paroxetine, Paxil
Evaluation of 3H-paroxetine as a radioligand for in vivo study of 5-hydroxytryptamine uptake sites in mouse brain.

Hashimoto K, Goromaru T.

Department of Radiopharmaceutical Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, University of Fukuyama, Japan.

The distribution of radioactivity in the mouse brain after intravenous administration of 3H-paroxetine was in the order (highest to lowest) hypothalamus greater than cerebral cortex greater than cerebellum. The radioactivity in the hypothalamus and cerebral cortex after injection of 3H-paroxetine was significantly decreased by treatment with 6-nitroquipazine or paroxetine. HPLC and TLC analyses show that no radioactive metabolites were found in the mouse brain 3 h after intravenous administration of 3H-paroxetine. The present results indicate that 3H-paroxetine would be a suitable radioligand for in vivo study of 5-HT uptake sites in mouse brain.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2146707&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Interaction of fluoxetine with the human placental serotonin transporter.

Cool DR, Liebach FH, Ganapathy V.

Department of Cell and Molecular Biology, Medical College of Georgia, Augusta 30912-2100.

The interaction of fluoxetine, a non-tricyclic antidepressant, with the human placental serotonin transporter was investigated by studying its influence on [3H]paroxetine binding to the transporter and on [3H]serotonin uptake via the transporter. These studies were done using brush-border membrane vesicles purified from normal term human placentas. Fluoxetine inhibited binding of paroxetine to the membrane vesicles in a concentration-dependent manner, with a Ki value of 3 nM. Kinetic analysis revealed that the inhibition was competitive because the presence of 10 nM fluoxetine increased the Kd for paroxetine from 72 to 461 pM, but had no effect on the Bmax. Fluoxetine also caused a time-dependent dissociation of paroxetine already bound to the transporter. The dissociation followed first-order kinetics. Uptake of serotonin in these membrane vesicles was also inhibited by fluoxetine. The inhibition was concentration dependent with a Ki value of 66 nM at pH 7.5 and 80 nM at pH 6.5. The effect of fluoxetine on the uptake kinetics was to increase the apparent dissociation constant (Kt) for serotonin without influencing the maximal transport capacity (Vmax). The results demonstrate that fluoxetine is a high-affinity ligand and a potent inhibitor of the serotonin transporter found in the human placental brush-border membrane.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2146964&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Preparation and characterization of anti-paroxetine antibodies.

Strijewski A, Tang SW.

Psychopharmacology Unit, Clarke Institute of Psychiatry, Toronto, Canada.

6-nitroparoxetine was synthesized and reduced to 6-aminoparoxetine. After coupling to glutaraldehyde at the 6-position and to bovine serum albumin, the resulting Schiff's base was further reduced into an amino-derivative which served as the antigen. Anti-paroxetine antibodies were raised against this antigen in rabbits and the anti-paroxetine IgG purified by Protein A affinity chromatography. The anti-paroxetine IgG demonstrated high specificity towards paroxetine and 6-nitroparoxetine without significant cross-reactivity with other commonly used antidepressant and neuroleptic drugs. These antibodies may be useful for both plasma paroxetine level assays and uptake inhibitor binding site studies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2147049&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Inhibition of MAO activity, 3H-imipramine binding, 3H-paroxetine binding and 3H-5-HT uptake by human cerebrospinal fluid.

Egashira T, Goto S, Murayama F, Yamanaka Y.

Department of Pharmacology, Medical College of Oita, Japan.

Addition of small amount of human cerebrospinal fluid (CSF) inhibited both types of MAO in monkey brain mitochondria. The specific binding of 3H-paroxetine decreased remarkably with increasing CSF volumes, while 3H-imipramine binding was slightly inhibited. Scatchard analysis of 3H-paroxetine binding in the presence and absence of CSF indicated that the inhibitory effect was associated with a decreased Bmax without an appreciable change in Kd. Addition of CSF induced an inhibition of uncompetitive 3H-5-HT uptake to monkey cerebral membranes. These results indicate that the materials in human CSF inhibit 3H-paroxetine binding, and modulate the uptake system for 5-HT.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2150970&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
In vivo labeling of serotonin uptake sites with [3H]paroxetine.

Scheffel U, Hartig PR.

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

Previous work has shown that [3H]paroxetine is a potent and selective in vitro label for serotonin uptake sites in the mammalian brain. In the present study, [3H]paroxetine was tested in mice as an in vivo label for serotonin uptake sites. Maximum tritium concentration in the whole brain (1.4% of the intravenous dose) was reached 1 h after injection into a tail vein. Distribution of the tracer at 3 h after injection followed the distribution of serotonin uptake sites known from previous in vitro binding studies (r = 0.85). The areas of highest [3H]paroxetine concentration, in decreasing order, were: hypothalamus greater than frontal cortex greater than olfactory tubercles greater than thalamus greater than upper colliculi greater than brainstem greater than hippocampus greater than striatum greater than cerebellum. Preinjection of carrier paroxetine (1 mg/kg) significantly decreased [3H]paroxetine concentration in all areas except in the cerebellum, which is known to contain a relatively low number of specific binding sites. Kinetic studies showed highest specific [3H]paroxetine binding (tissue minus cerebellum) at 2 h after injection and slow clearance of activity thereafter (half-time of dissociation from the hypothalamus, 215 min). The specificity of in vivo [3H]paroxetine binding was studied by preinjecting monoamine uptake blockers or receptor antagonists 5 min before administration of [3H]paroxetine. Serotonergic or muscarinic cholinergic receptor antagonists and dopamine or norepinephrine uptake blockers did not reduce the in vivo binding of [3H]paroxetine. In contrast, there was an excellent correlation (r = 0.99) between the in vivo inhibitory potencies of serotonin uptake blockers in this study and previously published in vitro data on inhibition of [3H] serotonin uptake in brain synaptosomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2523469&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
High affinity [3H]paroxetine binding to serotonin uptake sites in human brain tissue.

Backstrom I, Bergstrom M, Marcusson J.

Department of Geriatric Medicine, University of Umea, Sweden.

[3H]Paroxetine binding to human brain tissue was characterized. Competition studies in the putamen and frontal cortex revealed single-site binding models for binding sensitive to 5-hydroxytryptamine (5-HT) (Ki 1-3 microM) and citalopram (Ki 0.6 nM), which displaced the same amount of binding. However, desipramine, norzimeldine and fluoxetine displaced additional binding (10-20%) and these competitors fitted two-site binding models with high affinity components in the nanomolar range and low affinity components in the micromolar range. The high affinity components approximated the 5-HT- and citalopram-sensitive binding fraction. Most of the [3H]paroxetine binding sites were protease-sensitive, but the low-affinity (microM) sites appeared to be protease-resistant. Based on these findings, only the [3H]paroxetine binding representing the fraction sensitive to 30 microM 5-HT (or e.g. 0.3 microM norzimeldine), was regarded as specific binding. This binding fraction was saturable with an apparent binding affinity (Kd) of 0.03-0.05 nM throughout the brain. The highest binding densities were obtained in the hypothalamus and substantia nigra (Bmax 500 fmol/mg protein). The basal ganglia reached intermediate densities (Bmax 200 fmol/mg protein), whereas cortical areas had low Bmax values (less than 100 fmol/mg protein). The lowest B max value was noted in cerebellar cortex (30 fmol/mg protein). The [3H]paroxetine binding was competitively inhibited by low concentrations of 5-HT, imipramine and norzimeldine, suggesting that the substrate recognition site for 5-HT uptake was labeled. Compounds active at dopaminergic, noradrenergic, histaminergic, 5-HT1, 5-HT2 and cholinergic muscarinic sites did not affect the binding at 100 microM concentrations. It is concluded that [3H]paroxetine is a marker for the 5-HT uptake site in the human brain, provided that an adequate pharmacological definition of specific binding is performed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2525060&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
[Behavioral pharmacological properties of the novel antidepressant paroxetine, a selective 5-HT uptake inhibitor]

[Article in Japanese]

Yamamoto T, Shibata S, Shimazoe T, Iwasaki K, Ohno M, Minamoto Y, Furuya Y, Miyamoto K, Watanabe S, Ueki S, et al.

Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.

The behavioral effects of paroxetine were investigated in mice and rats in comparison with imipramine and amitriptyline. 1) Locomotor activities were decreased by imipramine and amitriptyline but not by paroxetine in both animal species. 2) Paroxetine antagonized methamphetamine-induced hyperactivity in mice as did imipramine and amitriptyline. 3) Paroxetine showed a more potent antimuricidal effect in raphe-lesioned rats than imipramine and amitriptyline, and it also inhibited muricide in olfactory bulbectomized rats. 4) The immobility of rats in the forced swimming test was markedly decreased by imipramine and amitriptyline, but only slightly by paroxetine. 5) Like imipramine and amitriptyline, paroxetine potentiated the methamphetamine- or L-DOPA-induced stereotyped sniffing, and it inhibited oxotremorine-induced tremor. 6) Paroxetine antagonized reserpine-induced hypothermia, tetrabenazine-induced ptosis, and enhanced ether-induced anesthesia, all less potently than imipramine and amitriptyline. 7) The analgesic action of paroxetine was stronger than that of imipramine and amitriptyline. 8) Paroxetine did not antagonize maximal electroshock- or pentetrazol-induced convulsions and haloperidol- or THC-induced catalepsy in rats. In addition, paroxetine neither exerted muscle relaxation nor affected the shuttle-box type conditioned avoidance in rats. From these results, the behavioral effects of paroxetine, as compared with imipramine and amitriptyline, were characterized by its potent antimuricidal action in raphe-lesioned rats and its weak effect in the forced swimming test and by its less potent muscle relaxant, anticonvulsant, anticataleptic and anesthesia-potentiating actions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2530142&dopt=Abstract paroxetine, Paxil, Paxil CR