paroxetine, Paxil
Induction and potentiation of parturition in fingernail clams (Sphaerium striatinum) by selective serotonin re-uptake inhibitors (SSRIs).

Fong PP, Huminski PT, D'Urso LM.

Department of Biology, Gettysburg College, Pennsylvania 17325, USA. pfong gettysburg.edu

Parturition in fingernail clams (Sphaerium spp.) can be induced by external application of serotonin and serotonergic ligands. Selective serotonin re-uptake inhibitors (SSRIs) increase neurotransmission at serotonergic synapses by blocking re-uptake transporters. We tested the efficacy of SSRIs (fluvoxamine, fluoxetine, paroxetine) at inducing parturition in the fingernail clam Sphaerium striatinum. Parturition was induced by fluvoxamine and paroxetine, but only potentiated by fluoxetine. Fluvoxamine was potent, significantly inducing parturition at concentrations from 10 nM to 100 microM compared with negative controls. Fluvoxamine also significantly potentiated a subthreshold (10 microM) concentration of serotonin. Paroxetine also induced parturition but was less potent. Only 10 microM paroxetine significantly induced parturition compared with controls. Fluoxetine (1-100 microM) did not induce any parturitions, but at 5 microM it potentiated parturition in subthreshold serotonin concentrations as low as 50 nM. These results suggest the presence of serotonin re-uptake transporters in bivalve molluscs and may provide a way of stimulating serotonergic mechanisms without using serotonin or its ligands.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9472482&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Repeated antidepressant drug treatment, time of death and frequency of handling do not affect [3H]paroxetine binding in rat cortex.

Dean B, Pereira A, Pavey G, Singh B.

Rebecca L. Cooper Research Laboratories, Mental Health Research Institute of Victoria, Parkville, Australia. bdean cooper.mhri.edu.au

[3H]Paroxetine binding to the serotonin transporter has been shown to be altered in brain tissue from schizophrenic subjects. Some schizophrenic subjects are treated with antidepressant drugs, some of which bind to the serotonin transporter and their time of death is variable. To determine if these confounding factors could affect [3H]paroxetine binding, [3H]paroxetine binding to cortical membrane from rats treated with the antidepressant drugs for 10 or 28 days and in non-treated rats that were killed at different times of the day was measured. Drug treatment, when compared to injection with 0.9% saline and time of death, did not affect [3H]paroxetine binding. Treatment with imipramine [10 days: mean +/- S.D.: 590 +/- 59 fmol/mg protein (P < 0.05); 28 days: 653 +/- 59 fmol/mg protein (P < 0.01)] or mianserin [10 days: 600 +/- 43 (P < 0.05)] caused a significant decrease in the density of [3H]paroxetine binding compared to that in fluoxetine-treated rats (10 days: 820 +/- 211 fmol/mg protein; 28 days: 764 +/- 100 fmol/mg protein). Thus, overall, these data do not suggest changes in [3H]paroxetine binding reported in the human brain tissue would be due to antidepressant drug treatment or time of death.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9481808&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
The role of 5-HT receptor subtypes in the anxiolytic effects of selective serotonin reuptake inhibitors in the rat ultrasonic vocalization test.

Schreiber R, Melon C, De Vry J.

CNS Research, Troponwerke GmbH & Co. KG, Cologne, Germany. rudy.schreiber.rs bayer-ag.de

We evaluated whether the anxiolytic effects of selective serotonin reuptake inhibitors (SSRIs) in the rat ultrasonic vocalization (USV) test are preferentially mediated by (indirect) activation of 5-HT1A, 5-HT1B/1D, 5-HT2A, 5-HT3 or 5-HT4 receptors. The SSRIs, paroxetine (ED50 in mg/kg, IP: 6.9), citalopram (6.5), fluvoxamine (11.7) and fluoxetine (> 30), dose dependently reduced shock-induced USV. The effects of paroxetine (3.0 mg/kg, IP) were not blocked by the selective 5-HT1A receptor antagonist, WAY-100635 (3.0 mg/kg, IP), the 5-HT1B/1D receptor antagonist, GR 127935 (30 mg/kg, IP), the nonselective 5-HT2A receptor antagonists, ritanserin (3.0 mg/kg, IP) and ketanserin (1.0 mg/kg, IP), the 5-HT3 receptor antagonist, ondansetron (0.1 mg/kg, IP), or the 5-HT4 receptor antagonist, GR 125487D (3.0 mg/kg, SC). In contrast, the selective 5-HT2A receptor antagonist, MDL 100,907 (0.1 mg/kg, IP), completely prevented the paroxetine-induced reduction of USV. Under similar conditions, WAY-100635 blocked the anxiolytic-like effects of the selective 5-HT1A receptor agonist, 8-OH-DPAT [(+/-)-8-hydroxy-2-(di-n-propylamino)tetralin, 1.0 mg/kg, IP], and ritanserin, ketanserin, and MDL 100,907 blocked the anxiolytic-like effects of the mixed 5-HT2A/2C receptor agonist, DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, 3.0 mg/kg, IP]. WAY-100635 (1.0 mg/kg, IP) in combination with ritanserin (3.0 mg/kg, IP), but not ondansetron (0.1 mg/kg, IP), GR 125487D (3.0 mg/kg, SC), or GR 127935 (30 mg/kg, IP), attenuated the USV reducing effects of paroxetine. Although the results suggest that selective stimulation of 5-HT1A and 5-HT2A receptors produces a decrease of USV, we postulate that only 5-HT2A receptors play a pivotal role in the effects of SSRIs in this model of anxiety.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9539263&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Circannual variations in the binding of [3H]lysergic acid diethylamide to serotonin2A receptors and of [3H]paroxetine to serotonin uptake sites in platelets from healthy volunteers.

Spigset O, Allard P, Mjorndal T.

Division of Clinical Pharmacology, Norrland University Hospital, Umea, Sweden.

BACKGROUND: Circannual variations occur in several serotonergic parameters, including platelet serotonin uptake and platelet [3H]imipramine binding. METHODS: Binding of [3H]lysergic acid diethylamide ([3H]LSD) to platelet serotonin (5-HT)2A receptors and binding of [3H]paroxetine to platelet serotonin uptake sites were studied longitudinally for 1 year in 12 healthy volunteers. RESULTS: For [3H]LSD, the number of binding sites (Bmax) showed no significant seasonal variation (two-way analysis of variance), although Bmax was significantly higher during the months October through February than during the months April through August (32.6 vs. 29.8 fmol/mg protein; p = .015). For [3H]paroxetine, Bmax showed a significant seasonal variation (p = .003) with maximum in August (1322 fmol/mg protein) and minimum in February (1168 fmol/mg protein). The affinity constant (Kd) showed a significant seasonal variation for [3H]LSD binding (p = .046), but not for [3H]paroxetine binding. The seasonal fluctuations in [3H]LSD binding and in paroxetine binding tended to be inversely correlated for Bmax (r = -.70; p = .08) and were significantly negatively correlated for Kd (r = -.88; p = .009). CONCLUSIONS: The present study demonstrates a seasonal effect on platelet serotonin uptake site binding and indicates a possible seasonal effect on 5-HT2A receptor binding. The results imply that circannual fluctuations should be taken into account when these platelet serotonin markers are studied.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9606533&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Intracerebral fetal raphe implants normalize hippocampal function but not cerebrovascular control in serotonin-depleted adult rat brain.

Kelly PA, McBean DE, Ritchie IM.

Department of Clinical Neurosciences, University of Edinburgh, Western General Hospital, UK.

The effects of hypercapnia upon local cerebral blood flow and local cerebral glucose utilization were measured by quantitative autoradiography in parallel groups of rats (six per group) which 14-16 weeks previously had been treated with the serotonergic neurotoxin, methylenedioxymethamphetamine, followed by implantation of fetal raphe or basal forebrain tissues. Following the experiments, transplants were visualized by acetylcholinesterase histochemistry, and serotonergic reinnervation assessed using [3H]paroxetine binding to serotonin reuptake sites. In methylenedioxymethamphetamine-treated rats, contralateral to the implants, [3H]paroxetine binding was reduced by between 50 and 90% in the neocortex and hippocampus. Hippocampal glucose utilization was significantly increased in these rats, and the normal increase in flow which accompanies hypercapnia was also significantly enhanced. High levels of [3H]paroxetine binding were found within the raphe transplants (308 +/- 13 fmol/mg tissue). In host brain adjacent to the implant, binding levels were normalized, and in these same areas glucose utilization was also normalized. Basal forebrain implants had no effect upon either [3H]paroxetine binding or glucose utilization. Raphe transplants did not, however, alter the enhanced cerebrovascular response to hypercapnia induced by methylenedioxymethamphetamine, even in those areas where there was evidence of serotonergic reinnervation. The transplants also showed the same enhanced response. In conclusion, intracerebral fetal raphe implants normalize hippocampal function but not cerebrovascular control in serotonin-depleted adult rat brain, and despite not sharing the serotonergic deficit, blood flow in the implants follows that of the dysfunctional host.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9607703&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Possible involvement of opioidergic and serotonergic mechanisms in antinociceptive effect of paroxetine in acute pain.

Duman EN, Kesim M, Kadioglu M, Yaris E, Kalyoncu NI, Erciyes N.

Department of Anesthesia, Karadeniz Technical University, School of Medicine, Trabzon, Turkey.

Antidepressant drugs, especially tricyclics have been widely used in the treatment of chronic pain, but not in acute pain. Because of numerous undesirable side effects, the selective serotonin reuptake inhibitors (SSRIs), with their favorable side effect profile, are preferred nowadays. An activation of the endogenous opioid mechanisms or potentiation of the analgesic effect mediated by serotonergic and/or noradrenergic pathways are thought to be involved in the antinociceptive action of SSRIs. In this study, the potential antinociceptive effect of paroxetine and its interaction with opioidergic system and serotonin receptors were evaluated. The antinociceptive effect of paroxetine was tested using a hot plate test in mice. Paroxetine, a SSRI antidepressant drug, induced an antinociceptive effect following i.p. administration. This antinociception was significantly inhibited by naloxone, an opioid receptor antagonist, suggesting the involvement of opioidergic mechanisms. While ondansetron (a 5-HT(3)-receptor antagonist) inhibited the effect of paroxetine, ketanserin (a 5-HT(2)-receptor antagonist) could not. In conclusion, paroxetine-induced antinociception, similar to morphine, suggests an involvement of direct or indirect action (via an increase in release of endogenous opioid peptide(s)) at opioid receptor sites and an involvement of serotonergic mechanisms mainly at the receptor level.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14978354&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Determinants of interindividual variability and extent of CYP2D6 and CYP1A2 inhibition by paroxetine and fluvoxamine in vivo.

Ozdemir V, Naranjo CA, Shulman RW, Herrmann N, Sellers EM, Reed K, Kalow W.

Sunnybrook Health Science Centre, Department of Pharmacology, University of Toronto, Ontario, Canada.

Major depression may require antidepressant treatment for several years. This necessitates consideration of the long-term effects of antidepressants on multiple clinical endpoints. The antidepressants paroxetine and fluvoxamine are potent in vitro inhibitors of CYP2D6 and CYP1A2 isozymes, respectively. CYP2D6 and CYP1A2 are important for the clearance of 30 or more frequently used medications. Moreover, CYP1A2 also contributes to metabolism of 17beta-estradiol and metabolic activation of environmental procarcinogens (e.g., arylamines in cigarette smoke). The aim of this study was to assess the determinants of interindividual variability and extent of CYP2D6 and CYP1A2 inhibition during paroxetine and fluvoxamine treatment. Healthy volunteers and patients received caffeine (100 mg) and dextromethorphan (30 mg) at baseline and at steady state of paroxetine (10-20 mg/day, 5-74 days, N = 13) or fluvoxamine (50-100 mg/day, 5-43 days, N = 8). The caffeine metabolic ratio (CMR) and the log O-demethylation ratio (ODMR) of dextromethorphan in overnight urine were used as in vivo indices of the CYP1A2 and CYP2D6 isozyme activities, respectively. All subjects had an extensive metabolizer phenotype for CYP2D6. After fluvoxamine treatment, baseline CMR 5.1 +/- 1.4 (mean +/- SD) decreased to 2.7 +/- 1.1 (p < 0.01). Paroxetine did not have a significant effect on CMR (p > 0.05). In seven of eight subjects in the fluvoxamine group, posttreatment CMR was comparable with the minimum CMR value (2.0) attainable in nonsmoking healthy volunteers. After paroxetine treatment, log ODMR changed from a baseline value of -2.28 +/- 0.37 to -1.13 +/- 0.44, indicating significant inhibition of CYP2D6 (p < 0.001). Subjects' CYP2D6 phenotype did not change after paroxetine treatment. Fluvoxamine had no significant effect on log ODMR (p > 0.05). The extent of inhibition of CYP2D6 and CYP1A2 by paroxetine and fluvoxamine, respectively, displayed a positive correlation with baseline enzyme activity (p < 0.05). In addition, a negative association was found between the plasma paroxetine concentration and the CYP2D6 activity after paroxetine treatment (r = -0.47, p < 0.05). These data indicate that paroxetine and fluvoxamine treatment with minimum clinically effective doses significantly inhibit CYP2D6 and CYP1A2, respectively. The extent of inhibition of CYP2D6 by paroxetine and of CYP1A2 by fluvoxamine is dependent in part on the baseline enzyme activity. The interindividual variability in CYP2D6 inhibition by paroxetine can also be explained by variability in plasma paroxetine concentration. Most patients treated with fluvoxamine (50-100 mg/day) will reach population minimums for CYP1A2 activity. These results have potential implications for interindividual variability in the risk for drug-drug interactions mediated by CYP2D6 and CYP1A2 as well as for the disposition of 17beta-estradiol and environmental procarcinogens.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9617978&dopt=Abstract paroxetine, Paxil, Paxil CR