Psychopharmacology

, Volume 195, Issue 3, pp 425–433 | Cite as

A PET study on regional coexpression of 5-HT1A receptors and 5-HTT in the human brain

  • Johan Lundberg
  • Jacqueline Borg
  • Christer Halldin
  • Lars Farde
Original Investigation

Abstract

Rationale

Several lines of evidence suggest inter-dependency between the serotonin transporter (5-HTT) and the 5HT1A receptor, two recognised targets for the treatment of anxiety and depression.

Objectives

to examine the correlation of regional expression levels for these two serotonergic markers in the human brain in vivo.

Methods

Twelve male control subjects were examined with PET twice on the same day, using the radioligands [11C]WAY 100635 and [11C]MADAM for quantification of the 5-HT1A receptor and the 5-HTT, respectively. The binding potential (BP) was calculated for raphe nuclei, hippocampus and frontal cortex.

Results

In all regions, the BP for both [11C]WAY 100635 (raphe nuclei 1.85–4.71, hippocampus 2.52–6.17, frontal cortex 2.03–3.79) and [11C]MADAM (2.70–7.65, 0.47–1.76, 0.18–0.51) varied several fold between subjects. In the raphe nuclei, where the two markers are situated on the same neurons, the ratio of [11C]WAY 100635 binding to [11C]MADAM BP binding varied considerably (0.43–1.05). There was a positive correlation between the two markers in the raphe nuclei (rxy = 0.68, p < 0.05) and in the hippocampus (rxy = 0.97, p < 0.001) but not in the frontal cortex (rxy = −0.25, p = 0.44).

Conclusions

The results support a correlation between density levels of the 5-HT1A-receptor and the 5-HTT in the raphe nuclei and hippocampus but not in the frontal cortex. A suggested clinical implication is that the inter-individual variability in 5-HT1A-receptor and 5-HTT densities, as well as the ratio of these, is of particular interest in relation to individual responses to selective serotonin reuptake inhibitor treatment.

Keywords

PET 5-HT1A-receptor 5-HTT [11C]MADAM [11C]WAY 100635 Human In vivo 

Introduction

Of the 14 5-HT receptors described so far (Hoyer and Martin 1997), the 5-HT1A subtype is one of the best characterised. This G-protein coupled receptor has a wide anatomical distribution in the human brain with highest concentration in the raphe nuclei, limbic structures and neocortex (Hoyer et al. 1986; Verge et al. 1986). A line of evidence from animal studies support its role in a variety of brain functions involving both cognition and emotion (for reviews, see e.g. Barnes and Sharp 1999; Buhot 1997; Pucadyil et al. 2005). These findings have not been confirmed in humans in vivo. Interestingly, in a recent PET study on 24 male control subjects, no significant correlation was found between inter-individual variability in 5-HT1A receptor density and cognitive performance (Borg et al. 2006).

While the 5-HT1A subtype is a postsynaptic receptor in serotonergic projection areas, it is situated presynaptically on cell bodies in the dorsal raphe nuclei (DRN), where it is the only 5-HT-receptor subtype hitherto identified (Barnes and Sharp 1999; Miquel et al. 1991; Sotelo et al. 1990). As these autoreceptors mediate inhibition of cell firing and, thereby, serotonin release in projection areas, it has been suggested that the 5-HT1A receptor in the raphe may have a role in the general regulation of serotonergic activity (Artigas et al. 1996; Borg et al. 2003).

The serotonin transporter (5-HTT) is another functionally important protein in serotonergic transmission. The 5-HTT protein is only expressed on 5-HT neurons and controls the 5-HT concentration in the synaptic cleft (Bengel et al. 1997; Fujita et al. 1993; Qian et al. 1995). With its high concentration on cell bodies and nerve terminals of the raphe nuclei, it may be in an equally good position as the 5-HT1A receptor to have a central role in regulation of serotonergic neurotransmission (Cortes et al. 1988; Hoffman et al. 1998; Plenge et al. 1990; Zhou et al. 1996).

The two proteins are of central interest in psychopharmacology. The 5-HTT is the target for selective serotonin reuptake inhibitors (SSRI), which have a well documented effect in the treatment of depression and anxiety disorders (for recent reviews, see Cryan et al. 2005; Vaswani et al. 2003). The 5-HT1A receptor is the target for the partial agonist buspirone, which is prescribed in anxiety disorders, and, interestingly, the 5-HT1A receptor partial agonist pindolol has been suggested to accelerate the onset of the antidepressant effect of SSRIs. The presynaptic 5-HT1A receptor inhibits 5-HT neurotransmission when stimulated. An acute effect of SSRI treatment is increased 5-HT concentration in the raphe nuclei and a 5-HT1A receptor-mediated decrease in 5-HT neurotransmission. This decrease is normalised in chronic SSRI administration because of a 5-HT1A receptor downregulation (Artigas et al. 1996; Ballesteros and Callado 2004; Hales et al. 1997).

The short (S) allele of the frequent 5-HTT gene (SLC6A4) polymorphism, 5-HTT gene-linked polymorphic region has been associated with restricted transcriptional activity in vitro (Collier et al. 1996). Interestingly, carriers of the S allele have also been shown to have an increased frequency of anxiety and mood disorders (Caspi et al. 2003; Heils et al. 1995; Lesch et al. 1996; Melke et al. 2001). In addition, it has been reported that carriers of the S allele have a lower 5-HT1A receptor density (David et al. 2005). This finding suggests a dependency between the expression levels of these two markers for serotonergic neurotransmission.

The possible relationship between 5-HT1A and 5-HTT gene expression levels has, to some extent, been approached experimentally. In 5-HTT knock-out (KO) mice, both 5-HT1A receptor proteins and mRNA have been shown to be decreased in the DRN, increased in the hippocampus and unchanged in other forebrain areas (Fabre et al. 2000). A pharmacological examination of the 5-HT1A receptor mediated cell activity in 5-HTT KO mice showed, correspondingly, a desensitisation in the DRN but no alteration in the hippocampus (Mannoury la Cour et al. 2001). In an autoradiography study on prefrontal cortex of suicide victims and control subjects, a negative correlation was found between the two markers, suggesting a common regulatory factor (Arango et al. 1995).

These experimental observations in animal models and humans together with the molecular genetic findings may support a relationship between expression levels of the two 5-HT markers. A direct examination of this hypothesis in humans in vivo has recently been allowed by the availability of [11C]WAY 100635 and [11C]MADAM, two suitable PET radioligands for regional quantification of 5-HT1A receptor and 5-HTT binding also in raphe (Farde et al. 1998; Gunn et al. 2000; Lundberg et al. 2005). PET studies of control subjects have shown an at least twofold inter-individual variability in protein expression levels of both 5-HTT and the 5-HT1A receptor (Borg et al. 2003; Lundberg et al. 2005). This high variability provides an advantageous biological condition for correlative studies on these markers.

The aim of the present study was to examine the regional correlation between expression levels of the 5-HT1A receptor and the 5-HTT in the human brain. Twelve control subjects were examined with [11C]WAY 100635 and [11C]MADAM in the same day. The selection of regions included DRN, where both markers are expressed on the 5-HT neurons and the projection areas frontal cortex and the hippocampal complex, where 5-HTT is expressed presynaptically and the 5-HT1A receptor is expressed postsynaptically.

Materials and methods

Subjects and design

The study was approved by the Ethics and the Radiation Safety committees of the Karolinska Hospital. Twelve male subjects, aged 22–55, participated after giving informed consent. All subjects were healthy according to history, psychiatric interview, physical examination, blood and urine analysis and magnetic resonance imaging (MRI) of the brain. They did not use any medication and they were all non-smokers. All subjects were examined with PET twice in the same day: at 11 am immediately after IV injection of [11C]MADAM and at 2 pm immediately after IV injection of [11C]WAY-100635 (eight subjects) or in the opposite order (four subjects).

MRI and the head fixation system

The MRI system used was Signa, 1.5 T (GE Medical Systems, Milwaukee, WI, USA). T2- and T1-weighted images (matrix 256 × 256 × 156; pixel size 1.0156 × 1.0156 × 1.0 mm) were obtained. The T2 sequence is a 2-D fast spin echo protocol with the following settings: relaxation time (TR) 5,000 ms, echo time (TE) 68 ms, axial field of view (FOV) 26 cm, 260 × 260 matrix, 44 × 3.0 mm slices, 1 number of excitations (NEX) 4 min. The slice gap is set to 0.125 mm to make the centre-to-centre distance 3.125 mm, which is that of the ECAT PET images. The T1 sequence is a 3-D spoiled gradient recalled protocol with the following settings: TR 23 ms, TE 4 ms, flip angle 50°, FOV 260 × 180 × 156, matrix 256 × 192 × 156, 156 × 1.0 mm slices, and 1 NEX 8 min 45 s. To allow the same head positioning in the two imaging modalities, a head fixation system with an individual plaster helmet was used in both the PET and MRI measurements (Bergstrom et al. 1981).

Radiochemistry

[11C]MADAM was obtained by methylation of ADAM using [11C]methyl iodide, as described previously (Hall et al. 1997; Tarkiainen et al. 2001). Between 286 and 318 MBq was injected intravenously. The specific radioactivity of the radioligand injected varied between 196 and >100,000 Ci/mmol, corresponding to a mass injected of <0.01 to 11.9 μg.

[11C]WAY-100635 was prepared from 11C-acylation of WAY100634 with carbonyl-11C-cyclohexanecarbonyl chloride, as described previously (Hall et al. 1997). Between 146 and 323 MBq was injected intravenously. The specific radioactivity of the radioligand injected varied between 199 and 1,983 Ci/mmol, corresponding to a mass injected of 1.5 to 15.2 μg. The variation of specific activity and injected mass was due to technical problems with the cyclotron unit.

PET experimental procedure

The PET system used was ECAT EXACT HR 47 (Siemens, Berlin and Munich, Germany), which was run in the 3-D mode (Wienhard et al. 1994). The in-plane and axial resolution are about 3.8 and 4.0 mm, respectively, full width at half maximum. The reconstructed volume was displayed as 47 sections with a centre-to-centre distance of 3.125 mm.

In each PET measurement, the subject was placed recumbent with his head in the PET system. A sterile physiological phosphate buffer (pH = 7.4) solution containing the radioligand was injected as a bolus for 2 s into a cannula inserted into the right antecubital vein. The cannula was then immediately flushed with 10 ml saline.

Brain radioactivity was measured in a series of consecutive time frames. After injection with [11C]MADAM, the examination lasted for 93 min and consisted of 20 frames (3 × 1′; 4 × 3′; 13 × 6′), except in one subject where the examination lasted for 87 min (3 × 1′; 4 × 3′; 12 × 6′). After injection with [11C]WAY100635, the examination lasted for 69 min and consisted of 16 frames (3 × 1′; 4 × 3′; 9 × 6′).

Coregistration

In addition to an elaborated head fixation system allowing for repositioning within less than 3 mm (Bergstrom et al. 1981), a coregistration procedure was applied. For each subject, the MR image was adjusted to position the anterior–posterior commissural (AC–PC) line in the horizontal plane, and the inter-hemispheric plane orthogonal to the AC–PC plane. It was resampled and cropped to generate a 256 × 256 × 141 matrix with 1 mm2 pixels before it was used for manual definition of regions of interest (ROIs). The PET images were resampled to a 2-mm2 pixel size and coregistered to a corresponding MRI half-resolution dummy. Coregistration was done using SPM2 (Maes et al. 1997).

Rationale for selection of ROIs

The aim of the study was to examine regional correlation between the two markers and to contrast regions with the two markers on the same neuron (the raphe nuclei) to regions where they are situated pre- (5-HTT) and postsynaptically (the 5-HT1A-receptor; hippocampus, frontal cortex). The latter two were chosen as they, together with the raphe nuclei, represent three different developmental levels of the central nervous system (brainstem, allocortex, isocortex).

Definition of ROIs

ROIs were defined according to anatomical boundaries for neocortex, hippocampal complex, raphe nuclei and cerebellum. All ROIs but those for raphe nuclei were delineated in ten consecutive sections on the MR images and transferred to the corresponding reconstructed PET images.

On MR images the raphe nuclei cannot be differentiated from surrounding tissue. Therefore, these ROIs were delineated directly on the summated PET images (frame 6-onwards) of [11C]MADAM and [11C]WAY 100635 in three to five sections, according to a method previously applied in PET measurements of the 5-HTT and 5-HT1A proteins in the raphe nuclei (Andree et al. 2002; Lundberg et al. 2005).

Time activity curves and quantitative analysis

To obtain the average radioactivity concentration for the whole volume of interest, data for each ROI were pooled. Regional radioactivity was calculated for each frame, corrected for decay and plotted vs time, thus providing time–activity curves for each region. Right and left regions for bilateral ROIs were analysed both separately and averaged.

Binding potentials (BPs; Bmax/Kd) (Mintun et al. 1984) were calculated by means of the simplified reference tissue model (Lammertsma and Hume 1996). The applicability of this method using the cerebellum as the reference region has previously been shown for both [11C]WAY-100635 and [11C]MADAM (Gunn et al. 1998; Lundberg et al. 2005).

Statistics

For each region, the association between [11C]MADAM and [11C]WAY 100635 binding was examined by calculation of the Pearson’s correlation coefficient using SPSS 12.0.1 for Windows. Two-tailed tests for significance were performed and the results were corrected for multiple comparisons.

Results

After intravenous injection of either [11C]MADAM or [11C]WAY 100635, there was a rapid increase of radioactivity in all ROIs (Fig. 1). After injection with [11C]WAY 100635, the highest radioactivity was found in hippocampal complex, followed by frontal cortex, raphe nuclei and cerebellum. After injection with [11C]MADAM, the highest radioactivity was found in raphe nuclei, followed by hippocampal complex, frontal cortex and cerebellum (Table 1). The BP of both [11C]WAY 100635 and [11C]MADAM binding to 5-HT1A receptor proteins and 5-HTT, respectively, varied several fold between subjects (Fig. 2). In all regions examined, BP values for both radioligands were approximately normally distributed.
Fig. 1

Example of MRI (top row) and summated PET images: [11C]MADAM (middle row) and [11C]WAY 100635 (bottom row). From left to right: horizontal, sagittal and coronal view

Table 1

[11C]WAY 100635 and [11C]MADAM binding potentials (BPs) in the three examined regions

Region

[11C]WAY 100635 BP

[11C]MADAM BP

Range

Mean ± SD

Range

Mean ± SD

Raphe nuclei

1.85–4.71

3.26 ± 1.13

2.70–7.65

4.64 ± 1.67

Hippocampal complex

2.52–6.17

4.69 ± 1.39

0.47–1.76

0.81 ± 0.33

Frontal cortex

2.03–3.79

2.78 ± 0.56

0.18–0.51

0.29 ± 0.11

Fig. 2

Illustration of the inter-individual variability in [11C]WAY100635/[11C]MADAM BP ratio in the raphe nuclei

No significant correlation was found between BP for [11C]MADAM and [11C]WAY 100635 binding in the frontal cortex (rxy = −0.25, p = 0.44; Fig. 3a). There was a positive correlation between BP for [11C]MADAM and [11C]WAY 100635 both in the hippocampal complex (rxy = 0.97, p < 0.001; Fig. 3b) and in the raphe nuclei (rxy = 0.68, p < 0.05; Fig. 3c).
Fig. 3

a Plot showing the relation between BPs for [11C]MADAM and [11C]WAY 100635 for the 12 subjects in the frontal cortex. b Plot showing the relation between BPs for [11C]MADAM and [11C]WAY 100635 for the 12 subjects in the hippocampal complex. c Plot showing the relation between BPs for [11C]MADAM and [11C]WAY 100635 for the 12 subjects in the raphe nuclei

Discussion

Experimental observations together with molecular genetic findings support a postulated relationship between expression levels of the 5-HT1A receptor and the 5-HT transporter. The large inter-individual variability in these expression levels detected in previous PET-studies provides a possibility to examine this relationship directly in humans in vivo.

In the present study in adult male subjects, there was a positive correlation between 5-HTT protein and 5-HT1A receptor protein binding in the raphe nuclei and in the hippocampal complex. No correlation was found in the frontal cortex. In the following, the implication of these findings will be discussed in relation to the organisation of the serotonin system and the pharmacology of mood and anxiety disorders.

In the raphe nuclei, the proteins are most likely situated on the same neurons (Burnet et al. 1995; Hoffman et al. 1998; Miquel et al. 1991; Sur et al. 1996; Zhou et al. 1996). This colocalisation of the proteins provides a neuroanatomical underpinning for the assumed linear correlation between expression levels should the density be an index of the number of neuronal cell bodies alone. Our data set can thus verify such a correlation.

In clinical SSRI treatment of depression, the response rate has been reported to be about 2/3 (Barbui and Hotopf 2001). A suggested interpretation of the relatively low response rate is that clinical patient samples might be heterogeneous with regards to aetiology. An individual variability in the molecular response to SSRI treatment is an alternative reading. Along this line, it has been suggested that a large group of non-responders share an unfavourable biochemical phenotype (Kampf-Sherf et al. 2004). Indeed, using single photon emission tomography and [123I]β-CIT high 5-HTT binding in diencephalon prior to SSRI treatment has been shown to predict better treatment response in subjects with major depression (Kugaya et al. 2004). In the present study, using PET and [11C]MADAM, we confirm a several-fold inter-individual variability in 5-HTT binding in three different brain regions. Thus, we conclude that individual 5-HTT binding, i.e. the target for SSRIs, might serve as a marker to predict SSRI response.

The 5-HT1A receptor has also been discussed extensively in relation to SSRI treatment of depression. The response rate has been shown to increase by co-administration with the 5-HT1A/β-adrenoreceptor partial agonist pindolol (Ballesteros and Callado 2004). Moreover, a substantial body of preclinical evidence suggests that this effect of pindolol is due to inhibition of somatodendritic 5-HT1A receptors that otherwise mediate an acute SSRI-induced decrease in 5-HT transmission (for a review, see Artigas et al. 1996). In our data set, there was a large inter-individual variability in the raphe nuclei 5-HT1A-receptor/5-HTT BP ratio (Fig. 2 range 0.43–1.10, mean 0.73, SD 0.21;). It would be of interest to examine if this variability also exists in depressed patients and if it also may be associated with SSRI treatment response.

The 5-HT1A-receptor and the 5-HTT have hitherto been used separately in research of the relation between mood disorders and the serotonin system in a large number of PET studies (Bhagwagar et al. 2003, 2004; Drevets et al. 1999; Meltzer et al. 2004; Meyer et al. 2004; Parsey et al. 2006a, b, c, d; Sargent et al. 2000). Importantly, the large inter-individual HT1A-receptor/5-HTT BP ratio variability in our data set suggests the two markers not to be mutually exchangeable but rather examined in parallel when used as markers for the 5-HT system.

In neocortex and hippocampal complex, the 5-HT1A-receptor and 5-HTT are expressed on separate neurons. The 5-HTT is most likely expressed presynaptically on 5-HT neurons projecting from the raphe nuclei and the 5-HT1A-receptor postsynaptically on glutamatergic pyramidal cells (Barnes and Sharp 1999; Burnet et al. 1995; Hoffman et al. 1998). A functional relation between the two molecules is still suggested from a study on prenatally stressed rats used as a model for depression. Here, 5-HTT blockade with imipramine was shown to normalise an initial 5-HT1A receptor mRNA level increase (Morley-Fletcher et al. 2004). In the present study, at the protein expression level, this could be confirmed in the hippocampal complex where a significant correlation between 5-HT1A-receptor and 5-HTT binding was found (Fig. 3b). Although this correlation to a large degree was driven by one subject, it also remained significant after exclusion of this subject (rxy = 0.63, p < 0.05).

It cannot be ruled out that the lack of correlation between 5-HT1A-receptor and 5-HTT binding in the frontal cortex is due to the fact that 5-HTT expression is driven not primarily by neurodevelopment but rather by ongoing regulatory mechanisms. One or more of the three other 5-HT receptors hitherto detected in cortex (the 1B, 1E, 1F, 2A and 2C subtypes) may have a role in this regard (Barnes and Sharp 1999; Moret and Briley 2000). Another possible reason for the lack of a significant correlation may be the less favourable [11C]MADAM signal-to-noise ratio in the neocortex (Lundberg et al. 2005).

Additionally, the finding in the raphe nuclei has to be viewed in relation to the reliability of the methodology. The DRN is a thin elongated structure of only about 70 mm3 (Baker et al. 1990). Its small size is not ideal for reliable PET measurements. This is true for both [11C]WAY 100635 and [11C]MADAM, and the findings thus have to be interpreted with some caution.

A strength of the present study is that the measurements of [11C]MADAM and [11C]WAY 100635 binding was performed with only about 1 h interval, giving a minimal possibility for changes in 5-HT1A receptor and 5-HTT densities to take place during the course of the study. The BP is related to the protein density (Bmax) and the apparent in vivo affinity for the radioligand binding to the protein examined (Kd). inter-individual differences in BP may thus be related to variation in Bmax or Kd (Mintun et al. 1984). In healthy volunteers, inter-individual variance in BP has been suggested to be due mainly to variability in Bmax rather than Kd (Farde et al. 1995). Accordingly, a basic assumption in this study on protein densities is that BP differences between individuals are mainly based on variation in Bmax. Another limitation is the small number of subjects examined. This is, however, compensated for by the considerable inter-individual variability in both [11C]MADAM and [11C]WAY 100635 binding previously reported (Borg et al. 2003; Lundberg et al. 2006). ROIs for the raphe nuclei were defined directly on the summated [11C]MADAM and [11C]WAY 100635 PET images. This allows for differences in partial volume effect on the calculation of BP for the two ligands. However, as the ROI volumes for the raphe nuclei did not differ statistically [ROI volume[11C]MADAM = 107 ± 45, ROI volume[11C]WAY 100635 = 98 ± 46 (mm3, mean ± SD, p = 0.33, paired t test, two-tailed)], this would not influence the result to a significant degree.

Conclusion

Our result provides support for a hypothesised correlation in expression of the 5-HT1A-receptor and the 5-HTT in the raphe nuclei. The large inter-individual variability in BP quotient in this region may represent a potential biological phenotype of SSRI non-responders. This hypothesis should be addressed in future studies. In addition, the variability, which is also present in the hippocampal complex and neocortex, suggests the two markers not to be mutually exchangeable but rather examined in parallel when used as markers for the 5-HT system.

Notes

Acknowledgements

All members of the PET group at Karolinska Institutet are greatly acknowledged. This work was supported by the Swedish Research Council (grant 09114). The experiments comply with Swedish law.

Statement of interest

None.

References

  1. Andree B, Halldin C, Pike VW, Gunn RN, Olsson H, Farde L (2002) The PET radioligand [carbonyl-(11)C]desmethyl-WAY-100635 binds to 5- HT(1A) receptors and provides a higher radioactive signal than [carbonyl-(11)C]WAY-100635 in the human brain. J Nucl Med 43:292–303PubMedGoogle Scholar
  2. Arango V, Underwood MD, Gubbi AV, Mann JJ (1995) Localized alterations in pre- and postsynaptic serotonin binding sites in the ventrolateral prefrontal cortex of suicide victims. Brain Res 688:121–133PubMedCrossRefGoogle Scholar
  3. Artigas F, Romero L, de Montigny C, Blier P (1996) Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists. Trends Neurosci 19:378–383PubMedCrossRefGoogle Scholar
  4. Baker KG, Halliday GM, Tork I (1990) Cytoarchitecture of the human dorsal raphe nucleus. J Comp Neurol 301:147–161PubMedCrossRefGoogle Scholar
  5. Ballesteros J, Callado LF (2004) Effectiveness of pindolol plus serotonin uptake inhibitors in depression: a meta-analysis of early and late outcomes from randomised controlled trials. J Affect Disord 79:137–147PubMedCrossRefGoogle Scholar
  6. Barbui C, Hotopf M (2001) Amitriptyline v. the rest: still the leading antidepressant after 40 years of randomised controlled trials. Br J Psychiatry 178:129–144PubMedCrossRefGoogle Scholar
  7. Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152PubMedCrossRefGoogle Scholar
  8. Bengel D, Johren O, Andrews AM, Heils A, Mossner R, Sanvitto GL, Saavedra JM, Lesch KP, Murphy DL (1997) Cellular localization and expression of the serotonin transporter in mouse brain. Brain Res 778:338–345PubMedCrossRefGoogle Scholar
  9. Bergstrom M, Boethius J, Eriksson L, Greitz T, Ribbe T, Widen L (1981) Head fixation device for reproducible position alignment in transmission CT and positron emission tomography. J Comput Assist Tomogr 5:136–141PubMedCrossRefGoogle Scholar
  10. Bhagwagar Z, Montgomery AJ, Grasby PM, Cowen PJ (2003) Lack of effect of a single dose of hydrocortisone on serotonin(1A) receptors in recovered depressed patients measured by positron emission tomography with [11C]WAY-100635. Biol Psychiatry 54:890–895PubMedCrossRefGoogle Scholar
  11. Bhagwagar Z, Rabiner EA, Sargent PA, Grasby PM, Cowen PJ (2004) Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635. Mol Psychiatry 9:386–392PubMedCrossRefGoogle Scholar
  12. Borg J, Andree B, Soderstrom H, Farde L (2003) The serotonin system and spiritual experiences. Am J Psychiatry 160:1965–1969PubMedCrossRefGoogle Scholar
  13. Borg J, Andrée B, Lundberg J, Halldin C, Farde L (2006) Search for correlations between serotonin 5-HT<sub>1A</sub> receptor expression and cognitive functionsâ”a strategy in translational psychopharmacology. Psychopharmacology 185:389–394PubMedCrossRefGoogle Scholar
  14. Buhot MC (1997) Serotonin receptors in cognitive behaviors. Curr Opin Neurobiol 7:243–254PubMedCrossRefGoogle Scholar
  15. Burnet PW, Eastwood SL, Lacey K, Harrison PJ (1995) The distribution of 5-HT1A and 5-HT2A receptor mRNA in human brain. Brain Res 676:157–168PubMedCrossRefGoogle Scholar
  16. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301:386–389PubMedCrossRefGoogle Scholar
  17. Collier DA, Stober G, Li T, Heils A, Catalano M, Di Bella D, Arranz MJ, Murray RM, Vallada HP, Bengel D, Muller CR, Roberts GW, Smeraldi E, Kirov G, Sham P, Lesch KP (1996) A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry 1:453–460PubMedGoogle Scholar
  18. Cortes R, Soriano E, Pazos A, Probst A, Palacios JM (1988) Autoradiography of antidepressant binding sites in the human brain: localization using [3H]imipramine and [3H]paroxetine. Neuroscience 27:473–496PubMedCrossRefGoogle Scholar
  19. Cryan JF, Valentino RJ, Lucki I (2005) Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci Biobehav Rev 29:547–569PubMedCrossRefGoogle Scholar
  20. David SP, Murthy NV, Rabiner EA, Munafo MR, Johnstone EC, Jacob R, Walton RT, Grasby PM (2005) A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans. J Neurosci 25:2586–2590PubMedCrossRefGoogle Scholar
  21. Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ, Huang Y, Gautier C, Mathis C (1999) Pet imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 46:1375–1387PubMedCrossRefGoogle Scholar
  22. Fabre V, Beaufour C, Evrard A, Rioux A, Hanoun N, Lesch KP, Murphy DL, Lanfumey L, Hamon M, Martres MP (2000) Altered expression and functions of serotonin 5-HT1A and 5-HT1B receptors in knock-out mice lacking the 5-HT transporter. Eur J Neurosci 12:2299–2310PubMedCrossRefGoogle Scholar
  23. Farde L, Hall H, Pauli S, Halldin C (1995) Variability in D2-dopamine receptor density and affinity: a PET study with [11C]raclopride in man. Synapse 20:200–208PubMedCrossRefGoogle Scholar
  24. Farde L, Ito H, Swahn CG, Pike VW, Halldin C (1998) Quantitative analyses of carbonyl-carbon-11-WAY-100635 binding to central 5-hydroxytryptamine-1A receptors in man. J Nucl Med 39:1965–1971PubMedGoogle Scholar
  25. Fujita M, Shimada S, Maeno H, Nishimura T, Tohyama M (1993) Cellular localization of serotonin transporter mRNA in the rat brain. Neurosci Lett 162:59–62PubMedCrossRefGoogle Scholar
  26. Gunn RN, Sargent PA, Bench CJ, Rabiner EA, Osman S, Pike VW, Hume SP, Grasby PM, Lammertsma AA (1998) Tracer kinetic modeling of the 5-HT1A receptor ligand [carbonyl-11C]WAY-100635 for PET. Neuroimage 8:426–440PubMedCrossRefGoogle Scholar
  27. Gunn RN, Lammertsma AA, Grasby PM (2000) Quantitative analysis of [carbonyl-11C]WAY-100635 PET studies. Nucl Med Biol 27:477–482PubMedCrossRefGoogle Scholar
  28. Hales RE, Hilty DA, Wise MG (1997) A treatment algorithm for the management of anxiety in primary care practice. J Clin Psychiatry 58(Suppl 3):76–80PubMedGoogle Scholar
  29. Hall H, Lundkvist C, Halldin C, Farde L, Pike VW, McCarron JA, Fletcher A, Cliffe IA, Barf T, Wikstrom H, Sedvall G (1997) Autoradiographic localization of 5-HT1A receptors in the post-mortem human brain using [3H]WAY-100635 and [11C]way-100635. Brain Res 745:96–108PubMedCrossRefGoogle Scholar
  30. Heils A, Teufel A, Petri S, Seemann M, Bengel D, Balling U, Riederer P, Lesch KP (1995) Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene. J Neural Transm Gen Sect 102:247–254PubMedCrossRefGoogle Scholar
  31. Hoffman BJ, Hansson SR, Mezey E, Palkovits M (1998) Localization and dynamic regulation of biogenic amine transporters in the mammalian central nervous system. Front Neuroendocrinol 19:187–231PubMedCrossRefGoogle Scholar
  32. Hoyer D, Martin G (1997) 5-HT receptor classification and nomenclature: towards a harmonization with the human genome. Neuropharmacology 36:419–428PubMedCrossRefGoogle Scholar
  33. Hoyer D, Pazos A, Probst A, Palacios JM (1986) Serotonin receptors in the human brain. I. Characterization and autoradiographic localization of 5-HT1A recognition sites. Apparent absence of 5-HT1B recognition sites. Brain Res 376:85–96PubMedCrossRefGoogle Scholar
  34. Kampf-Sherf O, Zlotogorski Z, Gilboa A, Speedie L, Lereya J, Rosca P, Shavit Y (2004) Neuropsychological functioning in major depression and responsiveness to selective serotonin reuptake inhibitors antidepressants. J Affect Disord 82:453–459PubMedGoogle Scholar
  35. Kugaya A, Sanacora G, Staley JK, Malison RT, Bozkurt A, Khan S, Anand A, van Dyck CH, Baldwin RM, Seibyl JP (2004) Brain serotonin transporter availability predicts treatment response to selective serotonin reuptake inhibitors. Biol Psychiatry 56:497–502PubMedCrossRefGoogle Scholar
  36. Lammertsma AA, Hume SP (1996) Simplified reference tissue model for PET receptor studies. Neuroimage 4:153–158PubMedCrossRefGoogle Scholar
  37. Lesch K-P, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531PubMedCrossRefGoogle Scholar
  38. Lundberg J, Odano I, Olsson H, Halldin C, Farde L (2005) Quantification of [11C]MADAM binding to the serotonin transporter in the human brain. J Nucl Med 46:1505–1515PubMedGoogle Scholar
  39. Lundberg J, Halldin C, Farde L (2006) Measurement of serotonin transporter binding with PET and [11C]MADAM: a test–retest reproducibility study. Synapse 60:256–263PubMedCrossRefGoogle Scholar
  40. Maes F, Collignon A, Vandermeulen D, Marchal G, Suetens P (1997) Multimodality image registration by maximization of mutual information. IEEE Trans Med Imaging 16:187–198PubMedCrossRefGoogle Scholar
  41. Mannoury la Cour C, Boni C, Hanoun N, Lesch KP, Hamon M, Lanfumey L (2001) Functional consequences of 5-HT transporter gene disruption on 5-HT(1a) receptor-mediated regulation of dorsal raphe and hippocampal cell activity. J Neurosci 21:2178–2185PubMedGoogle Scholar
  42. Melke J, Landen M, Baghei F, Rosmond R, Holm G, Bjorntorp P, Westberg L, Hellstrand M, Eriksson E (2001) Serotonin transporter gene polymorphisms are associated with anxiety-related personality traits in women. Am J Med Genet 105:458–463PubMedCrossRefGoogle Scholar
  43. Meltzer CC, Price JC, Mathis CA, Butters MA, Ziolko SK, Moses-Kolko E, Mazumdar S, Mulsant BH, Houck PR, Lopresti BJ, Weissfeld LA, Reynolds CF (2004) Serotonin 1A receptor binding and treatment response in late-life depression. Neuropsychopharmacology 29:2258–2265PubMedCrossRefGoogle Scholar
  44. Meyer JH, Houle S, Sagrati S, Carella A, Hussey DF, Ginovart N, Goulding V, Kennedy J, Wilson AA (2004) Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography: effects of major depressive episodes and severity of dysfunctional attitudes. Arch Gen Psychiatry 61:1271–1279PubMedCrossRefGoogle Scholar
  45. Mintun MA, Raichle ME, Kilbourn MR, Wooten GF, Welch MJ (1984) A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography. Ann Neurol 15:217–227PubMedCrossRefGoogle Scholar
  46. Miquel M-C, Doucet E, Boni C, El Mestikawy S, Matthiessen L, Daval G, Verge D, Hamon M (1991) Central serotonin 1A receptors: respective distributions of encoding mRNA, receptor protein and binding sites by in situ hybridization histochemistry, radioimmunohistochemistry and autoradiographic mapping in the rat brain. Neurochem Int 19:453–465CrossRefGoogle Scholar
  47. Moret C, Briley M (2000) The possible role of 5-HT1B/D receptors in psychiatric disorders and their potential as a target for therapy. Eur J Pharmacol 404:1–12PubMedCrossRefGoogle Scholar
  48. Morley-Fletcher S, Darnaudery M, Mocaer E, Froger N, Lanfumey L, Laviola G, Casolini P, Zuena AR, Marzano L, Hamon M, Maccari S (2004) Chronic treatment with imipramine reverses immobility behaviour, hippocampal corticosteroid receptors and cortical 5-HT1A receptor mRNA in prenatally stressed rats. Neuropharmacology 47:841–847PubMedCrossRefGoogle Scholar
  49. Parsey RV, Hastings RS, Oquendo MA, Hu X, Goldman D, Huang YY, Simpson N, Arcement J, Huang Y, Ogden RT, Van Heertum RL, Arango V, Mann JJ (2006a) Effect of a triallelic functional polymorphism of the serotonin-transporter-linked promoter region on expression of serotonin transporter in the human brain. Am J Psychiatry 163:48–51PubMedCrossRefGoogle Scholar
  50. Parsey RV, Hastings RS, Oquendo MA, Huang Y-y, Simpson N, Arcement J, Huang Y, Ogden RT, Van Heertum RL, Arango V, Mann JJ (2006b) Lower serotonin transporter binding potential in the human brain during major depressive episodes. Am J Psychiatry 163:52–58PubMedCrossRefGoogle Scholar
  51. Parsey RV, Olvet DM, Oquendo MA, Huang YY, Ogden RT, Mann JJ (2006c) Higher 5-HT(1A) receptor binding potential during a major depressive episode predicts poor treatment response: preliminary data from a naturalistic study. Neuropsychopharmacology 31:1745–1749PubMedCrossRefGoogle Scholar
  52. Parsey RV, Oquendo MA, Ogden RT, Olvet DM, Simpson N, Huang YY, Van Heertum RL, Arango V, Mann JJ (2006d) Altered serotonin 1A binding in major depression: a [carbonyl-C-11]WAY100635 positron emission tomography study. Biol Psychiatry 59:106–113PubMedCrossRefGoogle Scholar
  53. Plenge P, Mellerup ET, Laursen H (1990) Regional distribution of the serotonin transport complex in human brain, identified with 3H-paroxetine, 3H-citalopram and 3H-imipramine. Prog Neuropsychopharmacol Biol Psychiatry 14:61–72PubMedCrossRefGoogle Scholar
  54. Pucadyil TJ, Kalipatnapu S, Chattopadhyay A (2005) The serotonin 1A receptor: a representative member of the serotonin receptor family. Cell Mol Neurobiol 25:553–580PubMedCrossRefGoogle Scholar
  55. Qian Y, Melikian HE, Rye DB, Levey AI, Blakely RD (1995) Identification and characterization of antidepressant-sensitive serotonin transporter proteins using site-specific antibodies. J Neurosci 15:1261–1274PubMedGoogle Scholar
  56. Sargent PA, Kjaer KH, Bench CJ, Rabiner EA, Messa C, Meyer J, Gunn RN, Grasby PM, Cowen PJ (2000) Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry 57:174–180PubMedCrossRefGoogle Scholar
  57. Sotelo C, Cholley B, El Mestikawy S, Gozlan H, Hamon M (1990) Direct immunohistochemical evidence of the existence of 5-HT1A autoreceptors on serotoninergic neurons in the midbrain raphe nuclei. Eur J Neurosci 2:1144–1154PubMedCrossRefGoogle Scholar
  58. Sur C, Betz H, Schloss P (1996) Immunocytochemical detection of the serotonin transporter in rat brain. Neuroscience 73:217–231PubMedCrossRefGoogle Scholar
  59. Tarkiainen J, Vercouillie J, Emond P, Sandell J, Hiltunen J, Frangin Y, Guilloteau D, Halldin C (2001) Carbon-11 labelling of MADAM in two different positions: a highly selective PET radioligand for the serotonin transporter. J Labelled Compd Radiopharm 44:1013–1023CrossRefGoogle Scholar
  60. Vaswani M, Linda FK, Ramesh S (2003) Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review. Prog Neuropsychopharmacol Biol Psychiatry 27:85–102PubMedCrossRefGoogle Scholar
  61. Verge D, Daval G, Marcinkiewicz M, Patey A, el Mestikawy S, Gozlan H, Hamon M (1986) Quantitative autoradiography of multiple 5-HT1 receptor subtypes in the brain of control or 5,7-dihydroxytryptamine-treated rats. J Neurosci 6:3474–3482PubMedGoogle Scholar
  62. Wienhard K, Dahlbom M, Eriksson L, Michel C, Bruckbauer T, Pietrzyk U, Heiss W (1994) The ECAT EXACT HR: performance of a new high resolution positron scanner. J Comput Assist Tomogr 18:110–118PubMedCrossRefGoogle Scholar
  63. Zhou FC, Xu Y, Bledsoe S, Lin R, Kelley MR (1996) Serotonin transporter antibodies: production, characterization, and localization in the brain. Mol Brain Res 43:267–278PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Johan Lundberg
    • 1
    • 2
  • Jacqueline Borg
    • 1
  • Christer Halldin
    • 1
  • Lars Farde
    • 1
  1. 1.Department of Clinical Neuroscience, Section of PsychiatryKarolinska InstitutetStockholmSweden
  2. 2.Department of Clinical Neuroscience, Section of Psychiatry, Psykiatricentrum KarolinskaKarolinska University Hospital SolnaStockholmSweden

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