paroxetine, Paxil
Binding of [3H]paroxetine to platelets of depressed patients: seasonal differences and effects of diagnostic classification.

D'Hondt P, Maes M, Leysen JE, Gommeren W, Scharpe S, Cosyns P.

Department of Psychiatry, University Hospital of Antwerp (UZA), Edegem, Belgium.

[3H]Paroxetine is a more reliable ligand for studying the serotonin (5-HT) transporter complex than [3H]imipramine. The present study investigates [3H]paroxetine binding to platelets in 54 depressed in-patients (18 minor, 16 simple major and 20 melancholic depressed patients) and 16 healthy controls. There were no significant differences in maximal number of binding sites between depressed subjects and normal controls. There was no correlation between [3H]paroxetine binding to platelet membranes and severity of depression. [3H]Paroxetine binding to platelets was significantly higher in spring than in summer, fall and winter.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7798464&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Differential effects of 5,7-dihydroxytryptamine-induced serotoninergic degeneration of 5-HT1A receptors and 5-HT uptake sites in the rat brain.

Gobbi M, Regondi MC, Pompeiano M, Palacios JM, Mennini T.

Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.

The time-course of 5,7-dihydroxytryptamine-induced lesions (2, 5 and 14 days after i.c.v. injection of 150 micrograms) and the effects of acute reserpine treatment (10 mg/kg, i.p., one or 5 days before scheduled death), were evaluated by autoradiography of [3H]paroxetine binding sites in the rat brain. Reserpine had no significant effect on [3H]paroxetine binding, indicating that the depletion of serotonin is not sufficient per se to alter the serotonin uptake sites in any region. Two days after the 5,7-dihydroxytryptamine lesion, [3H]paroxetine binding was already decreased in the majority of brain regions. In the caudate putamen these binding sites were significantly decreased only 14 days after the lesion, whereas the ventral tegmental area (or the enclosed median forebrain bundle), the dorsal raphe (mainly the ventral portion) and the median raphe maintained their high density of serotonin uptake sites even after 14 days. Results were similar using [3H]citalopram as ligand for the serotonin uptake sites, in the brains of rats lesioned 5 days before death; an exception was the ventral portion of the dorsal raphe, where there was a significant increase with [3H]paroxetine and a decrease with [3H]citalopram binding. In adjacent sections of the same brains we also measured [3H]8-OH-DPAT binding, confirming that it completely disappears in the dorsal raphe after the lesion. Thus, considering the extent of serotonin cell body degeneration, there appears to be a paradoxical mismatch between the excessive loss of [3H]8-OH-DPAT binding and the resistance of [3H]citalopram or [3H]paroxetine binding in the dorsal raphe, suggesting that the two binding sites may undergo adaptive regulation in surviving neurons.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7802971&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Paroxetine retards disease onset and progression in Huntingtin mutant mice.

Duan W, Guo Z, Jiang H, Ladenheim B, Xu X, Cadet JL, Mattson MP.

Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, NIH, Baltimore, MD 21224, USA. duanwe grc.nia.nih.gov

We report that administration of paroxetine, a widely prescribed antidepressant drug that acts by inhibiting reuptake of the neurotransmitter serotonin, suppresses the neurodegenerative process and increases the survival of huntingtin mutant mice, an animal model of Huntington's disease (HD). Paroxetine attenuated motor dysfunction and body weight loss and improved glucose metabolism in the HD mice. Paroxetine was beneficial when treatment was initiated before or after the onset of motor dysfunction, suggesting a potential for such antidepressant drugs in the treatment of presymptomatic and symptomatic HD patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15048901&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Anxiolytic-like effect of paroxetine in a rat social interaction test.

Lightowler S, Kennett GA, Williamson IJ, Blackburn TP, Tulloch IF.

SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK.

The effects of short- and long-term administration of the selective serotonin reuptake inhibitor paroxetine were investigated in a rat social interaction test. A single administration of paroxetine at oral doses of 0.3, 1, 3 and 10 mg/kg had no effect on social interaction between pairs of male rats under bright light (high anxiety) conditions. After 21 days of daily administration, paroxetine given orally at 3 mg/kg significantly (p < 0.01) increased the time spent in social interaction by pairs of rats tested under the same conditions, with no effect on locomotor activity, indicating an anxiolytic-like effect. The magnitude of increase (+97%) was comparable to that seen after a single dose of chlordiazepoxide (4 mg/kg orally). Although there was also an increase in time spent in social interaction after 21 days of repeated oral administration of paroxetine at 0.3, 1, and 10 mg/kg (+44, +56, and +54% increases, respectively), statistical significance was not achieved. These results indicate that in the long term paroxetine has an anxiolytic action, and thus support the clinical evidence for its therapeutic use in the treatment of anxiety disorders in addition to its established role as an antidepressant.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7824539&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Modulation of 5-HT release in the guinea-pig brain following long-term administration of antidepressant drugs.

Blier P, Bouchard C.

Department of Psychiatry, McGill University, Montreal, Quebec, Canada.

1. The aims of the present study were to determine whether long-term 5-hydroxytryptamine (5-HT) reuptake blockade and inhibition of type-A monoamine oxidase (MAO-A) lead to an enhancement of the electrically evoked release of tritum from guinea-pig brain slices preloaded with [3H]-5-HT, and to assess the sensitivity of the terminal 5-HT1D autoreceptor, the alpha 2-adrenoceptor also located on 5-HT terminals, and the 5-HT3 receptor that modulates 5-HT release following these two types of antidepressant treatments. 2. The electrically evoked release of tritium was significantly enhanced following a 21-day treatment with the 5-HT reuptake blocker, paroxetine and the reversible MAO-A inhibitor, befloxatone, in preloaded slices of the hypothalamus, hippocampus and frontal cortex 48 h after removal of the osmotic minipumps used to deliver the drugs. 3. The inhibitory effect of the terminal 5-HT autoreceptor agonist, 5-methoxytryptamine, on the evoked release of tritium was attenuated in slices of the hypothalamus, hippocampus, but not frontal cortex, following the paroxetine treatment. In the befloxatone group, the effectiveness of 5-methoxytryptamine was unaltered in the same brain structures. 4. The sensitivity of the alpha 2-adrenoceptor on 5-HT terminals, assessed using UK 14.304, was attenuated in hypothalamus, hippocampus, but not frontal cortex slices prepared from befloxatone-treated guinea-pigs and preloaded with [3H]-5-HT. The paroxetine treatment did not alter the sensitivity of this alpha 2-adrenoceptor in the hypothalamus. 5. The sensitivity of the alpha 2-adrenoceptor on noradrenaline terminals, also assessed using UK 14.304, was not altered in hippocampus and hypothalamus slices preloaded with [3H]-noradrenaline following the long-term befloxatone treatment. 6. In frontal cortex slices, [3H]-5-HT uptake was no longer significantly attenuated after a 21-day treatment with paroxetine, whereas it was still markedly inhibited in hypothalamus slices. The enhancing effect of paroxetine on the evoked release of [3H]-5-HT in the superfusion medium was no longer evident in frontal cortex slices of the paroxetine group. These data indicate that long-term 5-HT reuptake blockade desensitized the 5-HT transporter in the frontal cortex. 7. The capacity of the 5-HT3 receptor agonist, 2 methyl-5-HT, to enhance the electrically evoked release of tritium was not altered in hypothalamus, hippocampus, and frontal cortex slices prepared from befloxatone-treated guinea-pigs, but was significantly attenuated in the paroxetine group also treated for 21 days.(ABSTRACT TRUNCATED AT 400 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7834200&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
[3H]paroxetine binding is altered in the hippocampus but not the frontal cortex or caudate nucleus from subjects with schizophrenia.

Dean B, Opeskin K, Pavey G, Naylor L, Hill C, Keks N, Copolov DL.

Rebecca L. Cooper Laboratories, Mental Health Research Institute of Victoria, Australia.

[3H]Paroxetine binding to particulate membrane from tissue, obtained at autopsy, from the hippocampus, frontal cortex, and caudate nucleus from subjects who had or had not had schizophrenia was measured. The density of [3H]paroxetine binding to membranes from subjects who had or had not had schizophrenia did not differ. Similarly, the affinity of [3H]paroxetine binding in the frontal cortex and caudate nucleus was not different. By contrast, the affinity of [3H]paroxetine binding to hippocampal membrane from subjects who had schizophrenia was significantly lower than the affinity of binding for the nonschizophrenic subjects (0.40 +/- 0.06 vs. 0.26 +/- 0.02; p < 0.05). As [3H]paroxetine binds to the serotonin transporter, these data suggest that the serotonin transporter is altered in the hippocampus in subjects with schizophrenia.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7861151&dopt=Abstract paroxetine, Paxil, Paxil CR



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

Arranz B, Marcusson J.

Department of Geriatric Medicine, University of Linkoping, Sweden.

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.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7888147&dopt=Abstract paroxetine, Paxil, Paxil CR