Effects of the antidepressant fluoxetine on the subcellular localization of 5-HT1A receptors and SERT
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Phil. Trans. R. Soc. B (2012) 367, 2416–2425
doi:10.1098/rstb.2011.0361
Review
Effects of the antidepressant fluoxetine on
the subcellular localization of 5-HT1A
receptors and SERT
Laurent Descarries1,2,* and Mustaph Riad1
1
Departments of Pathology and Cell Biology, and 2Department of Physiology and Groupe de recherche
sur le système nerveux central, Faculty of Medicine, Université de Montréal, Montreal, Quebec,
Canada H3C 3J7
Serotonin (5-HT) 5-HT1A autoreceptors (5-HT1AautoR) and the plasmalemmal 5-HT transporter
(SERT) are key elements in the regulation of central 5-HT function and its responsiveness to anti-
depressant drugs. Previous immuno-electron microscopic studies in rats have demonstrated an
internalization of 5-HT1AautoR upon acute administration of the selective agonist 8-OH-DPAT
or the selective serotonin reuptake inhibitor antidepressant fluoxetine. Interestingly, it was sub-
sequently shown in cats as well as in humans that this internalization is detectable by positron
emission tomography (PET) imaging with the 5-HT1A radioligand [18F]MPPF. Further immuno-
cytochemical studies also revealed that, after chronic fluoxetine treatment, the 5-HT1AautoR,
although present in normal density on the plasma membrane of 5-HT cell bodies and dendrites,
do not internalize when challenged with 8-OH-DPAT. Resensitization requires several weeks after
discontinuation of the chronic fluoxetine treatment. In contrast, the SERT internalizes in both
the cell bodies and axon terminals of 5-HT neurons after chronic but not acute fluoxetine treat-
ment. Moreover, the total amount of SERT immunoreactivity is then reduced, suggesting that
SERT is not only internalized, but also degraded in the course of the treatment. Ongoing and
future investigations prompted by these finding are briefly outlined by way of conclusion.
Keywords: serotonin; selective serotonin reuptake inhibitor; 5-HT1A receptors; SERT;
internalization; PET imaging
1. INTRODUCTION interest, because some of the observed changes
The central serotonin (5-hydroxytryptamine, 5-HT) proved to be detectable by brain imaging in humans.
system is implicated in the effects of a vast majority Here, we first review previous and recent data from
of antidepressant treatments [1], among which the our laboratory regarding the internalization of serotonin
selective serotonin reuptake inhibitors (SSRIs), such 5-HT1A autoreceptors (5-HT1AautoR) after acute but
as fluoxetine (Prozac), are the most widely used [2]. not chronic fluoxetine treatment. Preliminary results
How the 5-HT system reacts and adapts to chronic are then reported, indicating that the 5-HT transpor-
exposure to these drugs is an obvious determinant of ter, SERT, also internalizes after chronic (but not
their therapeutic efficacy. For many years, however, acute) fluoxetine treatment. By way of conclusion,
electrophysiological recordings and neurochemical related questions of biological and clinical relevance
measurements were the only means to investigate in are proposed as subject for future investigations.
vivo changes in 5-HT neuron activity, release and
effects resulting from SSRI treatment. The develop-
ment of approaches for the cellular and subcellular 2. 5-HT1A RECEPTORS AND THE MODE OF
visualization of molecules involved in 5-HT neuron ACTION OF SELECTIVE SEROTONIN REUPTAKE
function has opened new perspectives in this regard. INHIBITOR ANTIDEPRESSANTS
This made it possible to examine the subcellular local- 5-HT1AR are one of the fourteen 5-HT receptor sub-
ization of 5-HT1A receptors (5-HT1AR), the main types mediating the effects of 5-HT in mammalian
regulator of 5-HT neuron firing and that of SERT, brain. Particularly abundant in the midbrain raphe
the plasmalemmal 5-HT transporter, during and nuclei and the hippocampus, they are also present in
after SSRI treatment. The results were of particular cerebral cortex and most components of the limbic
system [3,4]. The pharmacological activation of
5-HT1AR induces membrane hyperpolarization and
* Author for correspondence (laurent.descarries@umontreal.ca). reduces neuronal excitability via direct interactions
One contribution of 11 to a Theme Issue ‘The neurobiology of
between G proteins and ion channels [5]. In nuclei
depression—revisiting the serotonin hypothesis. I. Cellular and of origin, such as the dorsal raphe nucleus (DRN),
molecular mechanisms’. 5-HT1AR thus negatively regulate the firing and
2416 This journal is q 2012 The Royal Society
Review. Internalization of 5-HT1A autoR and SERT L. Descarries and M. Riad 2417
hence release of 5-HT neurons as autoreceptors [5], and of non-5-HT neurons in the hippocampus [52].
whereas in territories of projection, such as hippo- This immunolabelling approach also allowed us to
campus (5-HT1A heteroreceptors), they mediate an quantify the respective amount of receptor on the
inhibition of non-5-HT neurons. plasma membrane versus the cytoplasm of immuno-
reactive neurons, by counting the number of silver-
intensified immunogold particles in these two cellular
(a) Essential role of 5-HT1A autoreceptors
compartments.
Numerous neurochemical, electrophysiological and
One hour after the administration of a single dose of
pharmacological studies have characterized the effects
either the 5-HT1AR agonist 8-OH-DPAT or the proto-
of the acute administration of an SSRI on brain 5-HT
typic SSRI fluoxetine, we could demonstrate an
neurons in rodents, revealing what might be happening
internalization of 5-HT1AautoR in rat DRN neurons,
at the onset of an SSRI antidepressant treatment. The
evidenced by a 30 – 40% reduction in the density of
extracellular concentration of 5-HT is then increased
5-HT1AR immunogold labelling on the plasma mem-
in various brain regions [6 – 11], which activates
brane of DRN cell bodies and dendrites, with a
5-HT1AautoR in the DRN, and consequently inhibits
concomitant increase in their cytoplasm and preferen-
the firing of 5-HT neurons [12– 17] and the release of
tial labelling of endosomes (figure 1a – c). The total
5-HT within this nucleus [18] and its territories of
number of receptors was unchanged. This internaliz-
projection [18– 25] (see earlier studies [26,27] for
ation could be observed as soon as 15 min after the
review). These studies have also shown that a rapid
injection of either drugs, was not greater after the com-
and transient desensitization of 5-HT1AautoR (but
bined administration of both 8-OH-DPAT and
not of heteroreceptors) ensues, evidenced by reduced
fluoxetine (figure 1d ) and it was blocked by prior
responsiveness of 5-HT neurons to a 5-HT1AR agonist
administration of the 5-HT1AR antagonist, WAY
such as 8-OH-DPAT (8-hydroxy-2-(di-n-propyl-
100635 (figure 1e,f), confirming that it was the result
amino)tetralin [19,28–30]). These effects are blocked
of 5-HT1AR activation. The fact that it was partial
by the specific 5-HT1AR antagonist, WAY 100635
(30 – 40%) suggests the existence of a functional and
[30], which by itself does not alter the firing of 5-HT
a non-functional pool of autoreceptors on the plasma
neurons [31–33].
membrane of DRN neurons. In hippocampus, there
When the SSRI treatment is chronic (e.g. three weeks
was no internalization, in keeping with the notion that
in rat), it is not certain that the increases in extracellular
5-HT1A heteroreceptors do not desensitize [27,48,53],
5-HT concentration persist in the nuclei of origin [34–
probably due to G-protein interactions different from
36] or the territories of 5-HT projection [35,37] (but
those in DRN [54] or different type and level of
see earlier studies [38–42]). However, during this
expression of regulatory proteins (e.g. kinases, arrest-
whole period, the sensitivity of 5-HT neurons to 5-
ins). Twenty-four hours after the treatment, the
HT1AR agonist decreases gradually, reflecting a pro-
plasmalemmal density of 5-HT1AautoR was back to
gressive desensitization of 5-HT1AautoR [17,43] (see
normal, and internalization occurred again upon
also earlier studies [44,45]). After a decrease in the
challenge with 8-OH-DPAT, indicating resensitization.
first week, the electrical activity of DRN 5-HT neurons
The subcellular localization of 5-HT1AR was then
reverts to its initial levels after three weeks [17]. This
examined after three weeks of treatment with fluoxetine
temporal course has led to the suggestion that the thera-
[36]. The 5-HT1AautoR are known to be desensitized
peutic delay in the efficacy of SSRIs (three to four
under these conditions [17,43,47,48], but were unexpect-
weeks) is due to the time necessary for a persistent deac-
edly found in normal density on the plasma membrane of
tivation of 5-HT1AautoR [44,45], i.e. removal of the
DRN neurons (figure 2a–c). Moreover, they did not
‘brake’ on 5-HT neurons’ activity. 5-HT transmission
internalize upon 8-OH-DPAT challenge, in keeping
may then be enhanced even if extracellular 5-HT is no
with their desensitized state. Together with the results of
longer increased. Note that after two to three weeks of
several [35S]GTPgS studies [48,55–57], this suggested
fluoxetine treatment, neither the Kd nor the Bmax of
that repeated internalization and retargeting resulted in
5-HT1AR binding sites in DRN (or hippocampus) are
a lack of coupling of 5-HT1AautoR to their G protein.
changed [46–48]. Similar results have been obtained
Thus, acute and chronic SSRI treatment induced two
with other SSRIs, such as paroxetine [47].
distinct types of 5-HT1AautoR desensitization: one
rapid and reversible (associated with internalization of
(b) The internalization of 5-HT1A autoreceptors the functional pool of membrane-bound receptors), the
Our first immuno-electron microscopic studies after other being progressive and long-lasting, no longer
immunogold labelling of 5-HT1AR in normal and trea- accompanied by internalization, but which probably
ted rats have shed a new light on these findings resulted from the reiteration of this process throughout
[49,50]. Following the development of specific anti- the course of the chronic SSRI treatment.
bodies against 5-HT1A receptors in the laboratory of Recently, we also assessed the functional state of
Michel Hamon in Paris [51], it became possible to 5-HT1AautoR by immuno-electron microscopy after
examine the cellular and subcellular localization of 8-OH-DPAT challenge at various time intervals
these receptors by light and electron microscopic after cessation of a chronic fluoxetine treatment
immunocytochemistry [3,4]. After immunogold (10 mg kg21 daily for 21 days, by minipump). The den-
pre-embedding labelling, we were able to demonstrate sity of plasmalemmal and cytoplasmic labelling of DRN
that, under normal conditions, 5-HT1AR were mostly dendrites was determined by comparison with saline
located on extrasynaptic portions of the somato- controls (n ¼ 5), in rats administered 8-OH-DPAT
dendritic plasma membrane of DRN 5-HT neurons, (0.5 mg kg21 i.p.) 1 h prior to sacrifice, 24 h, one week
Phil. Trans. R. Soc. B (2012)2418 L. Descarries and M. Riad Review. Internalization of 5-HT1A autoR and SERT
(a) (b) (c)
d
d d
d d
d d
control 8-OH-DPAT fluoxetine
(d) (e) (f)
d
d d d
d
8-OH-DPAT + WAY 100635 / WAY 100635 /
fluoxetine 8-OH-DPAT fluoxetine
raphe dorsalis
(g) 80 18F-MPPF (h) 18F-MPPF
control control
60 + Fluoxetine + WAY100635
+ Fluoxetine
Bq
40
20 fluoxetine –70 min
–60 min –60 min
0
5 15 25 35 45 55 65 75 85 5 15 25 35 45 55 65 75 85
fluoxetine (min) WAY 100635 + fluoxetine (min)
Figure 1. Internalization of 5-HT1AautoR after acute 8-OH-DPAT and/or fluoxetine treatment. (a–f ) Immuno-electron
microscopic visualization of the subcellular distribution of 5-HT1AautoR in DRN dendrites (d) 1 h after administration of
the selective 5-HT1AR agonist 8-OH-DPAT or the SSRI fluoxetine. In a saline control (a), note the predilection of the
silver-intensified immunogold particles for the plasma membrane as opposed to the cytoplasm of the dendrite. There is a
considerable reduction (30–40%) in the density of plasmalemmal labelling and a corresponding increase in the cytoplasmic
labelling of dendrites, after the administration of 8-OH-DPAT (0.5 mg kg21 i.v.; b), fluoxetine (10 mg kg21 i.p.; c) or both
these drugs (d), reflecting 5-HT1AautoR internalization. When the selective 5-HT1AR antagonist WAY 100635 (1 mg kg21
i.p.) is administered 10 min prior to either 8-OH-DPAT (e) or fluoxetine ( f ), the internalization does not occur. Adapted
from earlier studies [50,51] with permission; copyrights q 2001 and 2004, Elsevier. (g,h) b-microprobe measurements of
the binding kinetics of the specific 5-HT1AR radioligand [18F]MPPF in the DRN of rats administered fluoxetine (g; white dia-
monds; control, black diamonds), or fluoxetine preceded by WAY 100635 (h; white diamonds; control, black diamonds).
Arrows in each graph indicate the time of saline or drug administration and beginning of data acquisition. Vertical arrows
point at the time of [18F]MPPF injection. Data points are mean + s.e.m. from five rats in each group. In (g), note the con-
siderable decrease (30–40%) in the amount of radioactivity (Becquerel) detected from the DRN of rats administered
fluoxetine. Adapted from [50] with permission; copyright q 2004, Elsevier. Scale bars, 1 mm.
or six weeks after cessation of the chronic treatment 8-OH-DPAT was administered one week after cessation
(n ¼ 4 in each group). More than 250 5-HT1A- of the chronic fluoxetine treatment (figure 2e). After six
immunolabelled dendrites were examined in each weeks, however, the internalization was similar to the
group. One day after cessation of the chronic fluoxetine control (figure 2f ). Such a long duration suggested
treatment, there was no detectable internalization 1 h that resensitization required the synthesis of new
after the administration of 8-OH-DPAT (figure 2d). 5-HT1A autoreceptors (to replace inactivated receptors),
Nor did the 5-HT1AautoR internalize when or the replenishment of regulatory proteins.
Phil. Trans. R. Soc. B (2012)Review. Internalization of 5-HT1A autoR and SERT L. Descarries and M. Riad 2419
(a) (b) (c)
d
d d
d
d
d d
d
control 24 hours 3 weeks
(d) (e) (f)
d d
d
8-OH-DPAT 8-OH-DPAT 8-OH-DPAT
1 day after 1 week after 6 weeks after
Figure 2. Lack of responsiveness of 5-HT1AautoR after chronic fluoxetine treatment. (a –c) Subcellular distribution of
5-HT1AautoR in DRN dendrites (d) of a saline control (a), and rats treated for 1 day (b) or three weeks (c) with fluoxetine
(10 mg kg21 daily, by minipump). In the saline control (a), the predilection of the 5-HT1AautoR for the plasma membrane
of DRN dendrites is again obvious. After one day of fluoxetine administration (b), marked internalization is observed (35%
decrease in the density of plasmalemmal labelling), whereas after three weeks of treatment (c), the density of plasmalemmal
5-HT1AautoR labelling is equivalent to the control. Adapted from earlier studies [49,50]; copyright q 2001 and 2004, Else-
vier. (d– f ) Responsiveness of 5-HT1AautoR to 8-OH-DPAT challenge (0.5 mg kg21 i.p., 1 h prior to kill), at various time
intervals after cessation of a chronic fluoxetine treatment (10 mg kg21 daily for three weeks, by minipump). One day (d)
and 1 week (e) after cessation of the chronic treatment, the density of 5-HT1AautoR on the plasma membrane of DRN den-
drites is equivalent to that in control rats or that measured immediately at the end of the treatment. Six weeks after cessation of
the treatment, the internalization of 5-HT1AautoR caused by 8-OH-DPAT is of the same magnitude (30–40%) as in untreated
rats (M. Riad 2011, unpublished data). Scale bars, 1 mm.
3. SERT, THE PRIMARY TARGET OF SSRI of SERT have been described in heterologous cell lines
ANTIDEPRESSANTS under the action of psychostimulants [70], which has
SERT is a member of a family of Naþ/Cl2-dependent been interpreted as the result of a silencing or inacti-
transporters in which the transmembrane domains are vation of SERT protein already located on the plasma
relatively conserved [58]. In addition to 5-HT neurons, membrane, or else as an endocytosis and recycling of
SERT is transiently expressed by thalamo-cortical functional protein to the membrane [71–73]. SSRIs
neurons and other non-5-HT neurons during the post- may also internalize SERT in heterologous cell lines
natal period in the rat [59–61], but in adult human, [74,75] or in 5-HT neurons derived from stem cells [76].
rat and mouse brain, its mRNA is confined to 5-HT In animal studies, however, radioligand binding and
neurons [62–64]. Using immuno-electron microscopy, in situ hybridization studies have yielded equivocal
SERT has been localized to the plasma membrane results regarding the fate of SERT under chronic treat-
of 5-HT somata-dendrites, axons and axon terminals ment with various SSRIs. Increases [77], decreases
outside synaptic contact zones [65,66]; it may thus con- [78 – 83] or no changes [84,85] in density of SERT
trol not only 5-HT transmission at synapses, but also binding sites have been reported in the DRN and var-
diffuse 5-HT transmission [65,66] (see also earlier ious territories of 5-HT innervation, and increases
studies [67,68]). [83 – 86], decreases [79,83,87 – 89] or no changes
[48,85,90] in SERT mRNA in the DRN.
(a) Regulation of SERT during selective
serotonin reuptake inhibitor treatment (b) The internalization of SERT
SERT is selectively blocked by SSRIs, which increase We have obtained preliminary immuno-electron
extracellular 5-HT at the onset of a treatment [6–11]. microscopic evidence in rat indicating that there is
There is strong experimental evidence to suggest that internalization of SERT in cell bodies and dendrites
SERT may be regulated [69] and undergoes adaptive of DRN neurons as well as their axon terminals in hip-
changes during SSRI treatment. Changes in the efficacy pocampus after chronic (three weeks) but not acute
Phil. Trans. R. Soc. B (2012)2420 L. Descarries and M. Riad Review. Internalization of 5-HT1A autoR and SERT
(a) (b) (c)
d d
d
control acute chronic
Figure 3. Internalization and decrease in 5-HT transporter (SERT) after chronic fluoxetine treatment. (a–c) Immunogold lab-
elling of SERT in DRN dendrites (d) after acute (10 mg kg21 i.p.) or chronic treatment (10 mg kg21 daily for three weeks, by
minipump) with fluoxetine. One hour after the administration of fluoxetine (b), there were no apparent changes in the subcellular
distribution of SERT, either in cell bodies or dendrites of DRN neurons, as illustrated here, nor in axon terminals of the hippo-
campus (not shown). After chronic treatment (c), however, the localization of the SERT labelling was changed, with a significant
reduction in the density of plasmalemmal labelling in both DRN dendrites and hippocampal terminals. There was also a reduction
in the overall density of labelling in both DRN dendrites and hippocampal terminals, suggesting that SERT was not only
internalized, but also degraded, in the course of the chronic SSRI treatment (M. Riad 2011, unpublished data). Scale bars, 1 mm.
fluoxetine treatment (figure 3a–c). The subcellular internalization in the animal brain, offering hopes
localization of SERTwas examined in rats having received to detect this phenomenon by PET in the human
a single injection of fluoxetine (10 mg kg21 i.p.) 1 h prior brain [91].
to killing, after three weeks of treatment with fluoxetine
(10 mg kg21 daily, by minipump), and in saline controls
(n ¼ 5 in each group). Almost 300 immunolabelled den- (a) Radioligand binding studies of 5-HT1AR
drites in DRN and 200 immunolabelled axon terminals in vivo
in hippocampus were examined in each group. A quanti- Indeed, in rats, concordant results were obtained
tative analysis of this data showed no difference in the when radiosensitive brain-implanted microprobes (b–
density of plasmalemmal or cytoplasmic labelling 1 h microprobes) were used in Luc Zimmer’s laboratory
after fluoxetine, when compared with control. After the (Lyon, France), to examine the in vivo binding of
chronic treatment, however, the density of plasmalemmal [18F]MPPF, a selective 5-HT1AR antagonist amenable
labelling was reduced by 48 per cent in DRN dendrites, to brain imaging in humans, under the same experi-
and by 71 per cent in hippocampal terminals, with mental conditions examined by immunoelectron
a concomitant increase in the ratio of cytoplasmic/ microscopy [50,91]. As measured with one microprobe
plasmalemmal labelling in both locations. Interestingly, inserted next to the DRN and another in hippocampus,
there was also a reduction in the overall density of labelling the amount of radioactivity detected during 1 h after i.v.
in both the DRN dendrites and hippocampal terminals, injection of [18F]MPPF was decreased by 30–40% in
which suggested that SERT was not only internalized, the DRN of 8-OH-DPAT-treated rats, without any
but also degraded, in the course of the chronic fluoxetine change in the hippocampus, and this lowering in DRN
treatment. These results were consistent with the early did not occur after the prior administration of
report by Piñeyro et al. [80] of a ‘desensitization’ of the WAY100635. Similar findings were made after acute
neuronal 5-HT carrier following 21 days of treatment fluoxetine treatment (figure 1a,b), but, interestingly,
with the SSRI paroxetine, associated with a reduction in when autoradiography of tissue slices was used to
[3H]5-HT uptake in hippocampal and dorsal raphe measure [18F]MPPF binding in these same conditions
slices from rats subjected to this same treatment. of treatment, there were no differences in the regional
Similarly, Benmansour et al. [81] have reported a ‘down- density of binding sites in either the DRN or the hippo-
regulation’ of SERT after three weeks of treatment with campus of 8-OH-DPAT-treated when compared with
the SSRI sertraline, followed by a slow recovery more control rats [50]. Of course, the low resolution of
than 10 days after cessation of this treatment. In spite of ligand binding autoradiography in tissue slices did not
the potential clinical implications of these findings, allow for distinguishing between radiolabel located on
however, changes in the plasmalemmal (functional) the plasma membrane versus the cytoplasm of neurons.
localization of SERT in the DRN and its territories of Such a difference between the in vitro and in vivo results
5-HT innervation have not yet been investigated after indicated that, in vivo, [18F]MPPF did not access
cessation of an SSRI treatment. internalized 5-HT1A autoreceptors.
After chronic fluoxetine treatment, there were no
differences between the microprobe measurements of
4. FROM CELLULAR AND SUBCELLULAR [18F]MPPF binding in the DRN or hippocampus
LOCALIZATION STUDIES IN RAT TO BRAIN of controls versus treated rats, in keeping with the
IMAGING STUDIES IN HUMANS lack of internalization and normal density of plasma-
It was soon realized that [18F]MPPF binding in vivo lemmal 5-HT1A receptors in DRN observed in the
might be altered in conditions of 5-HT1AR immuno-electron microscopic experiments [36].
Phil. Trans. R. Soc. B (2012)Review. Internalization of 5-HT1A autoR and SERT L. Descarries and M. Riad 2421
(a) (b) (c)
placebo fluoxetine
0 4
(d) (e) (f) 8
7
6
5
4
3
2
1
x=2 y = –26 z = –12 t-value*
(Asterisk: spm2, k = 25 voxels, p = 0.001 uncorrected, FWHM = 8 mm isotropic.)
Figure 4. [18F]MPPF PET imaging of 5-HT1AautoR internalization in healthy volunteers administered a single oral dose of
fluoxetine. (a) and (b) are co-registered, colour-coded, parametric images of the average [18F]MPPF binding potential in the
brain of eight subjects who received placebo (a) or fluoxetine (b), 5 h before the scans. At white arrow in (b), note the selective
decrease in density of [18F]MPPF binding confined to a minute region of interest corresponding to the DRN; (c) delineates
this small region of interest in an averaged MRI image, in which a mesencephalic area encompassing the DRN is drawn in blue
and a 27-voxel cubic region of interest around the most active voxel within this area is drawn in red. (d–f ) The non-parametric
(SPM) analysis of the data is shown below. Note that the DRN is the only brain region in which there is a statistically significant
change (decrease) in [18]FMPPF binding potential. (Asterisk: spm2, k ¼ 25 voxels, p ¼ 0.001 uncorrected, FWHM ¼ 8 mm
isotropic.) Adapted from [94] with permission; copyright q 2008, Elsevier.
(b) Imaging of 5-HT1AautoR internalization in 20 mg) or placebo in a random order [94]. The results
the cat and the human brain were clear. In the DRN and nowhere else in the brain,
As the resolution of available microPET instruments was all eight subjects given fluoxetine showed a significant
likely to be insufficient to detect a partial decrease in and visible decrease in [18F]MPPF binding potential
binding potential in such a small anatomical region as (44% on average) compared with placebo (figure 4a –
the rat DRN [92], a preliminary investigation in animals c). This was confirmed by a non-parametric analysis,
was carried out in cats using a clinical PET [93]. After which indicated that the DRN was the only brain
demonstrating that the cat DRN could indeed be visual- region showing a significant difference in [18F]MPPF
ized with [18F]MPPF, [18F]MPPF binding potential was binding between fluoxetine and placebo (figure 4a –c).
measured in anaesthetized cats given or not a single dose
of fluoxetine, or treated chronically with fluoxetine
(three weeks). Compared with control, [18F]MPPF 5. ONGOING AND FUTURE STUDIES
binding potential was considerably and visibly decrea- Some clinical implications of the earlier-mentioned
sed (approx. 40%) in the DRN after acute fluoxetine findings have been discussed elsewhere [95]. Here, we
treatment, while it was unchanged in other brain regions. will merely list a series of fundamental, yet answerable
After the chronic fluoxetine treatment, [18F]MPPF questions raised by the results thus far obtained on the
binding potential was unchanged in all brain internalization of 5-HT1A autoreceptors. First: what
regions, including the DRN, as expected from the molecular mechanisms account for this internalization?
immuno-electron microscopic results in rats. Are G-protein-coupled receptor kinases (GRKs) and
The next step was to try imaging the internalization b-arrestins implicated, as in the case of other
of 5-HT1AautoR in the human brain. In collaboration G-protein-coupled receptors? Second: what accounts
with Chawki Benkelfat and co-workers at the McCon- for the long-term desensitization (loss of function) of
nell Brain Imaging Center of McGill University, 5-HT1A autoreceptors after chronic SSRI treatment?
[18F]MPPF PET was therefore performed in normal Third: which elements of the signalling cascade need
human volunteers subjected to the double-blind oral to be synthesized for these receptors to resensitize
administration of a single tablet of fluoxetine (Prozac, after cessation of a chronic fluoxetine treatment?
Phil. Trans. R. Soc. B (2012)2422 L. Descarries and M. Riad Review. Internalization of 5-HT1A autoR and SERT
Identification of these molecules might provide novel 7 Fuller, R. W. 1994 Uptake inhibitors increase extra-
targets for antidepressant drugs. cellular serotonin concentration measured by brain
From the physiopathological standpoint, it would also microdialysis. Life Sci. 55, 163 –167. (doi:10.1016/
be important to determine the functional state of 5-HT1A 0024-3205(94)00876-0)
8 Malagié, I., Trillat, A.-C., Jacquot, C. & Gardier, A. M.
autoreceptors in depression. All the earlier-described
1995 Effects of acute fluoxetine on extracellular seroto-
results have been obtained from normal animals or nin levels in the raphe: an in vivo microdialysis study.
from the healthy human brain. Further immuno-electron Eur. J. Pharmacol. 286, 213–217. (doi:10.1016/0014-
microscopic investigations of 5-HT1A autoreceptors 2999(95)00573-4)
need to be carried out in animal models of depression, 9 Rutter, J. J., Gundlah, C. & Auerbach, S. B. 1995 Sys-
and [18F]MPPF PET studies in depressed subjects. temic uptake inhibition decreases serotonin release via
It must also be pointed out that previous radioligand somatodendritic autoreceptor activation. Synapse 20,
binding and in situ hybridization studies on post- 225 –233. (doi:10.1002/syn.890200306)
mortem brain of suicide victims [96–103], as well as 10 Kreiss, D. S. & Lucki, I. 1995 Effects of acute and
recent PET studies in unmedicated depressed patients repeated administration of antidepressant drugs on
[104,105], suggest that 5-HT1A autoreceptors are pre- extracellular levels of 5-hydroxytryptamine measured
in vivo. J. Pharmacol. Exp. Ther. 274, 866 –876.
sent in excessive number in the DRN of depressed
11 Hervás, I. & Artigas, F. 1998 Effect of fluoxetine on
subjects (see also earlier studies [106,107]). This could extracellular 5-hydroxytryptamine in rat brain. Role of
imply that the firing and release of 5-HT neurons is 5-HT autoreceptors. Eur. J. Pharmacol. 358, 9 –18.
permanently toned down in such patients. Another testa- (doi:10.1016/S0014-2999(98)00579-2)
ble hypothesis is that of an impaired internalization of 12 Blier, P. & de Montigny, C. 1987 Modification of 5-HT
5-HT1A autoreceptors in depression, which could also neuron properties by sustained administration of the 5-
account for low 5-HT tone and/or for limited efficacy HT1A agonist gepirone: electrophysiological studies in
of SSRI treatments aimed at long-term desensitization the rat brain. Synapse 1, 470 –480. (doi:10.1002/syn.
of these receptors and resulting increase in 5-HT trans- 890010511)
mission. Lastly, another important issue is regards the 13 Lanfumey, L., Haj-Dahmane, S. & Hamon, M. 1993
Further assessment of the antagonist properties of the
fate of 5-HT1A autoreceptors after cessation of an SSRI
novel and selective 5-HT1A receptor ligands (þ)-WAY
treatment. This also needs to be studied in animal 100 135 and SDZ 216–525. Eur. J. Pharmacol. 249,
models of depression and in human subjects, and could 25– 35. (doi:10.1016/0014-2999(93)90658-5)
provide crucial information in terms of the mechanisms 14 Dong, J., de Montigny, C. & Blier, P. 1997 Effect of
involved in the permanence of effects versus recurrence acute and repeated versus sustained administration of
of the disease. the 5-HT1A receptor agonist ipsapirone: electrophysio-
logical studies in the rat hippocampus and dorsal raphe.
Both authors thank the numerous colleagues who have
Naunyn Schmiedebergs Arch. Pharmacol. 356, 303 –311.
contributed to their studies as co-authors. This research
(doi:10.1007/PL00005055)
was mainly funded by grants from the Canadian Institutes
for Health Research to L.D. (NRF-3544 and MOP- 15 Cunningham, K. A. & Lakoski, J. M. 1990 The
219408). It also benefitted from an infrastructure grant of interaction of cocaine with serotonin dorsal raphe
the Fonds de la Recherche en Santé du Québec to the neurons. Single-unit extracellular recording studies.
Groupe de Recherche sur le Système Nerveux Central. Neuropsychopharmacology 3, 41– 50.
16 Rigdon, G. C. & Wang, C. M. 1991 Serotonin uptake
blockers inhibit the firing of presumed serotonergic
dorsal raphe neurons in vitro. Drug Dev. Res. 22,
REFERENCES 135 –140. (doi:10.1002/ddr.430220204)
1 Blier, P. & El Mansari, M. In press. Serotonin and beyond: 17 Czachura, J. F. & Rasmussen, K. 2000 Effects of acute
therapeutics for major depression. Phil. Trans. R. Soc. B and chronic administration of fluoxetine on the activity
2 Hirschfeld, R. M. A. 2001 Antidepressants in the of serotonergic neurons in the dorsal raphe nucleus of
United States: current status and future needs. In the rat. Naunyn Schmiedebergs Arch. Pharmacol. 362,
Treatment of depression: bridging the 21st century (ed. M. 266 –275. (doi:10.1007/s002100000290)
M. Weissman), pp. 123–134. Washington, DC: Ameri- 18 Adell, A., Celada, P., Abellan, M. T. & Artigas, F.
can Psychiatric Press. 2002 Origin and functional role of the extracellular
3 Kia, H. K., Miquel, M. C., Brisorgueil, M. J., Daval, G., serotonin in the midbrain raphe nucleus. Brain Res.
Riad, M., El Mestikawy, S., Hamon, M. & Vergé, D. 1996 Rev. 39, 154 –180. (doi:10.1016/S0165-0173(02)
Immunocytochemical localization of serotonin1A recep- 00182-0)
tors in the rat central nervous system. J. Comp. Neurol. 19 Kennett, G. A., Marcou, M., Dourish, C.T. & Curzon,
365, 289–305. (doi:10.1002/(SICI)1096-9861(1996 G. 1987 Single administration of 5-HT1A agonists
0205)365:2,289::AID-CNE7.3.0.CO;2-1) decreases 5-HT1A presynaptic, but not postsynaptic
4 Kia, H. K., Brisorgueil, M. J., Hamon, M., Calas, A. & receptor-mediated responses: relationship to anti-
Vergé, D. 1996 Ultrastructural localization of 5-hydroxy- depressant-like action. Eur. J. Pharmacol. 138, 53–60.
tryptamine 1A receptors in the rat brain. J. Neurosci. Res. (doi:10.1016/0014-2999(87)90336-0)
46, 697–708. (doi:10.1002/(SICI)1097-4547(1996 20 Hamon, M., Fattacini, C. M., Adrien, J., Gallissot, M.
1215)46:6,697::AID-JNR7.3.0.CO;2-A) C., Martin, P. & Gozlan, H. 1988 Alterations of central
5 Sprouse, J. S. & Aghajanian, G. K. 1987 Electrophysio- serotonin and dopamine turnover in rats treated with
logical responses of serotonergic dorsal raphe neurons ipsapirone and other 5-hydroxytryptamine 1A agonists
to 5-HT1A and 5-HT1B agonists. Synapse 1, 3 –9. with potential anxiolytic properties. J. Pharmacol. Exp.
(doi:10.1002/syn.890010103) Ther. 246, 745–752.
6 Rutter, J. J. & Auerbach, S.B. 1993 Acute uptake inhi- 21 Hutson, P. H., Sarna, G.S., O’Connell, M. T. & Curzon,
bition increases extracellular serotonin in the rat G. 1989 Hippocampal 5-HT synthesis and release in vivo
forebrain. J. Pharmacol. Exp. Ther. 265, 1319– 1324. is decreased by infusion of 8-OH-DPAT into the nucleus
Phil. Trans. R. Soc. B (2012)Review. Internalization of 5-HT1A autoR and SERT L. Descarries and M. Riad 2423
raphe dorsalis. Neurosci. Lett. 100, 276–280. (doi:10. treated with fluoxetine. Neuroscience 151, 692– 700.
1016/0304-3940(89)90698-8) (doi:10.1016/j.neuroscience.2007.11.024)
22 Sharp, T., Branwell, S. R. & Grahame-Smith, D. G. 37 Invernizzi, R., Bramante, M. & Samanin, R. 1995
1989 5-HT1 agonists reduce 5-hydroxytryptamine Extracellular concentrations of serotonin in the dorsal
release in rat hippocampus in vivo as determined by hippocampus after acute and chronic treatment with
brain microdialysis. Br. J. Pharmacol. 96, 283–290. citalopram. Brain Res. 696, 62–66. (doi:10.1016/
23 Bohmaker, K., Eison, A. S., Yocca, F.D. & Meller, E. 1993 0006-8993(95)00730-E)
Comparative effects of chronic 8-OH-DPAT, gepirone 38 Rutter, J. J., Gundlah, C. & Auerbach, S. B. 1994
and ipsapirone treatment on the sensitivity of somatoden- Increase in extracellular serotonin produced by uptake
dritic 5-HT1A autoreceptors. Neuropharmacology 32, inhibitors is enhanced after chronic treatment with
527–534. (doi:10.1016/0028-3908(93)90048-8) fluoxetine. Neurosci. Lett. 171, 183– 186. (doi:10.1016/
24 Invernizzi, R., Bramante, M. & Samanin, R. 1996 Role 0304-3940(94)90635-1)
of 5-HT1A receptors in the effects of acute and chronic 39 Invernizzi, R., Bramante, M. & Samanin, R. 1996 Role
fluoxetine on extracellular serotonin in the frontal of 5-HT1A receptors in the effects of acute and chronic
cortex. Pharmacol. Biochem. Behav. 54, 143–147. fluoxetine on extracellular serotonin in the frontal
(doi:10.1016/0091-3057(95)02159-0) cortex. Pharmacol. Biochem. Behav. 54, 143– 147.
25 Sharp, T., Umbers, V. & Hjorth, S. 1996 The role of (doi:10.1016/0091-3057(95)021159-0)
5-HT1A autoreceptors and alpha 1-adrenoceptors in 40 Dawson, L. A., Nguyen, H. Q., Smith, D. I. &
the inhibition of 5-HT release. II. NAN-190 and SDZ Schechter, L. E. 2000 Effects of chronic fluoxetine
216 –525. Neuropharmacology 35, 735–741. (doi:10. treatment in the presence and absence of (þ/2)
1016/S0028-3908(96)00027-5) pindolol: a microdialysis study. Br. J. Pharmacol. 130,
26 Barnes, N. M. & Sharp, T. 1999 A review of central 5-HT 797–804. (doi:10.1038/sj.bjp.0703378)
receptors and their function. Neuropharmacology 38, 41 Hervás, I., Vilaró, M. T., Romero, L., Scorza, M. C.,
1083–1152. (doi:10.1016/S0028-3908(99)00010-6) Mengod, G. & Artigas, F. 2001 Desensitization of
27 Piñeyro, G. & Blier, P. 1999 Autoregulation of serotonin 5-HT1A autoreceptors by a low chronic fluoxetine
neurons: role in antidepressant drug action. Pharmacol. dose: effect of the concurrent administration of
Rev. 51, 533 –591. WAY-100635. Neuropsychopharmacology 24, 11–20.
28 Beer, M., Kennett, G. A. & Curzon, G. 1990 A single (doi:10.1016/S0893-133X(00)00175-5)
dose of 8-OH-DPAT reduces raphe binding of 42 Popa, D., Cerdan, J., Repérant, C., Guiard, B. P., Guilloux,
[3H]8-OH-DPAT and increases the effect of raphe J.-P., David, D. J. & Gardier, A. M. 2010 A longitudinal
stimulation on 5-HT metabolism. Eur. J. Pharmacol. study of 5-HT outflow during chroninc fluoxetine treat-
178, 179 –187. (doi:10.1016/0014-2999(90)90473-J) ment using a new technique of chronic microdialysis in a
29 Le Poul, E., Laaris, N., Hamon, M. & Lanfumey, L. 1997 highly emotional mouse strain. Eur. J. Pharmacol. 628,
Fluoxetine-induced desensitization of somatodendritic 5- 83–90. (doi:10.1016/ejphar.2009.11.037)
HT1A autoreceptors is independent of glucocorticoid(s). 43 Li, Q., Muma, N. A. & Van de Kar, L. D. 1996 Chronic
Synapse 27, 303–312. (doi:10.1002/(SICI)1098-2396 fluoxetine induces a gradual desensitization of 5-HT1A
(199712)27:4,303::AID-SYN4.3.0.CO;2-G) receptors: reductions in hypothalamic and midbrain Gi
30 Seth, P., Gajendiran, M. & Ganguly, D. K. 1997 Desensi- and G(o) proteins and in neuroendocrine responses to a
tization of spinal 5-HT1A receptors to 8-OH-DPAT: an in 5-HT1A agonist. J. Pharmacol. Exp. Ther. 279, 1035–1042.
vivo spinal reflex study. NeuroReport 8, 2489–2493. 44 Blier, P. & de Montigny, C. 1983 Electrophysiological
(doi:10.1097/00001756-199707280-00015) investigations on the effect of repeated zimelidine
31 Corradetti, R., Le Poul, E., Laaris, N., Hamon, M. & administration on serotonergic neurotransmission in
Lanfumey, L. 1996 Electrophysiological effects of N-(2- the rat. J. Neurosci. 3, 1270– 1278.
(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridi- 45 Blier, P. & de Montigny, C. 1994 Current advances and
nyl) cyclohexane carboxamide (WAY 100635) on dorsal trends in the treatment of depression. Trends Pharmacol.
raphe serotonergic neurons and CA1 hippocampal pyra- Sci. 15, 220–226. (doi:10.1016/0165-6147(94)90315-8)
midal cells in vitro. J. Pharmacol. Exp. Ther. 278, 678–688. 46 Hensler, J. G., Kovachich, G. B. & Frazer, A. 1991 A
32 Mundey, M.K., Fletcher, A. & Marsden, C.A. quantitative autoradiographic study of serotonin1A
1994 Effect of the putative 5-HT1A antagonist receptor regulation. Effect of 5,7-dihydroxytryptamine
WAY-100635 on 5-HT neuronal firing in the guinea- and antidepressant treatments. Neuropsychopharmacology
pig dorsal raphe nucleus. Neuropharmacology 3, 4, 131–144.
61– 66. (doi:10.1016/0028-3908(94)90097-3) 47 Le Poul, E., Laaris, N., Doucet, E., Laporte, A. M.,
33 Martin, L. P., Jackson, D. M., Wallsten, C. & Waszczak, Hamon, M. & Lanfumey, L. 1995 Early desensitization
B. L. 1999 Electrophysiological comparison of of somato-dendritic 5-HT1A autoreceptors in rats trea-
5-hydroxytryptamine1A receptor antagonists on dorsal ted with fluoxetine or paroxetine. Naunyn Schmiedebergs
raphe cell firing. J. Pharmacol. Exp. Ther. 288, 820– 826. Arch Pharmacol. 352, 141–148.
34 Bel, N. & Artigas, F. 1993 Chronic treatment with flu- 48 Le Poul, E., Boni, C., Hanoun, N., Laporte, A. M.,
voxamine increases extracellular serotonin in frontal Laaris, N., Chauveau, J., Hamon, M. & Lanfumey, L.
cortex but not in raphe nuclei. Synapse 15, 243–245. 2000 Differential adaptation of brain 5-HT1A and
(doi:10.1002/syn.890150310) 5-HT1B receptors and 5-HT transporter in rats treated
35 Cremers, T. I., Spoelstra, E. N., de Boer, P., Bosker, chronically with fluoxetine. Neuropharmacology 39,
F. J., Mork, A., den Boer, J. A., Westerink, B. H. & 110–122. (doi:10.1016/S0028-3908(99)00088-X)
Wikstrom, H. V. 2000 Desensitisation of 5-HT auto- 49 Riad, M., Watkins, K. C., Doucet, E., Hamon, M. &
receptors upon pharmacokinetically monitored chronic Descarries, L. 2001 Agonist-induced internalization of
treatment with citalopram. Eur. J. Pharmacol. 397, serotonin-1A receptors in the dorsal raphe nucleus
351 –357. (doi:10.1016/S0014-2999(00)00308-3) (autoreceptors) but not hippocampus (heterorecep-
36 Riad, M., Rbah, L., Verdurand, M., Aznavour, N., tors). J. Neurosci. 21, 8378– 8386.
Zimmer, L. & Descarries, L. 2008 Unchanged density 50 Riad, M., Zimmer, L., Rbah, L., Watkins, K. C.,
of 5-HT1A autoreceptors on the plasma membrane of Hamon, M. & Descarries, L. 2004 Acute treatment
nucleus raphe dorsalis neurons in rats chronically with the antidepressant fluoxetine internalizes 5-HT1A
Phil. Trans. R. Soc. B (2012)2424 L. Descarries and M. Riad Review. Internalization of 5-HT1A autoR and SERT
autoreceptors and reduces the in vivo binding of the RNA by 5-hydroxytryptamine neurons. Neuroscience
PET radioligand [18F]MPPF in the nucleus raphe dor- 88, 169–183. (doi:10.1016/S0306-4522(98)00231-0)
salis of rat. J. Neurosci. 24, 5420–5426. (doi:10.1016/j. 65 Zhou, F.C., Tao-Cheng, J.-H., Segu, L., Patel, T. &
neuroimage.2004.03.020) Wang, Y. 1998 Serotonin transporters are located on
51 El Mestikawy, S., Riad, M., Laporte, A. M., Vergé, D., the axons beyond the synaptic junctions: anatomical
Daval, G., Gozlan, H. & Hamon, M. 1990 Production and functional evidence. Brain Res. 895, 241 –254.
of specific anti-rat 5-HT1A receptor antibodies in rab- (doi:10.1016/S0006-8993(98)00691-X)
bits injected with a synthetic peptide. Neurosci. Lett. 66 Tao-Cheng, J. H. & Zhou, F. C. 1999 Differential
118, 189 –192. (doi:10.1016/0304-3940(90)90623-H) polarization of serotonin transporters in axons versus
52 Riad, M., Garcia, S., Watkins, K. C., Jodoin, N., soma-dendrites: an immunogold electron microscopic
Doucet, E., Langlois, X., El Mestikawy, S., Hamon, study. Neuroscience 94, 821–830. (doi:10.1016/S0306-
M. & Descarries, L. 2000 Somatodendritic localization 4522(99)00373-5)
of 5-HT1A and preterminal axonal localization of 67 Pickel, V. M. & Chan, J. 1999 Ultrastuctural localiz-
5-HT1B serotonin receptors in adult rat brain. ation of the serotonin transporter in limbic and motor
J. Comp. Neurol. 417, 181– 194. (doi:10.1002/(SICI) compartments of the nucleus accumbens. J. Neurosci.
1096-9861(20000207)417:2) 19, 7356–7366.
53 Haddjeri, N., Blier, P. & de Montigny, C. 1998 68 Miner, L. H., Schroeter, S., Blakely, R. D. & Sesack,
Long-term antidepressant treatments result in a tonic S. R. 2000 Ultrastructural localization of the serotonin
activation of forebrain 5 HT1A receptors. J. Neurosci. transporter in superficial and deep layers of the rat pre-
18, 10 150 –10 156. limbic prefrontal cortex and its spatial relationship to
54 La Cour, C. M., El Mestikawy, S., Hanoun, N., dopamine terminals. J. Comp. Neurol. 427, 220–234.
Hamon, M. & Lanfumey, L. 2006 Regional differences (doi:10.1002/1096-9861(20001113)427:2,220::AID-
in the coupling of 5 hydroxytryptamine-1A receptors to CNES.3.0.CO;2-P)
G proteins in the rat brain. Mol. Pharmacol. 70, 69 Haase, J., Killian, A. M., Magnani, F. & Williams, C.
1013–1021. (doi:10.1124/mol.106.022756) 2001 Regulation of the serotonin transporter by inter-
55 Hensler, J. G. 2002 Differential regulation of 5-HT1A acting proteins. Biochem. Soc. Trans. 2, 722–728.
receptor-G protein interactions in brain following chronic (doi:10.1042/BST0290722)
antidepressant administration. Neuropsychopharmacology 70 Ramamoorthy, S. & Blakely, R. D. 1999 Phosphoryl-
26, 565–573. (doi:10.1038/S0893-133X (01)00395-5) ation and sequestration of serotonin transporters
56 Pejchal, T., Foley, M. A., Kosofsky, B. E. & Waeber, C. differentially modulated by psychostimulants. Science
2002 Chronic Fluoxetine treatment selectively uncouples 285, 763 –766. (doi:10.1126/science.285.5428.763)
raphe 5-HT(1A) receptors as measured by [(35)S]-GTP 71 Ramamoorthy, S., Giovanetti, E., Qian, Y. & Blakely,
gamma S autoradiography. Br. J. Pharmacol. 135, R. D. 1998 Phosphorylation and regulation of anti-
1115–1122. (doi:10.1038/sj.bjp.0704555) depressant-sensitive serotonin transporters. J. Biol.
57 Hanoun, N., Mocaer, E., Boyer, P. A., Hamon, M. & Chem. 273, 2458–2466. (doi:10.1074/jbc.273.4.2458)
Lanfumey, L. 2004 Differential effects of the novel anti- 72 Haase, J., Killian, A.-M., Magnani, F. & Williams, C.
depressant agomelatine (S 20098) versus fluoxetine on 2001 Regulation of the serotonin transporter by inter-
5-HT1A receptors in the rat brain. Neuropharmacology acting proteins. Biochem. Soc. Trans. 29, 722–728.
47, 515–526. (doi:10.1016/j.neuropharm.2004.06.003) (doi:10.1042/BST0290722)
58 Borowsky, B. & Hoffman, B. J. 1995 Neurotransmitter 73 Müller, H. K., Wiborg, O. & Haase, J. 2006 Subcellular
transporters: molecular biology, function, and regu- redistribution of the serotonin transporter by secretory
lation. Int. Rev. Neurobiol. 38, 139 –199. (doi:10.1016/ carrier membrane protein 2. J. Biol. Chem. 281, 28
S0074-7742(08)60526-7) 901 –28 909. (doi:10.1074/jbc.M602848200)
59 Lebrand, C., Cases, O., Adelbrecht, C., Doye, A., 74 Qian, Y., Galli, A., Ramamoorthy, S., Risso, S.,
Alvarez, C., El Mestikawy, S., Seif, I. & Gaspar, P. DeFelice, L. J. & Blakely, R.D. 1997 Protein kinase C
1996 Transient uptake and storage of serotonin in activation regulates human serotonin transporters in
developing thalamic neurons. Neuron 17, 823 –835. HEK-293 cells via altered cell surface expression.
(doi:10.1016/S0896-6773(00)80215-9) J. Neurosci. 17, 45–57.
60 Hansson, S. R., Mezey, É. & Hoffman, B. J. 1998 Ser- 75 Iceta, R., Mesonero, J.E. & Alcalde, A.I. 2007 Effect of
otonin transporter messenger RNA in the developing long-term fluoxetine treatment on the human serotonin
rat brain: early expression in serotonergic neurons and transporter in Caco-2 cells. Life Sci. 80, 1517 –1524.
transient expression in non-serotonergic neurons. (doi:10.1016/j.lfs.2007.01.020)
Neuroscience 83, 1185–1201. (doi:10.1016/S0306- 76 Lau, T., Horschitz, S., Berger, S., Bartsch, D. &
4522(97)00444-2) Schloss, P. 2008 Antidepressant-induced internalization
61 Zhou, F.C., Sari, Y. & Zhang, J. K. 2000 Expression of of the serotonin transporter in serotonergic neurons.
serotonin transporter protein in developing rat brain. FASEB J. 22, 1702–1714. (doi:10.1096/fj.07-095471)
Dev. Brain Res. 119, 35–45. (doi:10.1016/S0165- 77 Hrdina, P. D. & Vu, T. B. 1993 Chronic fluoxetine treat-
3806(99)00152-2) ment upregulates 5-HT uptake sites and 5-HT2
62 Austin, M. C., Bradley, C. C., Mann, J. J. & Blakely, R. receptors in rat brain: an autoradiographic study.
D. 1994 Expression of serotonin transporter messenger Synapse 14, 324 –331. (doi:10.1002/syn.890140410)
mRNA in the human brain. J. Neurochem. 62, 2362– 78 Kovachich, G. B., Aronson, C. E. & Brunswick, D. J.
2367. (doi:10.1046/j.1471-4159.1994.62062362.x) 1992 Effect of repeated administration of antidepress-
63 Zhou, F. C., Xu, Y., Bledsoe, S., Lin, R. & Kelley, M. ants on serotonin uptake sites in limbic and
R. 1996 Serotonin transporter antibodies: production neocortical structures of rat brain determined by quanti-
characterization, and localization in the brain. Mol. tative autoradiography. Neuropsychopharmacology 7,
Brain Res. 43, 267 –278. (doi:10.1016/S0169-328X 317 –324.
(96)00209-4) 79 Kuroda, Y., Watanabe, Y. & McEwen, B. S. 1994 Tia-
64 Rattray, M., Michael, G. J., Lee, J., Wotherspoon, G., neptine decreases both serotonin transporter mRNA
Bendotti, C. & Priestley, J. V. 1999 Intraregional vari- and binding sites in rat brain. Eur. J. Pharmacol. 268,
ation in expression of serotonin transporter messenger R3 –R5. (doi:10.1016/0922-4106(94)90127-9)
Phil. Trans. R. Soc. B (2012)Review. Internalization of 5-HT1A autoR and SERT L. Descarries and M. Riad 2425
80 Piñeyro, G., Blier, P., Dennis, T. & de Montigny, C. 1994 dose of fluoxetine: a PET study in healthy volunteers.
Desensitization of the neuronal 5-HT carrier following its Biol. Psychiatry 63, 1135 –1140. (doi:10.1016/j.bio
long-term blockade. J. Neurosci. 14, 3036–3047. psych.2007.11.016)
81 Benmansour, S., Cecchi, M., Morilak, D. A., Gerhardt, 95 Zimmer, L. & Descarries, L. 2012 Internalization of
G. A., Javors, M. A., Gould, G. G. & Frazer, A. 1999 serotonin 5-HT1A autoreceptors as a biomarker of anti-
Effects of chronic antidepressant treatments on seroto- depressant response. WIREs Membr. Transport Signal.
nin transporter function, density, and mRNA level. 1, 239 –245. (doi:10.1002/wmts.11)
J. Neurosci. 19, 10 494– 10 501. 96 Cheetham, S. C., Crompton, M. R., Katona, C. L. &
82 Benmansour, S., Owens, W. A., Cecchi, M., Morilak, D. Horton, R. W. 1990 Brain 5-HT1 binding sites in
A. & Frazer, A. 2002 Serotonin clearance in vivo is altered depressed suicides. Psychopharmacology 102, 544– 548.
to a greater extent by antidepressant-induced downregu- (doi:10.1007/BF02247138)
lation of the serotonin transporter than by acute blockade 97 Dillon, K. A., Gross-Isseroff, R., Israeli, M. & Biegon,
of this transporter. J. Neurosci. 22, 6766–6772. A. 1991 Autoradiographic analysis of serotonin
83 Hirano, K., Seki, T., Sakai, N., Kato, Y., Hashimoto, 5-HT1A receptor binding in the human brain postmor-
H., Uchida, S. & Yamada, S. 2005 Effects of continu- tem: effects of age and alcohol. Brain Res. 554, 56–64.
ous administration of paroxetine on ligand binding site (doi:10.1016/0006-8993(91)90171-Q)
and expression of serotonin transporter protein in 98 Arranz, B., Eriksson, A., Mellerup, E., Plenge, P. &
mouse brain. Brain Res. 1053, 154 –161. (doi:10.1016/ Marcusson, J. 1994 Brain 5-HT1A, 5– HT1D, and 5
j.brainres.2005.06.038) HT2 receptors in suicide victims. Biol. Psychiatry 35,
84 Cheetham, S. C., Viggers, J. A., Slater, N. A., Heal, D. 457–463. (doi:10.1016/0006-3223(94)90044-2)
J. & Buckett, W. R. 1993 [3H]paroxetine binding in rat 99 Arango, V., Underwood, M. D., Gubbi, A.V. & Mann,
frontal cortex strongly correlates with [3H]5-HT uptake: J.J. 1995 Localized alterations in pre- and postsynaptic
effect of administration of various antidepressant treat- serotonin binding sites in the ventrolateral prefrontal
ments. Neuropharmacology 32, 737–743. (doi:10.1016/ cortex of suicide victims. Brain Res. 688, 121 –133.
0028-3908(93)90181-2) (doi:10.1016/0006-8993(95)00523-S)
85 Spurlock, G., Buckland, P., O’Donovan, M. & McGuffin, 100 Arango, V., Underwood, M. D., Boldrini, M., Tamir,
P. 1994 Lack of effect of antidepressant drugs on the levels H., Kassir, S. A., Hsiung, S., Chen, J. J. & Mann, J.
of mRNAs encoding serotonergic receptors, synthetic J. 2001 Serotonin 1A receptors, serotonin transporter
enzymes and 5-HT transporter. Neuropharmacology 33, binding and serotonin transporter mRNA expression
433–440. (doi:10.1016/0028-3908(94) 90073-6) in the brainstem of depressed suicide victims.
86 López, J. F., Chalmers, D. T., Vázquez, D. M., Watson, Neuropsychopharmacology 25, 892–903. (doi:10.1016/
S. J. & Akil, H. 1994 Serotonin transporter mRNA in S0893-133X(01)00310-4)
rat brain is regulated by classical antidepressants. Biol. 101 Lowther, S., De Paermentier, F., Cheetham, S. C.,
Psychiatry 35, 287 –290. (doi:10.1016/0006-3223(94) Crompton, M. R., Katona, C. L. & Horton, R. W.
01262-9) 1997 5-HT1A receptor binding sites in post-mortem
87 Lesch, K. P., Aulakh, C. S., Wolozin, B. L., Tolliver, T. brain samples from depressed suicides and controls.
J., Hill, J. L. & Murphy, D. L. 1993 Regional brain J. Affect. Disord. 42, 199 –207. (doi:10.1016/S0165-
expression of serotonin transporter mRNA and its 0327(96)01413-9)
regulation by reuptake inhibiting antidepressants. 102 Stockmeier, C. A., Dilley, G. E., Shapiro, L. A.,
Brain Res. Mol. Brain Res. 17, 31–35. (doi:10.1016/ Overholser, J. C., Thompson, P. A. & Meltzer, H. Y.
0169-328X(93)90069-2) 1997 Serotonin receptors in suicide victims with
88 Linnet, K., Koed, K., Wiborg, O. & Gregersen, N. major depression. Neuropsychopharmacology 16,
1995 Serotonin depletion decreases serotonin transpor- 162 –173. (doi:10.1016/S0893-133X(96)00170-4)
ter mRNA levels in rat brain. Brain Res. 697, 251– 253. 103 Stockmeier, C. A., Shapiro, L. A., Dilley, G. E., Kolli,
(doi:10.1016/0006-8993(95)00906-7) T. N., Friedman, L. & Rajkowska, G. 1998 Increase in
89 Neumaier, J. F., Root, D. C. & Hamblin, M. W. 1996 serotonin-1A autoreceptors in the midbrain of suicide
Chronic fluoxetine reduces serotonin transporter victims with major depression-postmortem evidence
mRNA and 5-HT1B mRNA in a sequential manner in for decreased serotonin activity. J. Neurosci. 18,
the rat dorsal raphe nucleus. Neuropsychopharmacology 7394–7401.
15, 515– 522. (doi:10.1016/S0893-133X(96)00095-4) 104 Parsey, R. V., Oquendo, M. A., Ogden, R. T., Olvet, D.
90 Koed, K. & Linnet, K. 1997 The serotonin transporter M., Simpson, N., Huang, Y. Y., Van Heertum, R. L.,
messenger RNA level in rat brain is not regulated by Arango, V. & Mann, J. J. 2006 Altered serotonin
antidepressants. Biol. Psychiatry 42, 1177–1180. 1A binding in major depression: a [carbonyl-C-
(doi:10.1016/S0006-3223(97)00345-4) 11]WAY100635 positron emission tomography study.
91 Zimmer, L., Riad, M., Rbah, L., Belkacem-Kahlouli, Biol. Psychiatry 59, 106– 113. (doi:10.1016/j.biopsych.
A., Le Bars, D., Renaud, B. & Descarries, L. 2004 2005.06.016)
Toward brain imaging of serotonin 5-HT1A autorecep- 105 Parsey, R. V. et al. 2010 Higher serotonin 1A binding
tor internalization. NeuroImage 22, 1421 –1426. in a second major depression cohort: modeling and
(doi:10.1016/j.neuroimage.2004.03.020) reference region considerations. Biol. Psychiatry 68,
92 Moulin-Sallanon, M. et al. 2009 Acute and chronic 170 –178. (doi:10.1016/j.biopsych.2010.03.023)
effects of citalopram on 5-HT1A receptor-labeling by 106 Parsey, R. V., Olvet, D. M., Oquendo, M. A., Huang,
[18F]MPPF and coupling to receptors-G proteins. Y. Y., Ogden, R. T. & Mann, J. J. 2006 Higher 5-HT1A
Synapse 63, 106 –116. (doi:10.1002/syn.20588) receptor binding potential during a major depressive epi-
93 Aznavour, N., Rbah, L., Riad, M., Reilhac, A., Costes, sode predicts poor treatment response: preliminary data
N., Descarries, L. & Zimmer, L. 2006 A PET imaging from a naturalistic study. Neuropsychopharmacology 31,
study of 5-HT1A receptors in cat brain after acute and 1745–1749. (doi:10.1038/sj.npp.1300992)
chronic fluoxetine treatment. NeuroImage 33, 834– 842. 107 Hesselgrave, N. & Parsey, R. V. In press. Imaging the
(doi:10.1016/j.neuroimage.2006.08.012) serotonin 1A receptor using [11C]WAY-100635 in
94 Sibon, I. et al. 2008 Decreased [18F]MPPF binding healthy controls and major depression. Phil.
potential in the dorsal raphe nucleus after a single oral Trans. R. Soc. B.
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