation between serotonin uptake and imipramine binding in schizophrenic patients.  Prog Neuropsychopharmacol Biol Psychiatry. 1982;  6 57-61
  PubMedSearch in Google Scholar
• 21 Rotondo A, Giannaccini G, Betti L, Chiellini G, Marazziti D, Martini C, Cassano G B, Lucacchini A. The serotonin transporter: purification and partial characterization from human brain.  Neurochem Int. 1996;  28 299-307
  CrossrefPubMedSearch in Google Scholar
• 22 Stahl S M. The human platelets.  Arch Gen Psychiatry. 1977;  34 509-516
  PubMedSearch in Google Scholar
• 23 Stahl S M, Woo D J, Mefford I M, Berger P A, Ciaranello R D. Hyperserotonemia and platelet serotonin uptake and release in schizophrenia and affective disorders.  Am J Psychiatry. 1983;  140 26-30
  PubMedSearch in Google Scholar
• 24 Weizman A, Gonen N, Tyano S, Szekely G A, Rehavi M. Platelet [³H]imipramine binding in autism and schizophrenia.  Psychopharmacol. 1987;  91 101-103
  PubMedSearch in Google Scholar

Dr. Donatella Marazziti

Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie

University of Pisa

via Roma 67

56100 Pisa

Italy

Phone: +39 050 835412

Fax: +39 050 21581

Email: dmarazzi@psico.med.unipi.it

References

• 1 American Psychiatric Association. DSM IV, Diagnostic and Statistical Manual of Mental Disorders. 4th Edition 1994 American Psychiatric Press Washington, DC;
• 2 Arora R C, Meltzer H Y. Serotonin uptake by blood platelets of schizophrenic patients.  Psychiatry Res. 1982;  6 327-333
  CrossrefPubMedSearch in Google Scholar
• 3 Arora R C, Meltzer H Y. Effects of chlorpromazine on serotonin uptake in blood platelets.  Psychiatry Res. 1983;  9 23-28
  CrossrefPubMedSearch in Google Scholar
• 4 Bruening G, Liangos O, Baumgartner H G. Prenatal development of the serotonin transporter in mouse brain.  Cell Tissue Res. 1997;  289 211-221
  CrossrefPubMedSearch in Google Scholar
• 5 Dean B, Tomaskovic-Crook E, Opeskin K, Keks N, Copolov V. No change in the density of the serotonin-1A receptor, the serotonin- or the serotonin transporter in the dorsolateral prefrontal cortex from subjects with schizophrenia.  Neurochem Int. 1999;  34 109-115
  CrossrefPubMedSearch in Google Scholar
• 6 Egan M F, Hyde T M. Schizophrenia: neurobiology. In: Sadock BJ, Sadock VA (Eds.) Kaplan and Sadock’s Comprehensive Textbook of Psychiatry. 7th edition Lippincott Williams and Wilkins USA; 2000: pp 1129-1147
  Search in Google Scholar
• 7 First M B, Spitzer R L, Gibbon M, Williams J BW. Structured Clinical interview for DSM-IV Axis I disorders-Patient Edition (SCID-I/P, Version 2.0, 4/97 revision), Biometrics Research Department. New York State Psychiatric Institute 1997
  Search in Google Scholar
• 8 Govitrapong P, Mukda S, Turakitwanakan W, Dumrongphol H, Chindaduangratn A, Sanvarinda Y. Platelet serotonin transporter in schizophrenic patients with and without neuroleptic treatment.  Neurochem Int. 2002;  41 209-216
  CrossrefPubMedSearch in Google Scholar
• 9 Joyce J N, Shane A, Lexow N, Winokur A, Casanova M F, Kleinman J E. Serotonin uptake sites and serotonin are altered in the limbic system of schizophrenics.  Neuropsychopharmacology. 1993;  8 315-336
  PubMedSearch in Google Scholar
• 10 Kaplan R D, Mann J J. Altered platelet serotonin uptake kinetics in schizophrenia and depression.  Life Sci. 1982;  31 583-588
  CrossrefPubMedSearch in Google Scholar
• 11 Kornhuber J, Wiltfang J, Bleich S. The etiopathogenesis of schizophrenias.  Pharmacopsychiatry. 2004;  37 (Suppl. 2) S103-112
  PubMedSearch in Google Scholar
• 12 Lesch K P, Wolozin B L, Murphy D L, Riederer P. Primary structure of the human platelet serotonin uptake site: identity with the brain serotonin transporter.  J Neurochem. 1993;  60 2319-2322
  CrossrefPubMedSearch in Google Scholar
• 13 Lingjaerde O. Serotonin uptake and efflux in blood platelets from untreated and neuroleptic-treated schizophrenics.  Biol Psychiatry. 1983;  18 1345-1356
  PubMedSearch in Google Scholar
• 14 Marazziti D, Placidi G F, Cassano G B, Akiskal H S. Lack of specificity of reduced platelet imipramine binding in different psychiatric conditions.  Psychiatry Res. 1989;  30 21-29
  CrossrefPubMedSearch in Google Scholar
• 15 Marazziti D, Rossi A, Gemignani A, Giannaccini G, Pfanner C, Milanfranchi A, Presta S, Lucacchini A, Cassano G B. Decreased platelet ³H-paroxetine binding in obsessive-compulsive patients.  Neuropsychobiology. 1996;  34 184-187
  PubMedSearch in Google Scholar
• 16 Marazziti D, Rossi A, Giannaccini G, Baroni S, Lucacchini A, Cassano G B. Presence and characterization of the serotonin transporter in human resting lymphocytes.  Neuropsychopharmacology. 1998;  19 154-159
  CrossrefPubMedSearch in Google Scholar
• 17 Meyerson L R, Ieni J R, Wennogle L P. Allosteric interaction between the site labelled by ³H-imipramine and the serotonin transporter in human platelets.  J Neurochem . 1987;  48 560-565
  PubMedSearch in Google Scholar
• 18 Muller-Oerlinghausen K R, Filler D, Tremblay P B, Berghofer A, Roots I, Brockmoller J. Correlation between serotonin uptake in human blood platelets with the 44-bp polymorphism and the 17-bp variable number of tandem repeat of the serotonin transporter.  Am J Med Genet. 2002;  114 323-328
  CrossrefPubMedSearch in Google Scholar
• 19 Overall G. Brief Psychiatric Rating Scale.  Psychol Rep. 1962;  10 799-812
  CrossrefPubMedSearch in Google Scholar
• 20 Rotman A, Shatz A, Szekely G -A. Correlation between serotonin uptake and imipramine binding in schizophrenic patients.  Prog Neuropsychopharmacol Biol Psychiatry. 1982;  6 57-61
  PubMedSearch in Google Scholar
• 21 Rotondo A, Giannaccini G, Betti L, Chiellini G, Marazziti D, Martini C, Cassano G B, Lucacchini A. The serotonin transporter: purification and partial characterization from human brain.  Neurochem Int. 1996;  28 299-307
  CrossrefPubMedSearch in Google Scholar
• 22 Stahl S M. The human platelets.  Arch Gen Psychiatry. 1977;  34 509-516
  PubMedSearch in Google Scholar
• 23 Stahl S M, Woo D J, Mefford I M, Berger P A, Ciaranello R D. Hyperserotonemia and platelet serotonin uptake and release in schizophrenia and affective disorders.  Am J Psychiatry. 1983;  140 26-30
  PubMedSearch in Google Scholar
• 24 Weizman A, Gonen N, Tyano S, Szekely G A, Rehavi M. Platelet [³H]imipramine binding in autism and schizophrenia.  Psychopharmacol. 1987;  91 101-103
  PubMedSearch in Google Scholar

Dr. Donatella Marazziti

Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie

University of Pisa

via Roma 67

56100 Pisa

Italy

Phone: +39 050 835412

Fax: +39 050 21581

Email: dmarazzi@psico.med.unipi.it