paroxetine, Paxil
Effect of prolonged 5-hydroxytryptamine uptake inhibition by paroxetine on cortical beta 1 and beta 2-adrenoceptors in rat brain.

Nelson DR, Palmer KJ, Johnson AM.

SmithKline Beecham Pharmaceuticals, Research and Development, Harlow, Essex, UK.

The effects of prolonged (21 day) oral administration of the antidepressants paroxetine (0.9 to 8.9 mg/kg/day) and amitriptyline (2.7 to 27 mg/kg/day), on rat brain cortical beta 1- and beta 2-adrenoceptor numbers and affinities were investigated using [3H]-CGP 12177. Although amitriptyline, 27 mg/kg, caused a significant (p less than 0.05) 20% reduction in the number of beta 1-adrenoceptors, paroxetine, at doses up to 8.9 mg/kg p.o., did not influence binding of [3H]-CGP 12177 to cortical beta 1- or beta 2-adrenoceptors. This study with paroxetine provides further evidence that the down-regulation of central beta 1-adrenoceptors in rat brain after repeated administration is not a property of all antidepressant drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1979137&dopt=Abstract paroxetine, Paxil, Paxil CR



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

Scheffel U, Ricaurte GA.

Department of Radiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205.

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.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1980843&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Antidepressant binding sites in brain: autoradiographic comparison of [3H]paroxetine and [3H]imipramine localization and relationship to serotonin transporter.

Hrdina PD, Foy B, Hepner A, Summers RJ.

Department of Pharmacology, University of Ottawa, Ontario, Canada.

Binding of two different antidepressant drugs, [3H]paroxetine and [3H]imipramine in 30 rat brain regions was visualized, compared and quantified by means of autoradiography and densitometry. Specific binding of [3H]paroxetine to coronal sections of diencephalon represented 85% of total binding and was saturable and of high affinity (KD, 0.36 +/- 0.07 nM) with a maximum number of binding sites of 276 +/- 41 fmol/mg protein. The autoradiograms showed a heterogenous distribution of [3H]paroxetine in brain with selective accumulation of label in brain regions known to contain serotonergic terminals, axons and cell bodies (amygdaloid and raphe nuclei, superior colliculus, substantia nigra and medial forebrain bundle). Binding was displaced selectively with other serotonin uptake inhibitors (clomipramine and fluoxetine) and almost abolished by lesioning the serotonergic neurons with p-chloroamphetamine. The desipramine-sensitive [3H]imipramine binding was more diffuse with relatively high density in cerebral cortex and hippocampus and was only decreased partially in animals treated with p-chloroamphetamine. The results indicate that [3H]paroxetine, but not [3H]imipramine, is a ligand of choice to selectively label serotonergic structures in brain.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2137177&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Regional distribution of the serotonin transport complex in human brain, identified with 3H-paroxetine, 3H-citalopram and 3H-imipramine.

Plenge P, Mellerup ET, Laursen H.

Psychochemistry Institute, University of Copenhagen, Rigshospitalet, Denmark.

1. Regional distribution of the serotonin transport complex was studied in 12 different brain areas from human brains. The serotonin uptake complex was measured with 3H-paroxetine, and 3H-imipramine. The binding site density was highest in the nucleus of raphe, medium in the basal ganglia, and lowest in cortical areas. The specific binding measured with 3H-paroxetine and 3H-citalopram was compared with the high affinity 3H-imipramine binding determined with either 100 microM 5HT or 1 microM imipramine as non specific displacers. 3H-paroxetine and 3H-citalopram allowed a more precise determination of Bmax, and are both good ligands for the serotonin uptake site, but the determinations with 3H-imipramine were within the same range. 2. Protease digestion of brain membranes showed that the binding site measured with all three ligands disappeared with the same rate as other membrane proteins, and not faster as might be expected from the literature. 3. Left/right hemisphere distribution was measured in cortical tissue from 6 brains using 3H-paroxetine. No difference between the two hemispheres was found. In one brain from a lithium treated patient a very low binding was measured, possibly indicating that the lithium treatment had decreased the serotonin uptake mechanism.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2137251&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
High-affinity paroxetine binding to the human placental serotonin transporter.

Cool DR, Leibach FH, Ganapathy V.

Department of Cell and Molecular Biology, Medical College of Georgia, Augusta 30912.

We investigated the interaction of paroxetine, a nontricyclic antidepressant, with the serotonin transporter of the human placental brush-border membrane. Paroxetine bound to the purified placental brush-border membranes with a high affinity [dissociation constant (Kd) = 72 pM]. The maximal binding capacity (Bmax) was 3.9 pmol/mg protein. Imipramine, desipramine, and serotonin inhibited the binding in a dose-dependent manner with inhibition constant (Ki) values of 4.4 nM, 48.7 nM, and 1.77 microM, respectively, whereas reserpine, ketanserin, and 5-hydroxytryptophan did not have any effect. Imipramine and serotonin inhibited paroxetine binding by increasing the Kd with essentially no effect on Bmax. Binding of paroxetine to the membranes increased hyperbolically with increasing concentrations of Na+ in the assay medium. Cl- had little effect on the binding. The effect of Na+ was primarily to increase the affinity of the transporter for paroxetine with no effect on Bmax. The association constant (Ka) increased hyperbolically as the concentration of Na+ increased, indicating a 1Na+:1paroxetine stoichiometry. The maximal value for Ka was 12.1 +/- 2.5 x 10(12) M-1, and Kd for Na+ was 10.0 +/- 3.5 mM. Treatment of the membranes with tyrosyl group-specific reagents reduced the Na(+)-dependent binding, suggesting the involvement of tyrosyl residues in the binding process. This inhibition was, however, significantly reduced when treatment with the reagent was performed in the presence of Na+, suggesting that the reactive tyrosyl residues were located at or near the Na(+)-binding site. Paroxetine inhibited NaCl gradient-dependent serotonin uptake in placental brush-border membrane vesicles both at pH 6.5 and 7.5.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2143355&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Effects of high-dose fenfluramine treatment on monoamine uptake sites in rat brain: assessment using quantitative autoradiography.

Appel NM, Mitchell WM, Contrera JF, De Souza EB.

Laboratory of Neurobiology, NIDA Addiction Research Center, Baltimore, Maryland 21224.

Fenfluramine is an amphetamine derivative that in humans is used primarily as an anorectic agent in the treatment of obesity. In rats, subchronic high-dose d,l-fenfluramine treatment (24 mg/kg subcutaneously, twice daily for 4 days) causes long-lasting decreases in brain serotonin (5HT), its metabolite 5-hydroxyindoleacetic acid, and high-affinity 5HT uptake sites. Moreover, this high-dose treatment regimen causes both selective long-lasting decreases in fine-caliber 5HT-immunoreactive axons and appearance of other 5HT-immunoreactive axons with morphology characteristic of degenerating axons. Determination of the potential neurotoxic effects of fenfluramine treatment using immunohistochemistry is limited from the perspectives that staining is difficult to quantify and that it relies on presence of the antigen (in this case 5HT), and the 5HT-depleting effects of fenfluramine are well known. In the present study, we used quantitative in vitro autoradiography to assess, in detail, the density and regional distribution of [3H]paroxetine-labeled 5HT and [3H]mazindol-labeled catecholamine uptake sites in response to the high-dose fenfluramine treatment described above. Because monoamine uptake sites are concentrated on monoamine-containing nerve terminals, decreases in uptake site density would provide a quantitative assessment of potential neurotoxicity resulting from this fenfluramine treatment regimen. Marked decreases in densities of [3H]paroxetine-labeled 5HT uptake sites occurred in brain regions in which fenfluramine treatment decreased the density of 5HT-like immunostaining when compared to saline-treated control rats. These included cerebral cortex, caudate putamen, hippocampus, thalamus, and medial hypothalamus. Smaller, but nonetheless significant, decreases in density of [3H]paroxetine-labeled 5HT uptake sites were noted in brain regions in which partial sparing of 5HT-like immunoreactive fibers had been reported following fenfluramine treatment, specifically septum, lateral hypothalamus, and amygdala. In contrast, [3H]mazindol autoradiography revealed that total catecholamine (i.e., dopamine and norepinephrine) uptake sites in cerebral cortex, caudate putamen, and locus coeruleus, areas in which [3H]paroxetine-labeled 5HT uptake sites were significantly decreased, were unaffected by this fenfluramine treatment. These data support the hypothesis that subchronic, high-dose fenfluramine treatment causes selective degeneration of 5HT axons in rat brain. Since pharmacokinetic studies show that the dosing regimen used in this study exposes rat brain to concentrations of fenfluramine that are approximately 600 times greater than those resulting from the therapeutic oral dose, caution must be exercised in extrapolating these data to humans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2144664&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Seasonal variations in binding of 3H-paroxetine to blood platelets in healthy volunteers: indications for a gender difference.

Klompenhouwer JL, Fekkes D, van Hulst AM, Moleman P, Pepplinkhuizen L, Mulder PG.

Department of Psychiatry, Academic Hospital Rotterdam-Dijkzigt, The Netherlands.

Binding of paroxetine to blood platelet membranes was studied longitudinally in 20 healthy volunteers (11 men and 9 women) in order to determine seasonal and gender variations. Blood samples were obtained in September, December, March, and June, and repeated in September. A significant seasonal variation in the maximal number of binding sites (Bmax) was found. Men were found to have significantly lower (Bmax) values than women. Although the pattern of seasonal variation was not identical in men and women, no significant differences were detected. The affinity constant (KD) of paroxetine binding showed a significant seasonal variation. Men were found to have a significantly higher KD (lower affinity) than women. The pattern of seasonal variation was identical in men and women. These data support the evidence indicating a substantial seasonal effect on the serotonergic system, and show that in paroxetine binding studies, groups of subjects should be matched for season and gender.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2145983&dopt=Abstract paroxetine, Paxil, Paxil CR