Paroxetine as an in vivo indicator of 3,4-methylenedioxymethamphetamine neurotoxicity: a presynaptic serotonergic positron emission tomography ligand?

The present study sought to determine whether [3H]paroxetine, a potent and selective inhibitor of serotonin uptake in vitro, could be used to label the serotonin transporter in the rat brain in vivo such that it might be employed to develop a presynaptic serotonergic positron emission tomography ligand. Tritium labeled paroxetine was administered intravenously to rats by means of tail vein injection. Four hours later, specific [3H]paroxetine binding was determined by subtracting non-specific binding in the cerebellum from total binding in other brain regions of interest. The distribution of specific [3H]paroxetine binding paralleled the distribution of serotonin uptake sites in all brain regions examined. Pretreatment with serotonin re-uptake inhibitors (citalopram or sertraline) reduced in vivo specific [3H]paroxetine binding by as much as 99%. Specific in vivo [3H]paroxetine binding was further characterized through the use of 5,7-dihydroxytryptamine (5,7-DHT), a known serotonergic neurotoxin. 5,7-DHT (200 micrograms, i.c.v.) caused a marked reduction in specific [3H]paroxetine binding, and induced a prolonged depletion of regional brain serotonin. In a final study, the feasibility of using in vivo [3H]paroxetine binding as an indicator of serotonergic damage induced by another neurotoxin (3,4-methylenedioxymethamphetamine, MDMA) was tested. MDMA-treated rats showed a profound reduction in in vivo [3H]paroxetine binding, along with a lasting depletion of regional brain serotonin. These results demonstrate that [3H]paroxetine can be used to label serotonin uptake sites in the rat brain in vivo, and that the damage induced by serotonergic neurotoxins can be detected using in vivo [3H]paroxetine binding as an indicator. Paroxetine (or one of its derivatives) therefore holds promise as a PET ligand for studying serotonergic neurons in the living human brain in health as well as after neurotoxic injury.     

Kinetics of the uptake of [3H]paroxetine in the rat brain

Paroxetine, an antidepressant with a high affinity for serotonin (5-HT) re-uptake sites, is a potential tracer of these sites. We determined the kinetic properties of [³H]paroxetine in rat brain in vivo. Relative to [¹⁴C]iodo-antipyrine, the brain uptake index (BUI) of [³H]paroxetine was 60–70%. The unidirectional blood clearance of [³H]paroxetine were 0.05–0.12 ml g^?1 min^?1, lower than expected from the BUI values. The steady state volume of distribution was 3.5 ml hg^?1 in the diencephalon and 1.8 ml ^?1 in the cerebellum, suggesting a binding potential of unity. Autoradiographs at four hours after [³H] paroxetine injection (300 μCi, i.p.) revealed heterogenous binding consistent with the calculated binding potentials. Binding was nearly absent from cerebellum and was highest in the dorsal raphé, superior colliculus, dorsal hypothalamus, and entorhinal cortex, but did not reach equilibrium in four hours of tracer circulation. The specific binding relative to vermis was displaced by pretreatment with fluonotino (10 mg/kg, i.p.). © 1993 Wiley-Liss. Inc.     

Quantitative autoradiography of serotonin uptake sites in rat brain using [H]cyanoimipramine

The binding of [³H]cyanoimipramine to serotonin uptake sites in rat brain slices was studied using quantitative autoradiography. Binding was of high affinity and was to a single class of binding site. This is in contrast to results previously obtained by others with [³H]imipramine where two binding sites were observed. The sites labeled by [³H]cyanoimipramine had properties consistent with this ligand labeling serotonin uptake sites, as: (1) binding is displaced by drugs which are potent inhibitors of serotonin uptake but not by drugs which are weak inhibitors of uptake; (2) binding is dependent on the presence of sodium ions as is the uptake of serotonin; (3) binding is almost completely eliminated in the brains of rats lesioned by the serotonin neurotoxin 5,7-dihydroxytryptamine; (4) the distribution of binding sites throughout the rat brain is highly correlated with that found previously for [³H]indalpine, a potent serotonin uptake inhibitor, and for [³H]imipramine. The properties of binding of [³H]cyanoimipramine make it an ideal ligand for the quantitative autoradiography of serotonin uptake sites.     

Quantitative autoradiography of [H]nitroimipramine binding sites in rat brain

We have used the recent tritium-sensitive film method of quantitative autoradiography to localize in rat brain high-affinity binding sites for nitroimipramine (NI), a long-lasting inhibitor of serotonin (5-HT) transport in platlets. The distribution of NI binding sites in rat brain closely parallels the location of 5-HT terminals. There are high concentrations of binding sites in the dorsal and medial raphe nuclei, the basal portion of the mammilary nuclei, the medial forebrain bundle, the olfactory tubercule and the posterior basal nucleus of the amygdala. The association of [³H]NI binding sites with regions having a high content of 5-HT supports the notion that the high-affinity binding site for [³H]NI corresponding to some aspect of the presynaptic uptake site for 5-HT.     

In vivo-synthesized radioactively labelled α-methyl serotonin as a selective tracer for visualization of brain serotonin neurons

To investigate the use of α-[³H]methyl tryptophan (α-[³H]MTrp) as a tracer for the in vivo study of brain serotonergic neurons, we examined whether α-[³H]MTrp and its metabolite α-[³H]methyl serotonin (α-[³H]M5-HT) selectively label serotonergic neurons and whether once accumulated in these neurons, the radioactive metabolite behaves like endogenous serotonin. Rats received a systemic injection of 1–5 mCi of α-[³H]MTrp and 24 h later their brains were immediately removed or fixed by perfusion before removal. Tissue sections in which serotonergic neurons had been immunostained for 5-HT or its synthesizing enzyme, tryptophan hydroxylase, were processed for radioautography at the light and electron microscopic level. In another group of rats, the release of radioactivity from different brain areas was studied both under basal and depolarizing conditions. In the dorsal raphe nucleus, the light microscopic examination revealed almost complete colocalization between serotonergic neurons and those that accumulated radioactivity, with a heterogeneity in the content of α-[³H]M5-HT among the various cells. At the ultrastructural level, immunoidentified serotonergic perikarya and dendritic processes in the dorsal raphe nucleus, as well as nerve terminals in the cerebral cortex were also found to contain α-[³H]M5-HT. Under basal conditions, radioactivity was released from the brainstem raphe region and from projection areas such as the striatum and hippocampus. The basal output of α-[³H]M5-HT increased approximately twofold after a depolarizing 50 mM KCl solution was added to the perfusion fluid. These findings suggest that newly synthesized α-[³H]M5-HT can be released both at somatodendritic and terminal sites. In sum, the present results demonstrate the selectivity of α-[³H]MTrp as a tracer for serotonergic cells, and further suggest that α-[³H]MTrp radiolabelling provides for a direct assessment of the in vivo dynamics of brain serotonergic neurons at the cellular level. © 1995 Wiley-Liss, Inc.     

Sodium-independent binding of [H]cocaine in mouse striatum is serotonin related

There was a highly significant correlation between IC₅₀ values of various drugs in inhibiting the Na⁺-independent [³H]cocaine binding in the mouse striatum and their values in inhibiting the synaptosomal uptake of [³H]serotonin. In contrast, there was no correlation between the inhibition of binding in the absence of Na⁺ and the inhibition of [³H]dopamine uptake. Lesioning of serotonergic nerve terminals with 5, 7-dihydroxytryptamine reduced the Na⁺-independent [³H]cocaine binding, without affecting the Na⁺-dependent binding. These results indicate that the bulk of the Na⁺-independent [³H]cocaine binding in the mouse striatum is associated with serotonergic nerve terminals.     

Enkephalin-like immunoreactivity in rat area postrema: ultrastructural localization and coexistence with serotonin

The ultrastructure of enkephalin-containing neurons and their capacity to take-up [³H]serotonin were examined in the area postrema. Untreated adult rats and rats with intraventricular infusions of 10⁻⁴ M tritiated serotonin, 5-hydroxytryptamine ([³H]5-HT) were perfused with 4% paraformaldehyde and 0.2–0.5% glutaraldehyde. Coronal Vibratome sections through the area postrema from both groups of animals were immunocytochemically labeled with an antiserum to leucine Leu⁵-enkephalin. The sections from the animals infused with the isotope subsequently were processed for autoradiography. Enkephalin-like immunoreactivity (ELI) was detected in perikarya, dendrites, axons and axon terminals most frequently located along the ventricular and ventrolateral portions of the area postrema. The labeled perikarya were few in number and were characterized by a thin rim of cytoplasm containing peroxidase immunoreactivity. Dendrites and terminals containing ELI formed synapses primarily with unlabeled axon terminals and dendrites, respectively. However, terminals containing ELI also formed synaptic junctions with other unlabeled axon terminals. Appositions between enkephalin-containing processes and modified glia were occasionally seen near the ventricular surface. In sections processed for both immunocytochemistry and autoradiography, approximately 5% of the terminals containing ELI showed uptake of [³H]5-HT. We conclude that neurons containing ELI are primarily, but not exclusively, associated with other intrinsic neurons or afferents in the rat area postrema and that some of the enkephalin-labeled terminals have the capacity to take-up serotonin. Specificity of uptake of [³H]5-HT in neurons containing endogenous serotonin and factors which may contribute to the low probability of detecting both peroxidase and autoradiographic markers in single sections are discussed.     

Autoradiographic characterization of [3H]imipramine and [3H]citalopram binding in rat and human brain: species differences and relationships to serotonin innervation patterns.

The neuroanatomical distribution of binding sites for [3H]imipramine and [3H]citalopram was assessed by in vitro autoradiography in select regions of the rat and human forebrain. To determine involvement of serotonin-containing terminals in the binding of [3H]imipramine and [3H]citalopram, binding of these compounds was measured in rats after destroying serotonin-containing neurons with 5,7-dihydroxytryptamine (5,7-DHT). Treatment with this neurotoxin decreased serotonin content by 90% and reduced [3H]citalopram binding to a similar extent. These results demonstrate that [3H]citalopram binding is a reliable marker for serotonin-containing terminals. Binding of [3H]imipramine was reduced by only 15-35% after 5,7-DHT treatment. These latter results suggest that only a small fraction of [3H]imipramine binding to brain sections is associated with serotonergic terminals under standard conditions used in autoradiographic studies with the ligand. Dose-response effects of fluoxetine and desipramine on displacement of [3H]imipramine binding in forebrain regions indicate that the ligand labels predominantly high capacity, low affinity binding sites. To determine the utility of the rat brain as a model for [3H]imipramine and [3H]citalopram binding in the human brain, binding of the ligands was compared in human and rat hypothalamus, amygdala, and hippocampus. The pharmacological characteristics of [3H]imipramine and [3H]citalopram binding were similar in the rat and human brain. However, substantial species differences were observed in topographic patterns of [3H]imipramine binding within the hippocampus and hypothalamus. The distribution of [3H]citalopram binding sites within the amygdala and hypothalamus were also strikingly different in rats compared to humans. This work provides the first demonstration that marked species differences exist in the topography of serotonergic innervation and in the distribution of [3H]imipramine binding sites within the rat and human brain regions examined.     

3H]paroxetine binding and serotonin content of rat and rabbit cortical areas, hippocampus, neostriatum, ventral mesencephalic tegmentum, and midbrain raphe nuclei region.

The high-affinity binding of [3H]paroxetine to membranes was measured in different regions of the rat and rabbit brain: cingulate, frontal, parietal, piriform, entorhinal, and visual cortical areas; dorsal and ventral hippocampus; rostral and caudal halves of neostriatum (rat) or caudate nucleus and putamen (rabbit); ventral mesencephalic tegmentum; and midbrain raphe nuclei region. The tissue concentrations of serotonin (5-HT), 5-hydroxyindole-3-acetic acid (5-HIAA) and 5-hydroxy-l-tryptophan (5-HTP) were also determined by high-performance liquid chromatography (HPLC) in the same brain samples. The regional density of [3H]paroxetine binding varied in both species; the highest values (Bmax) were found in the midbrain raphe region and ventral mesencephalic tegmentum. The cortical values ranged from moderate to low, with a significantly higher density in the cingulate cortex of the rat compared with rabbit. In the rat, there was also a higher density in the ventral than dorsal hippocampus, and the caudal than rostral neostriatum. In the rabbit, the hippocampal and neostriatal values were generally lower and more uniform. In both species, there was an excellent correlation between regional 5-HT levels and specific [3H]paroxetine binding (r = 0.87 in the rat and 0.96 in the rabbit). Considering the available quantitative data on the number of 5-HT nerve cell bodies and axon terminals in different regions of the rat brain, it appears likely that the high amount of [3H]paroxetine binding in the midbrain raphe region and ventral mesencephalic tegmentum reflects the presence of 5-HT uptake sites on 5-HT nerve cell bodies and dendrites as well as axon terminals. In other brain regions, the heterogeneous distribution of [3H]paroxetine binding parallels that of the number of 5-HT axon terminals, emphasizing the potential usefulness of this radioligand as a marker of 5-HT innervation density.     

[3H]Paroxetine and [3H]citalopram as markers of the human brain 5-HT uptake site: a comparison study

Summary The binding of [3H]paroxetine and [3H]citalopram to the human brain serotonin (5-HT) uptake site has been characterized and compared. Our results reveal that the binding exclusively involved with the 5-HT uptake site is identical for both [3H]ligands. The selective 5-HT uptake inhibitor citalopram displays the highest affinity for this uptake site, as compared with the affinities obtained for desipramine and norzimeldine, which is in accordance with their respective blockage of 5-HT uptake. Similar Bmax values were obtained for both radioligands in the brain regions studied, indicating their binding to the same presynaptic membrane protein. Together these findings suggest that both [3H]paroxetine and [3H]citalopram are good markers of the 5-HT transporter as both bind selectively and with high affinity to the serotonin uptake sites. However, the higher affinity of [3H]paroxetine confirms that this compound is the best radioligand for the 5-HT uptake site available today.     

High affinity [3H]imipramine and [3H]paroxetine binding sites in suicide brains

Summary Specific binding of [3H]imipramine and [3H]paroxetine was simultaneously examined in human brains (frontal cortex, temporal cortex, cingulate cortex, hypothalamus, hippocampus and amygdala) from 11 controls and 11 depressed suicide victims. A single saturable high affinity site was obtained for both radioligands. Age was not related to significant changes in [3H]imipramine and [3H]paroxetine binding parameters, which indicates the stability of the brain serotonergic system with increasing age.A major finding of the present study concerns the existence of a significant decrease in the maximum number (Bmax) of [3H]imipramine binding sites in hippocampus from depressed suicides as compared with the control group, without changes in the binding affinity (Kd). In contrast, when [3H]paroxetine was used as radioligand, no changes in either Bmax or Kd were detected in any of the brain regions studied. These findings suggest that [3H]imipramine may be a better marker than [3H]paroxetine when alterations in the presynaptic serotonergic uptake site are to be detected.     

In vivo labeling of sigma receptors in mouse brain with [3H]4-phenyl-1-(4-phenylbutyl)piperidine

4-Phenyl-1-(4-phenylbutyl)piperidine(4-PPBP) is a very potent ligand for σ (Sigma) receptors. The present study was undertaken to evaluate [³H]4-PPBPas a radioligand for in vivo labeling of cerebral σ receptors. After intravenous administration of [³H]4-PPBP to mice, there is high uptake of radioactivity in the brain. The regional distribution of radioactivity in the brain 2 h after intravenous injection of [³H]4-PPBP parallels the in vitro binding of the radioligand in rat brain (pons/medulla > cerebellum ≥ prefrontal cortex ≥ parietal cortex > hypothalamus > olfactory tubercle ≥ thalamus > hippocampus > striatum). Pretreatment with haloperidol (2 mg/kg) significantly decreases the radioactivity measured in the brain 30–120 min after injection of [³H]4-PPBP. Pretreatment with unlabeled 4-PPBP or ifenprodil also significantly decreases radioactivity in the brain 2 h after injection of [³H]4-PPBP, in a dosedependent manner. The in vivo binding of [³H]4-PPBP in the brain also is significantly inhibited by SL 82.0715, BMY 14802, 1,3-di-o-tolylguanidine (DTG), and (+)-enantiomers of pentazocine, SKF 10,047, and 3-PPP, but not by the corresponding (?)-enantiomers, consistent with stereoselectivity of inhibition obtained in in vitro binding studies. In contrast, pretreatment with dizocilpine and spiperone does not inhibit in vivo binding of [³H]4-PPBP. The results indicate that [³H]4-PPBP would be a suitable radioligand for in vivo labeling of σ receptors in brain. © 1995 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America

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Uptake and retention of androgen in neurons of the brain of the golden hamster

The distribution of cells capable of concentrating androgen was studied in the male hamster after injection of 5α-dihydro-[1,2,4,5,6,7,(n)-³H]testosterone([³H]DHT) using the technique of thaw-mount autoradiography. Castrated adult male hamsters were injected with 0.2 μg/100 g body weight of [³H]DHT (107 Ci/mmol) and killed 1.5 h later. Brains were rapidly removed and processed for autoradiography. Localization of radioactivity in high concentrations occurred chiefly in limbic forebrain structures and hypothalamic nuclei associated with the control of reproductive function including the following areas: the septal-preoptic region, the amygdala, and the anterior, ventromedial and arcuate nuclei of the hypothalamus. In addition, labeled cells in lesser concentrations were found in the lateral preoptic area, lateral hypothalamus, hippocampus, mesencephalon and various cortical regions. Treatment with 100-fold excess of testosterone, but not estradiol or diethylstilbestrol, inhibited nuclear localization. These studies provide information on the precise anatomical localization of androgen concentrating cells in the hamster brain and demonstrate the similarity of distribution of anrdrogen binding in the rat, mouse and hamster.     

Quantitative autoradiography of serotonin uptake sites in rat brain using [3H]cyanoimipramine

The binding of [3H]cyanoimipramine to serotonin uptake sites in rat brain slices was studied using quantitative autoradiography. Binding was of high affinity and was to a single class of binding site. This is in contrast to results previously obtained by others with [3H]imipramine where two binding sites were observed. The sites labeled by [3H]cyanoimipramine had properties consistent with this ligand labeling serotonin uptake sites, as: (1) binding is displaced by drugs which are potent inhibitors of serotonin uptake but not by drugs which are weak inhibitors of uptake; (2) binding is dependent on the presence of sodium ions as is the uptake of serotonin; (3) binding is almost completely eliminated in the brains of rats lesioned by the serotonin neurotoxin 5,7-dihydroxytryptamine; (4) the distribution of binding sites throughout the rat brain is highly correlated with that found previously for [3H]indalpine, a potent serotonin uptake inhibitor, and for [3H]imipramine. The properties of binding of [3H]cyanoimipramine make it an ideal ligand for the quantitative autoradiography of serotonin uptake sites.     

[H]Spiperone binding sites in brain: autoradiographic localization of multiple receptors

[³H]Spiperone ([³H]SP) binding sites were localized by light microscopic autoradiography, after in vitro labeling. The kinetic and pharmacological characteristics of these binding sites were studied in slide-mounted sections of rat forebrain, and optimal labeling conditions were defined. Autoradiograms were obtained by apposing emulsion-coated coverslips to labeled sections. Diffetrential drug sensitivity allowed the selective displacement of [³H]SP from dopamine receptors by ADTN, from serotonin receptors by cinanserin, from both by haloperidol and from unique spiperone sites by unlabeled spiperone. The various sites presented a differential anatomical localization. For example, only dopaminergic sites were found in the glomerular laver of the olfactory bulb; only serotonergic sites were found in lamina IV of the neocortex, and a high concentration of unique spiperone sites was found in parts of the hippocampus.     

Binding of [3H]paroxetine to serotonin uptake sites and of [3H]lysergic acid diethylamide to 5-HT2A receptors in platelets from women with premenstrual dysphoric disorder during gonadotropin releasing hormone treatment

Changes in serotonergic parameters have been reported in psychiatric conditions such as depression but also in the premenstrual dysphoric disorder (PMDD). In addition, hormonal effects on serotonergic activity have been established. In the present study, binding of [3H]paroxetine to platelet serotonin uptake sites and binding of [3H]lysergic acid diethylamide ([3H]LSD) to platelet serotonin (5-HT)2A receptors were studied in patients with PMDD treated with a low dose of a gonadotropin releasing hormone (GnRH) agonist (buserelin) or placebo and compared to controls. The PMDD patients were relieved of premenstrual symptoms like depression and irritability during buserelin treatment. The number of [3H]paroxetine binding sites (Bmax) were significantly higher in the follicular phase in untreated PMDD patients compared to controls. When treated with buserelin the difference disappeared. No differences in [3H]LSD binding between the three groups were shown. The present study demonstrated altered platelet [3H]paroxetine binding characteristics in women with PMDD compared to controls. Furthermore, [3H]paroxetine binding was affected by PMDD treatment with a low dose of buserelin. The results are consistent with the hypothesis that changes in serotonergic transmission could be a trait in the premenstrual dysphoric disorder.     

Localization of GABAA and GABAB receptor subtypes on serotonergic neurons

The effect of selective destruction of serotonin (5-HT)-containing neurons with 5,7-dihydroxytryptamine (5,7-DHT) on [3H] muscimol and (-)-[3H]baclofen binding was investigated in various rat brain regions. Ten days after intracerebroventricular 5,7-DHT, serotonin levels and [3H]imipramine binding were markedly decreased. 5,7-DHT reduced [3H]muscimol binding only in the mesencephalon, and (-)-[3H]baclofen binding was unmodified in all the areas considered. These results suggest that except in the mesencephalon GABA receptors may not be localized on serotonergic nerve terminals.     

The pattern of [3H]cyclofoxy retention in rat brain after in vivo injection corresponds to the in vitro opiate receptor distribution

Cyclofoxy, a fluorinated analog of naltrexone, has been designed specifically to permit in vivo labeling of opiate receptors in experimental animals and ultimately, humans. Recently, using positron emission tomography (PET), 3-[18F]acetylcyclofoxy was shown to accumulate in opiate receptor-rich brain regions of a live baboon and to be stereospecifically displaced by injections of (-)-naloxone but not (+)-naloxone. Autoradiographic evidence is presented here that the unacetylated compound, [3H]cyclofoxy, labels a population of opiate receptors in brain after in vivo injections that is virtually identical to that labeled by [3H]naloxone. The in vivo binding patterns of [3H]cyclofoxy in brain were similar to those obtained following incubation of slide-mounted brain sections in vitro. Intravenous injections of [3H]cyclofoxy to rats yielded high (greater than 4:1) striatal and thalamic to cerebellar binding ratios in brain homogenates, supernatants and in 24 micron-thick brain sections 60 min after 30 mu Ci per animal (spec. act. = 16.4 Ci/mmol). Autoradiographs revealed the typical opiate antagonist binding profile with marked retention of [3H]cyclofoxy in the striatal patches, subcallosal streak, medial habenula and central thalamus with little retention of label in cerebellum. [3H]Cyclofoxy binding was reversible since the radiolabeled drug disappeared from brain tissue within 2 h after injections to rats, or could be removed from brain slices in vitro by washing slide-mounted tissue sections for 45 min. In addition, after in vitro washing the same brain sections again bound [3H]cyclofoxy or [3H]naloxone in the same pattern. When pre-washed brain sections were incubated with [3H]cyclofoxy in the presence of unlabeled naloxone, [3H]cyclofoxy binding was reduced to background levels. These data show that [3H]cyclofoxy labels-sensitive opiate receptors in vivo and in vitro. The present results combined with evidence that cyclofoxy demonstrates a low level of toxicity in animals suggest that cyclofoxy is an excellent tool with which to study the physiological role of opiate receptors in living animals using in vivo autoradiography, and in humans using PET.     

Effect of chronic administration of duloxetine on serotonin and norepinephrine transporter binding sites in rat brain.

BACKGROUND: Chronic treatment of rats with certain selective serotonin or norepinephrine reuptake inhibitors produces significant decreases, respectively, in serotonin and norepinephrine transporter binding sites in brain. Duloxetine may be a dual serotonin/norepinephrine reuptake inhibitor, as it is only a slightly more potent inhibitor of serotonin than norepinephrine uptake in vitro. Consequently, we hypothesized that chronic duloxetine treatment, at doses producing serum levels within its therapeutic range, would affect both monoamine transporters dose-dependently, with a higher dose causing greater reductions of binding sites for both transporters. METHODS: Rats were treated with either 4 or 8 mg/kg/d of duloxetine, paroxetine, desipramine, or vehicle via subcutaneous osmotic minipumps for 21 days. Binding sites for serotonin and norepinephrine transporters were measured in amygdala and hippocampus using quantitative autoradiography. RESULTS: Both doses of duloxetine and paroxetine produced equivalent and significant decreases in [3H] cyanoimipramine binding to serotonin transporters, but only desipramine treatment significantly reduced [3H] nisoxetine binding to norepinephrine transporters. CONCLUSIONS: At doses producing rat serum concentrations in the range achieved in patients at recommended daily doses of the drug, duloxetine behaves in vivo more as a selective serotonin reuptake inhibitor than a dual reuptake inhibitor in its capacity to selectively reduce serotonin transporter density.     

Quantitative autoradiography of [3H]nitroimipramine binding sites in rat brain

We have used the recent tritium-sensitive film method of quantitative autoradiography to localize in rat brain high-affinity binding sites for nitroimipramine (NI), a long-lasting inhibitor of serotonin (5-HT) transport in platelets. The distribution of NI binding sites in rat brain closely parallels the location of 5-HT terminals. There are high concentrations of binding sites in the dorsal and medial raphe nuclei, the basal portion of the mammilary nuclei, the medial forebrain bundle, the olfactory tubercule and the posterior basal nucleus of the amygdala. The association of [3H]NI binding sites with regions having a high content of 5-HT supports the notion that the high-affinity binding site for [3H]NI corresponds to some aspect of the presynaptic uptake site for 5-HT.