paroxetine, Paxil
Early desensitization of somato-dendritic 5-HT1A autoreceptors in rats treated with fluoxetine or paroxetine.

Le Poul E, Laaris N, Doucet E, Laporte AM, Hamon M, Lanfumey L.

Neurobiologie Cellulaire et Fonctionnelle, INSERM U 288, Faculte de Medecine Pitie-Salpetriere, Paris, France.

Electrophysiological and autoradiographic approaches were used to assess possible changes in 5-hydroxytryptamine (serotonin) 5-HT1A receptors in the rat dorsal raphe nucleus after a subchronic treatment with fluoxetine or paroxetine, two specific serotonin reuptake inhibitors with antidepressant properties. Fluoxetine or paroxetine were injected daily (5 mg/kg, i.p.) for various time periods up to 21 days. Electrophysiological recordings performed 24 h after the last injection showed that the potency of the 5-HT1A receptor agonist, 8-OH-DPAT, to depress the firing of serotoninergic neurons in the dorsal raphe nucleus within brain stem slices was significantly reduced as early as after a 3-day treatment with either drug. The proportion of recorded neurons showing desensitization of somatodendritic 5-HT1A autoreceptors increased along the treatment from approximately 40% on the 3rd day to 60-80% on the 21st day. At no time during the treatment, was the specific binding of [3H]8-OH-DPAT (agonist radioligand) or [3H]WAY-100 635 (antagonist radioligand) to 5-HT1A receptors modified in the dorsal raphe nucleus or in other brain areas, suggesting that neither the density nor the coupling of these receptors to G-proteins were probably altered in rats injected with fluoxetine or paroxetine for up to 21 days. These results show that adaptive desensitization of somatodendritic 5-HT1A autoreceptors within the dorsal raphe nucleus can already be detected after a 3-day treatment with selective serotonin reuptake inhibitors. Rather than the desensitization per se, it may be the progressive increase in the number of serotoninergic neurons with desensitized 5-HT1A autoreceptors which plays a critical role in the (slowly developing) antidepressant action of these drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7477436&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Effect of paroxetine on seizure length during electroconvulsive therapy.

Curran S.

Department of Psychiatry, University of Leeds, United Kingdom.

This study reports the effect of paroxetine, a selective serotonin reuptake inhibitor, on seizure length during electroconvulsive therapy. Seven inpatients taking paroxetine were compared with 7 controls taking tricyclic antidepressants. The mean seizure length of the paroxetine group was approximately twice that of the control group.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7484206&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Synthesis and characterization of an aryl-azidoparoxetine. A novel photo-affinity probe for serotonin-transporter.

Chudzik J, McCarthy D, Bakish D, Ravindran A, Hrdina PD.

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

Paroxetine is an effective antidepressant drug and potent serotonin (5-HT) uptake inhibitor. It selectively labels 5-HT transporter on platelets and neurons. We report here the synthesis of an aryl-azido derivative of paroxetine, which is a novel photoactive and irreversible ligand for the [3H]paroxetine binding site on the platelet 5-HT transporter. The compound inhibited [3H]paroxetine binding (IC50, 55 nM) and 5-HT uptake (IC50, 12 nM) at equilibrium conditions and inactivated 10-20% of [3H]paroxetine binding sites upon irradiation at 320 nm. SDS-PAGE of platelet protein extract labelled with the radioactive analogue of the synthesized probe revealed the presence of four radioactive bands of which the 71-kDa one was the most prominent.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7488236&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
The effect of paroxetine on cerebrospinal fluid concentrations of neurotransmitter metabolites in depressed patients.

Lundmark J, Walinder J, Alling C, Manniche PM, Dalgaard L.

Department of Psychiatry, University Hospital, Linkoping, Sweden.

This paper describes the effect of the selective serotonin reuptake inhibiting drug (SSRI), paroxetine, on cerebrospinal fluid concentrations of neurotransmitter metabolites in depressed patients. 5-Hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) were measured at baseline and after 3 weeks of treatment with 30 mg paroxetine daily. In line with similar studies on other SSRIs, influence on both the serotonin and noradrenaline metabolite was found. The mechanism behind the action of paroxetine on both 5-HIAA and MHPG is assumed to be an expression of the linkage between the serotonergic and noradrenergic systems in the brain. A frequently reported correlation between 5-HIAA and HVA was also found. The analysis of paroxetine in CSF proves the transportation of the drug into the central nervous system.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7515737&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Mechanisms for the inhibition of genital vascular responses by antidepressants in a female rabbit model.

Angulo J, Cuevas P, Cuevas B, Gupta S, Saenz de Tejada I.

Fundacion para la Investigacion y el Desarrollo en Andrologia, Madrid, Spain.

Vaginal and clitoral vasodilator responses (genital vascular responses; GVRs) to pelvic nerve electrical stimulation in female rabbits were measured by laser Doppler flow needle probes. The intravenous administration of various treatments was evaluated. GVRs were attenuated by a nitric-oxide synthase inhibitor (48.5 and 51.8% of control at 8 Hz in the vagina and clitoris, respectively) and norepinephrine (NE) (78.5 and 61.5%), whereas serotonin (5-HT) had no inhibitory effect. The selective 5-HT reuptake inhibitor (SSRI) escitalopram did not modify GVRs, whereas the SSRI paroxetine dose-dependently inhibited GVRs in female rabbits (43.3 and 53.1% at 5 mg/kg). GVRs were also significantly inhibited by the 5-HT and NE reuptake inhibitors venlafaxine (53.4 and 52.6% at 5 mg/kg) and duloxetine (40.9 and 37.4% at 1 mg/kg). L-arginine prevented the inhibitory effects of paroxetine (105.5 and 115.3%) and partially prevented duloxetine-induced reduction of GVRs but had no effect on the inhibition of GVRs induced by venlafaxine. Conversely, the alpha-adrenergic receptor blocker phentolamine had no effect on paroxetine-induced reduction of GVRs, partially prevented the inhibitory effects of duloxetine, and fully prevented the effects of venlafaxine (93.0 and 96.7%). Duloxetine-induced inhibition of GVRs was completely prevented by combined administration of L-arginine and phentolamine (123.5 and 103.6%). Although 5-HT or the highly selective SRI escitalopram did not inhibit GVRs, NE or inhibition of nitric oxide (NO) synthesis did. Inhibition of the NO pathway by paroxetine and duloxetine or activation of alpha-adrenergic mechanisms by venlafaxine and duloxetine lead to antidepressant-induced inhibition of GVRs in female rabbits.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15034084&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Interaction between a selective 5-HT1A receptor antagonist and an SSRI in vivo: effects on 5-HT cell firing and extracellular 5-HT.

Gartside SE, Umbers V, Hajos M, Sharp T.

University of Oxford Department of Clinical Pharmacology, Radcliffe Infirmary, Oxford.

1. The acute inhibitory effect of selective 5-hydroxytryptamine (serotonin) reuptake inhibitors (SSRIs) on 5-HT neuronal activity may offset their ability to increase synaptic 5-HT in the forebrain. 2. Here, we determined the effects of the SSRI, paroxetine, and a novel selective 5-HT1A receptor antagonist, WAY 100635, on 5-HT cell firing in the dorsal raphe nucleus (DRN), and on extracellular 5-HT in both the DRN and the frontal cortex (FCx). Extracellular electrophysiological recording and brain microdialysis were used in parallel experiments, in anaesthetized rats. 3. Paroxetine dose-dependently inhibited the firing of 5-HT neurones in the DRN, with a maximally effective dose of approximately 0.8 mg kg-1, i.v. WAY 100635 (0.1 mg kg-1, i.v.) both reversed the inhibitory effect of paroxetine and, when used as a pretreatment, caused a pronounced shift to the right of the paroxetine dose-response curve. 4. Paroxetine (0.8 mg kg-1, i.v.), doubled extracellular 5-HT in the DRN, but did not alter extracellular 5-HT in the FCx. A higher dose of paroxetine (2.4 mg kg-1, i.v.) did increase extracellular 5-HT in the FCx, but to a lesser extent than in the DRN. Whereas 0.8 mg kg-1, i.v. paroxetine alone had no effect on extracellular 5-HT in the FCx, in rats pretreated with WAY 100635 (0.1 mg kg-1), paroxetine (0.8 mg kg-1, i.v.) markedly increased extracellular 5-HT in the FCx.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7582504&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Hypodensity of platelet serotonin uptake sites in posttraumatic stress disorder: associated clinical features.

Fichtner CG, O'Connor FL, Yeoh HC, Arora RC, Crayton JW.

Psychiatry Service, Veterans Affairs Medical Center, North Chicago, Illinois 60064, USA.

We have previously reported that binding to blood platelets of paroxetine, a selective serotonin (5-HT) reuptake inhibitor which binds to 5-HT uptake sites, is decreased in patients with posttraumatic stress disorder (PTSD). Specifically, we found a lower number of platelet 3H-paroxetine binding sites (Bmax) and a lower dissociation constant (Kd) for 3H-paroxetine binding in combat veterans with PTSD compared to normal control subjects. In the current study we assessed the relationship of platelet 3H-paroxetine binding to clinical features in 41 Vietnam combat veterans with SCID-diagnosed PTSD. The results indicated that Bmax of platelet 3H-paroxetine binding was negatively correlated with both state and trait anxiety, as well as with depressive and overall PTSD symptoms. However, there was no evidence that platelet 3H-paroxetine binding differed as a function of comorbid psychiatric diagnoses including major depression, other anxiety disorders, and substance abuse in these patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7603291&dopt=Abstract paroxetine, Paxil, Paxil CR