123I] beta-CIT and single photon emission computed tomography reveal reduced brain serotonin transporter availability in bulimia nervosa.

BACKGROUND: Impaired serotonin transmission has been implicated in the pathophysiology of eating disorders. We investigated the in vivo availability of brain serotonin transporters and dopamine transporters in bulimia nervosa patients. METHODS: Approximately 24 hours after injection of [123I]-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([123I] beta-CIT), single photon emission computed tomography scans were performed in 10 medication-free, female bulimic patients and 10 age-matched, healthy females. For quantification of brain serotonin transporter and dopamine transporter availability, a ratio of specific to nonspecific [123I] beta-CIT brain binding was used (V(3)" = target region - cerebellum/cerebellum). RESULTS: Drug-free bulimia nervosa patients showed a 17% reduced brain serotonin transporter availability in the hypothalamus and thalamus, as compared with healthy control subjects (2.4 +/- 0.4 vs. 2.9 +/- 0.4, p =.026), and a similar reduction in striatal dopamine transporter availability. There was a negative correlation of illness duration and serotonin transporter availability (r = -.65; p =.042) and a strong positive correlation between hypothalamic/thalamic and striatal V(3)" (r =.80, p <.001). CONCLUSIONS: This first report of reduced [123I] beta-CIT binding in a relatively small group of patients with bulimia nervosa suggests a reduced hypothalamic and thalamic serotonin transporter availability in bulimia, which is more pronounced with longer duration of illness.     

Effects of long-term lithium treatment on monoaminergic functions in major depression.

Platelet [14C]serotonin uptake, the density of serotonin transporters and 5HT(2) receptors, and 5HT(2) and alpha(2) receptor function in platelets were investigated in 29 outpatients (15 women and 14 men) diagnosed as having a major affective disorder (21 bipolar and 8 unipolar). The data were compared with data for 26 healthy volunteers matched for age, sex and season. No differences were found in the mean values for the uptake velocity (V(max)) and the affinity (K(m)) of the transport carrier for serotonin between patients and controls. However, female patients had lower V(max) compared to male patients and female control subjects. A positive correlation between plasma lithium and V(max) and a tendency toward a negative correlation between plasma lithium and K(m) was observed. Furthermore, there were no differences in platelet B(max) and K(d) for [3H]paroxetine binding and K(d) for [3H]LSD binding between patients and controls. However, there was an increased number of platelet 5-HT(2) receptors and a difference in serotonin-mediated potentiation of platelet ATP secretion between patients compared to controls, especially in women. The findings in the present study suggest that lithium has a net ameliorating impact on serotonin uptake which may render it resistant to change. They also postulate that the effect of lithium may be attained by a dual influence on postsynaptic serotonergic structures, as it increases both the density and the sensitivity of 5-HT(2) receptors.     

Reduced platelet [3H]paroxetine binding in anorexia nervosa: relationship to eating symptoms and personality pathology

Alterations in serotonin function have been implicated in both anorexia and bulimia nervosa, and previous studies suggest associations between serotonin function and variations in pathological personality traits. Women meeting DSM-IV criteria for anorexia nervosa (AN, 16 with the restricting subtype and 14 with the binge-purge subtype) and 49 healthy control women (CW) provided blood samples for analyses of platelet [(3)H]paroxetine binding. Participants also filled out questionnaires tapping eating disorder symptoms, depression, and personality pathology. Compared with CW, women with restricting and binge-purge AN had significantly lower levels of paroxetine binding (respectively: 1012 + 487 vs. 560 + 253 vs. 618 + 217 fmol/mg protein). Simple correlation analyses showed that, within AN but not within controls, paroxetine binding was inversely related to dieting preoccupations, affective instability, anxiousness, compulsivity, restricted expression and social avoidance but independent of age, body mass index, depression, and other eating symptoms. Findings suggest that reduced peripheral serotonin transporter density in AN relates to increased dieting preoccupations, affective instability and anxiousness-fearfulness.     

Serotonergic activity measured by platelet [3H]paroxetine binding in patients with eating disorders

Most of the evidence from pharmacological studies supports the hypothesis of a serotonergic (5-HT) dysregulation in eating disorders (ED), though a specific alteration related to the major ED subtypes, anorexia (AN) and bulimia nervosa (BN), has not been identified yet, possibly because of changes over time in ED nosology. The aim of the present study was to verify whether differences in serotonergic activity, measured by platelet [3H]paroxetine binding, would validate current ED classification. Platelet [3H]paroxetine binding was investigated in 26 patients with eating disorders diagnosed in accord with DSM-IV criteria (AN, n=11; BN, n=15) and 26 normal weight controls of comparable age; ED symptomatology was assessed by the Diagnostic Schedule for Eating Disorders. ED patients had significantly lower B(max) values than controls (288.5+/-109.2 vs. 1396.8+/-251.3 fmol/mg), whereas the K(d) was not significantly altered (0.12+/-0.13 and 0.12+/-0.05 nM, respectively). Among patients, differences in B(max) were related neither to DSM-IV subtypes nor to clinical variables such as presence of binge-eating, purging, impulsive behaviors, or symptoms of depression. Although ED patients share a dysregulation in serotonergic activity, DSM-IV subtype classification was not validated by [3H]paroxetine binding, and hence does not correspond to a specific 5-HT profile.     

Serotonin transporter gene polymorphisms and platelet [3H] paroxetine binding in premenstrual dysphoria

The purpose of this study was to investigate if women with premenstrual dysphoria differ from controls with respect to the number of platelet serotonin transporters, and with respect to three polymorphisms in the gene coding for the serotonin transporter: a 44 base pair insertion/deletion in the promoter region, a variable number of tandem repeats in the second intron, and a single nucleotide polymorphism in the 3' untranslated region. Also, the possible relationship between the three polymorphisms and platelet serotonin transporter density was analyzed. The density of platelet [(3)H]paroxetine binding sites was significantly lower in women with premenstrual dysphoria than in controls, but patients and controls did not differ with respect to allele or genotype frequency for any of the three polymorphisms examined. A significant association between the number of platelet serotonin transporters and the promoter polymorphism was observed, subjects being homozygous for the short (deletion) variant having higher platelet serotonin transporter density than subjects carrying the long (insertion) allele. The results support the assumption that serotonin-related psychiatric disorders-such as premenstrual dysphoria-may be associated with a reduction in platelet [(3)H]paroxetine binding, but argue against the notion that this reduction is due to certain variants of the serotonin transporter gene being more common in patients than in controls.     

Characterization of serotonin transporter in blood lymphocytes of rats. Modulation by in vivo administration of mitogens

Serotonin transporter sites were characterized in blood lymphocytes of rats. Pharmacological characteristics of drug interactions were in concordance with recent studies in nervous and human immune cells. The potency order of inhibition of [(3)H]paroxetine binding was imipramine>citalopram>alaproclate>serotonin. Selective inhibitors of dopamine or noradrenaline transporters did not inhibit it. The specific binding of [(3)H]paroxetine was higher at intermediate than at low concentrations, and the plot of free vs. specific binding had a sigmoid shape. The affinity constant or K(d), 1.77 nM, was in close agreement with data obtained from kinetic studies (K(d)=1.33 nM), which evidences that the equilibrium was reached. In addition, serotonin transporter was evaluated by lipopolysaccharide or concanavalin A administration in vivo (0.1 mg/kg, i.p., 18 h). After the treatment with lipopolysaccharide, no changes were observed in the numbers of sites or B(max) or in the affinity, K(d). The treatment with concanavalin A showed a significant reduction in B(max) and reduction in K(d). Additionally, serotonin and 5-hydroxyindoleacetic acid levels were determined in plasma and lymphocytes by high-performance liquid chromatography. Treatment with lipopolysaccharide produced a significant increased of serotonin levels in lymphocytes without changes in 5-hydroxyindoleacetic acid level; in plasma, it produced an increase in serotonin and 5-hydroxyindolacetic acid levels. In addition, serotonin synthesis was evaluated by adding 300 microM of tryptophan in the medium, which significantly increased serotonin levels in control lymphocytes. Moreover, the concentrations of 5-hydroxyindoleacetic acid was enhanced significantly, both in plasma and lymphocytes in the presence of tryptophan after treatment with lipopolysaccharide. The administration of concanavalin A significantly decreased plasma levels of serotonin, as well as the concentrations of serotonin and 5-hydroxyindoleacetic acid in lymphocytes. These results demonstrate the presence of serotonin transporter in lymphocytes of rat blood, the capacity for serotonin synthesis in lymphocytes, and the modulation of these parameters by systemic administration of mitogens. The findings of this work contribute to understanding the immunological role of serotonin and the communication of immune and nervous systems.     

In vivo measurement of density and affinity of the monoamine vesicular transporter in a unilateral 6-hydroxydopamine rat model of PD.

This is the first in vivo determination of the vesicular monoamine transporter (VMAT2) density (B(max)) and ligand-transporter affinity (K(d)(app)) in six unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats using micro-positron emission tomography (PET) imaging with [(11)C]-(+)-alpha-dihydrotetrabenazine (DTBZ). A multiple ligand concentration transporter assay (MLCTA) was used to determine a B(max) value of 178+/-32 pmol/mL and a K(d)(app) of 47.7+/-9.3 pmol/mL for the non-lesioned side and 30.52+/-5.84 and 43.4+/-15.52 pmol/mL for the lesioned side, respectively. While B(max) was significantly different between the two sides, no significant difference was observed for the K(d)(app). In addition to demonstrating the feasibility of in vivo Scatchard analysis in rats, these data confirm the expectation that a 6-OHDA lesion does not affect the affinity; a much simpler binding potential (BP) measure can thus be used as a marker of lesion severity (LS) in this rat model of Parkinson's disease. A transporter occupancy curve demonstrated negligible transporter occupancy ( approximately 1%) at a specific activity (SA) of 1100 nCi/pmol (assuming an injected dose of 100 microCi/100 g), while 10% occupancy was estimated at 100 nCi/pmol. An indirect measurement indicated that the degree of occupancy as a function of SA is independent of LS. Finally, BP measurement reproducibility was assessed and found to be 11%+/-7% for the healthy and 8%+/-12% for the lesioned side. Quantitative PET results can thus be obtained even for severely lesioned animals with the striatum on one side not clearly visible provided accurate image analysis methods are used.     

Metabolic abnormalities in bulimia nervosa

Resting metabolic rate was measured in a group of 22 women of normal body weight with bulimia nervosa and in 19 age-, sex-, and weight-matched control subjects. Mean resting metabolic rate of patients was significantly lower than that of controls (5162 +/- 928 vs 5636 +/- 449 kJ/24 h [1229 +/- 221 vs 1342 +/- 107 kcal/24 h]), as was mean fasting blood glucose level (4.0 +/- 0.6 vs 4.6 +/- 0.6 mmol/L). Mean basal thyrotropin level was significantly lower in patients than controls, but other thyroid indexes did not differ. There were no group differences in body fat mass, fat cell size, or lipoprotein lipase activity. These data suggest that there is a disturbance in energy regulation in bulimia nervosa. However, the origins and role of this disturbance in the pathophysiology of bulimia are unclear.     

Childhood abuse and platelet tritiated-paroxetine binding in bulimia nervosa: implications of borderline personality disorder

BACKGROUND: Co-occurrence of bulimia nervosa and borderline personality disorder has been attributed to shared factors, including childhood abuse and disturbances in central serotonin (5-hydroxytryptamine; 5-HT) mechanisms. To explore this notion, we conducted a controlled assessment of childhood abuse and 5-HT function in bulimics with and without borderline personality disorder. METHOD: Forty patients with bulimia nervosa, confirmed with the Eating Disorders Examination interview (14 with borderline personality disorder and 26 without), and 25 normal-eater controls were assessed for clinical symptoms (eating disturbances, mood lability, impulsivity, and dissociation) and childhood sexual and physical abuse. We also conducted tests of platelet tritiated-paroxetine binding in blood samples from 27 of the bulimics (11 with borderline personality disorder and 16 without) and 16 of the controls. RESULTS: Relative to normal eaters, bulimics showed greater affective instability, overall impulsivity, and a history of physical abuse. However, borderline bulimics alone showed elevated motor impulsivity, dissociation, and rates of sexual abuse. Paroxetine-binding tests indicated no differences attributable to comorbid borderline personality disorder, instead linking bulimia nervosa with or without borderline personality disorder to substantially reduced 5-HT transporter density. CONCLUSION: Results suggest relatively autonomous pathologic entities: one, relevant to bulimia nervosa, being associated with abnormal 5-HT transporter function and affective instability, but relatively independent of childhood sexual abuse; another, relevant to borderline personality disorder, onto which sexual abuse, dissociative symptoms, and behavioral impulsivity converge. We propose that abnormal 5-HT function may, however, constitute one basis for the frequent co-occurrence of bulimic and borderline disturbances.     

Seasonal variation of availability of serotonin transporter binding sites in healthy female subjects as measured by [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single photon emission computed tomography.

BACKGROUND: Previous studies have indicated annual variations in central and peripheral serotonergic activity. In the present study we studied five women in summer and six women in winter and evaluated possible differences in availability of brain serotonin transporters between summer and winter. METHODS: We employed the single photon emission computed tomography ligand [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane ([123I] beta-CIT) to visualize binding to the serotonin transporter site in the human thalamus/hypothalamus midbrain area in vivo. Brain imaging studies were performed in one group between May and August and in the other between November and December. RESULTS: We found significant differences in displaceable [123I] beta-CIT binding in the region corresponding to thalamus/hypothalamus between the summer group and the winter group (1.9 +/- 0.3 vs. 1.4 +/- 0.2, respectively; p < .01). CONCLUSIONS: The results of the present study suggest reduced brain serotonin transporter availability in winter. This finding further substantiates evidence of seasonal variations in brain serotonergic function.     

Decreased platelet imipramine binding in Tourette syndrome children with obsessive-compulsive disorder.

[3H]Imipramine binding to blood platelets was assessed in eight untreated Tourette syndrome (TS) children, nine drug-free TS children with obsessive-compulsive disorder (OCD), and nine age-matched and gender-matched control subjects. The density of [3H]imipramine binding sites in TS + OCD patients was significantly lower compared with TS-OCD patients (28%) as well as when compared with controls (31%). This alteration was not accompanied by differences in the affinity of the binding site to the ligand. The decreased density of the platelet serotonin "transporter" might implicate the involvement of the serotonergic system in the pathophysiology of OCD in TS patients, but not in TS per se.     

Platelet serotonin transporters and the transporter gene in control subjects, unipolar patients and bipolar patients

OBJECTIVE: The purpose of the present study was to relate the number of platelet serotonin transporters in unipolar and bipolar patients and in control subjects to two polymorphisms in the serotonin transporter gene: a VNTR in intron 2 and a deletion/insertion in the promoter region. METHOD: Density of platelet serotonin transporters was determined by radioligand binding analysis. Genotyping was performed by PCR amplification of polymorphic regions followed by size determination of the obtained fragments. RESULTS: The control subjects and the two groups of patients were similar with respect to the genotype and allele distribution belonging to the two polymorphisms in the serotonin transporter gene for. An interaction between status (control, unipolar- or bipolar patient) and VNTR genotype regarding the number of platelet serotonin transporters was observed; unipolar patients with the genotype 12/10 had more platelet serotonin transporters than bipolar patients and controls with this genotype. No association related to the polymorphism was found in the promoter region of the serotonin transporter gene. CONCLUSION: An association was observed between the polymorphism in intron 2 of the serotonin transporter gene and the number of platelet serotonin transporters. Unipolar patients with a particular genotype had more platelet serotonin transporters than the corresponding controls and bipolar patients.     

Binding of [(3)H]lysergic acid diethylamide to serotonin 5-HT(2A) receptors and of [(3)H]paroxetine to serotonin uptake sites in platelets from healthy children, adolescents and adults

Possible age effects on binding of [(3)H]lysergic acid diethylamide ([(3)H]LSD) to serotonin 5-HT(2A) receptors and of [(3)H]paroxetine to serotonin uptake sites were studied in platelets from healthy children (11-12 years of age), adolescents (16-17 years of age) and adults. Significant overall age effects were found both for the number of binding sites (B(max)) for [(3)H]LSD binding (p < 0.001), the affinity constant (K(d)) for [(3)H]LSD binding (p < 0.001), B(max) for [(3)H]paroxetine binding (p < 0.001) and K(d) for [(3)H] paroxetine binding (p = 0.006). In general, there was a decrease in B(max) with increasing age, which predominantly occurred between the ages 11-12 years and 16-17 years for the 5-HT(2A) receptor, and after 16-17 years of age for the serotonin uptake site. These developmental changes might have an impact on the effect of treatment with serotonergic drugs in children and adolescents. When the platelet serotonin variables investigated are employed in studies in children or adolescents, age matching or, alternatively, introduction of age control in the statistical analysis should be performed.     

(3)H]Flumazenil binding in the human hippocampal formation, frontal cortex and cerebellum detected by high-resolution phosphorimaging

The pharmacological characterisation of the benzodiazepine binding site associated with the gamma-aminobutyric acid (GABA(A)) receptor in human brain has been demonstrated using in situ radioligand binding and autoradiography. The use of high-resolution phosphorimaging has allowed both the affinity (K(d)) and density (B(max)) of [(3)H]flumazenil binding to be measured within regions of the hippocampal formation as well as the cerebellum and frontal cortex. The Scatchard plots of data from all brain regions were linear with Hill coefficients close to unity consistent with the presence of a single binding site for [(3)H]flumazenil. The affinities of [(3)H]flumazenil binding within all the brain regions were similar (K(d) 1.57+/-0.20-3.08+/-0.01 nM), while the density of [(3)H]flumazenil binding varied significantly between the brain regions analysed (B(max) 182.7+/-7.3-596.7+/-34.0 fmol/mg ETE; P<0.0001). In conclusion, the present results indicate that in situ radioligand binding and high-resolution phosphorimaging techniques can be utilized to measure the distribution, density and affinity of [(3)H]flumazenil to the GABA(A) receptor within the human frontal cortex, cerebellum and hippocampal formation.     

Platelet vesicular monoamine transporter density in untreated patients diagnosed with social phobia

The vesicular monoamine transporter (VMAT2) is important in the storage and release of monoamines. Platelet VMAT2 was characterized using high-affinity [(3)H]dihydrotetrabenazine ([(3)H]TBZOH) binding in untreated social phobia (SP) patients (n=20) compared with sex- and age-matched healthy controls (n=15). No significant differences in VMAT2 density (B(max)) and affinity constants (K(d)) were observed.     

Atipamezole, an imidazoline-type alpha(2)-adrenoceptor inhibitor, binds to human platelets and inhibits their adrenaline-induced aggregation more effectively than yohimbine

To investigate the usefulness of atipamezole [MPV-1248, 4-(2-ethyl-2, 3-dihydro-1H-inden-2-yl)-1H-imidazole], a novel alpha(2)-adrenoceptor-specific antagonist, as a tool in platelet studies, the ability of this antagonist: (1) to bind to platelet alpha(2)-adrenoceptors, and (2) to inhibit adrenaline-induced platelet aggregation was compared to that of yohimbine, another commonly used alpha(2)-adrenoceptor antagonist. It was found that atipamezole binds to platelet alpha(2)-adrenoceptors more effectively than yohimbine: [3H]atipamezole has more than three times higher alpha(2)-adrenoceptor binding affinity in intact gel-filtered human platelets (equilibrium dissociation constant (K(d)) 0.7+/-0.21 vs. 2.9+/-0.77 nM, p<0.05), but only one-third of the binding capacity of [3H]yohimbine (B(max) 27.0+/-3.8 vs. 100+/-19 pM/10(5) cells, p<0.01). Functionally, in comparison with yohimbine, an almost threefold lower concentration of atipamezole inhibited adrenaline (5 microM)-induced platelet aggregation. A concentration of atipamezole, which inhibited this aggregation by 50% (IC(50)), was 0.37+/-0.07 microM, whereas IC(50) for yohimbine was 0.98+/-0.12 microM, p<0.0001. Thus, atipamezole represents a functionally undisputed alpha(2)-adrenoceptor antagonist, more effective than yohimbine. Its distinct binding profile as a radioligand also suggests the presence of imidazol(in)e binding sites in platelets.     

(125)I]3beta-(4-ethyl-3-iodophenyl)nortropane-2beta-carboxylic acid methyl ester ([(125)I]EINT): a potent and selective radioligand for the brain serotonin transporter.

The binding characteristics of [(125)I]3beta-(4-ethyl-3-iodophenyl)nortropane-2beta-carboxylic acid methyl ester ([(125)I]EINT), a high-affinity selective ligand for the serotonin transporter (5-HTT), and its binding characteristics to rat brain membranes were determined. [(125)I]EINT binding to rat cerebral cortex membranes was saturable and reversible, and its specific binding represented approximately 90% of the total binding. [(125)I]EINT labeled a single site with K(d) = 0.22 +/- 0.03 nM and B(max) = 583 +/- 38 fmol/mg protein. Kinetic analysis revealed a t(1/2) for association and dissociation of 20 and 24 min, respectively. Pharmacological characterization of [(125)I]EINT confirmed its high specificity for the 5-HTT. The pattern of brain region distribution in vivo of intravenously administered [(125)I]EINT indicated greater accumulation of the radioligand in 5-HTT-rich brain regions. However, the signal-to-background ratio was low. Thus, [(125)I]EINT appears to be a useful radioligand for studying the 5-HTT in vitro, but it may not be a good in vivo ligand.     

No correlation between aggression and platelet (3)H-paroxetine binding in obsessive-compulsive disorder patients

Different findings suggest that the serotonin (5-HT) system may be involved in both the regulation of aggression and the pathophysiology of obsessive-compulsive disorder (OCD). Our study aimed to evaluate the aggressive features of a group of OCD patients and to explore possible correlations with a serotonergic marker, namely platelet 5-HT transporter. Psychopathological and biological patterns were compared with those of a group of healthy controls and those of patients with major depression. Twenty-one patients affected by OCD, 21 by depression and 21 healthy controls were included in the study. Aggressive features were measured by means of the Buss and Durkee Hostility Inventory (BDHI). The platelet 5-HT transporter was evaluated by means of the (3)H-paroxetine binding parameters (maximum binding capacity, B(max) and dissociation constant, K(d)). The OCD patients showed a total score on the BDHI not significantly different from that of healthy controls and lower than that of depressed patients. The factor profile was similar in the 3 groups, but higher in the depressed patients. The irritability, resentment, guilt, negativism and suspiciousness factors were significantly more pronounced in depressed patients. Some sex-related difference in single factors were also observed. The B(max) of (3)H-paroxetine binding was lower in OCD patients than in depressives or healthy controls. OCD patients were more similar to healthy controls than to depressed patients with regard to aggressive features measured by means of the BDHI. This suggests that aggression in OCD is a complex phenomenon that probably requires specific instruments of evaluation.     

Association of serotonin and cortisol indices with childhood abuse in bulimia nervosa.

BACKGROUND: Bulimia nervosa (BN) is reported to co-occur with childhood abuse and alterations in central serotonin (5-hydroxytryptamine [5-HT]) and cortisol mechanisms. However, findings also link childhood abuse to anomalous 5-HT and cortisol function, and this motivated us to explore relationships between childhood abuse and neurobiological variations in BN. METHODS: Thirty-five bulimic and 25 nonbulimic women were assessed for childhood physical and sexual abuse, eating symptoms, and comorbid psychopathological tendencies. These women provided blood samples for measurement of platelet hydrogen-3-paroxetine binding and serial prolactin and cortisol responses following oral administration of the partial 5-HT agonist meta-chlorophenylpiperazine (m-CPP). RESULTS: Bulimic women showed markedly lower mean +/- SD density (B(max)) of paroxetine-binding sites (631.12 +/- 341.58) than did normal eaters (1213.00 +/- 628.74) (t(54) = -4.47; P =.001). Paroxetine binding did not vary with childhood abuse. In contrast, measures of peak change on prolactin levels after m-CPP administration (Delta-peak prolactin) indicated blunted response in abused bulimic women (7.26 +/- 7.06), nonabused bulimic women (5.62 +/- 3.95), and abused women who were normal eaters (5.73 +/- 5.19) compared with nonabused women who were normal eaters (13.57 +/- 9.94) (F(3,51) = 3.04, P =.04). Furthermore, individuals reporting childhood abuse showed decreased plasma cortisol levels relative to nonabused women who were normal eaters. CONCLUSION: Findings imply that BN and childhood abuse are both generally associated with reduced 5-HT tone but that childhood abuse may be somewhat more specifically linked to reduced cortisol levels (ie, hypothalamic-pituitary-adrenal axis) activity.     

Elevated platelet vesicular monoamine transporter density in untreated patients diagnosed with major depression

The intraneuronal uptake of monoamines into brain synaptic vesicles is mediated by the vesicular monoamine transporter (VMAT2). This transporter plays a major role in monoamine storage and quantal release. Recently we demonstrated a high degree of similarity between the pharmacodynamic characteristics of platelet and brain VMAT2. In the present study we measured the VMAT2 density, using [3H]dihydrotetrabenazine ([3H]TBZOH) as a ligand, in platelets of untreated patients diagnosed with major depressive disorder (MDD) (n=10; three with recurrent depression and seven with first episode depression) compared to sex- and age-matched healthy control subjects (n=23). A significant elevation in the VMAT2 density (B(max)) was observed in the platelets of untreated MDD patients (+24%) compared to healthy control subjects. No significant change was found in the affinity constant (K(d)). The increased platelet VMAT2 density may reflect depression-related enhancement of the capacity to accumulate monoamines in the vesicles in the presence of lower monoamine turnover.