paroxetine, Paxil
Electroencephalographic effects of the new antidepressant paroxetine in the rabbit.

Watanabe S, Ohta H, Ohno M, Tani Y, Furuya Y, Ueki S, Man'no K, Sugihara K.

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

The electroencephalographic (EEG) effect of (-)-trans-4-(4'-fluorophenyl)-3-(3',4'-methylene-dioxyphenoxy-met hyl)piperidine hydrochloride (paroxetine, BRL 29060A) a new antidepressant, was investigated in conscious rabbits with chronic electrode implants and was compared with those of imipramine and amitriptyline. Paroxetine induced an arousal pattern of the spontaneous EEG consisting of low voltage fast waves in the cortex and synchronization of hippocampal theta waves with decreased amplitude, while imipramine and amitriptyline elicited drowsy patterns of the spontaneous EEG. Paroxetine failed to suppress the EEG arousal responses induced not only by auditory stimulation but also by electrical stimulation of the mesencephalic reticular formation, centromedian thalamus and posterior hypothalamus, whereas imipramine and amitriptyline markedly inhibited these responses. The EEG arousal response induced by i.v. injection of physostigmine 0.2 mg/kg was slightly enhanced by paroxetine, while the response was significantly suppressed by imipramine and amitriptyline. Paroxetine, imipramine and amitriptyline showed no significant effect on the photic driving response and recruiting response. Paroxetine did not show any effects on the limbic afterdischarges elicited by either hippocampal or amygdaloid stimulation, while imipramine and amitriptyline caused an initial suppression followed by slight enhancement of these afterdischarges. These results indicate paroxetine to be an antidepressant of a new type which induces a sustained arousal pattern of the spontaneous EEG and has no central anticholinergic action.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2968081&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Regional and subcellular localization in human brain of [3H]paroxetine binding, a marker of serotonin uptake sites.

Laruelle M, Vanisberg MA, Maloteaux JM.

Service de Psychiatrie, Universite Catholique de Louvain, Brussels, Belgium.

The characteristics of the binding of [3H]paroxetine, a selective serotonin (5-HT) uptake blocker, were investigated in human brain. The Kd value was 0.23 +/- 0.07 nM, and the Bmax value was 190 +/- 39 fmol/mg protein in the putamen. The capacity of various antidepressive drugs to inhibit [3H]paroxetine-specific binding in human brain was well correlated with their capacity to inhibit [3H]5-HT uptake in rat brain. The highest concentrations of [3H]paroxetine-specific binding sites were found in the substantia nigra, hypothalamus, and hippocampus. Lower values were obtained in the basal ganglia and the thalamus. The specific binding was very low in cerebral and cerebellar cortices. The regional distribution of [3H]paroxetine binding sites differs from that of [3H]ketanserin binding to S2 serotonin receptors. The subcellular distribution of the [3H]paroxetine-specific binding sites obtained by differential centrifugation revealed a synaptosomal enrichment in the frontal cortex and striatum, whereas an enrichment in the microsomal fraction was found in striatum. The results show that [3H]paroxetine is a ligand of choice to label the 5-HT uptake molecular complex in human brain.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2969755&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Immunological studies on paroxetine, a novel anti-depressant drug.

Henderson DC, Edwards RG, Weston BJ, Dewdney JM.

Beecham Pharmaceuticals Research Division, Biosciences Research Centre, Epsom, Surrey, England.

Paroxetine is a novel and selective neuronal 5-hydroxy-tryptamine uptake inhibitor with anti-depressant activity. Paroxetine was examined for its ability to induce adverse immunological reactions, either as a consequence of a specific immune response or by a direct or indirect effect on the immune system. Paroxetine did not react in vitro with protein amino or thiol groups, suggesting that it lacks the capacity to form potentially immunogenic hapten protein conjugates. No anti-paroxetine antibody was detected in plasma or serum samples from patients and rats following oral administration over prolonged periods, or from epicutaneously exposed guinea pigs, or from rabbits given paroxetine in Freund's adjuvant, suggesting that paroxetine does not have the capacity to elicit humoral immune responses. Guinea pigs epicutaneously exposed to paroxetine did not develop contact sensitivity, suggesting that it does not have the capacity to elicit cell-mediated immune responses. These results suggest that paroxetine lacks intrinsic immunogenicity. Anti-SRBC antibody plaque-forming cell responses in mice were unaffected by oral administration of paroxetine, and paroxetine had no significant effect on ex vivo and in vitro murine macrophage phagocytosis of opsonized SRBC or on ex vivo murine splenocyte mitogen responses, suggesting that paroxetine does not exert modulatory effects on the immune system or on macrophage function. These findings, together with the results of pre-clinical safety evaluation studies, suggest that paroxetine is unlikely to have immunotoxic effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2971630&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Autoradiographic localization of 3H-paroxetine-labeled serotonin uptake sites in rat brain.

De Souza EB, Kuyatt BL.

Neuroscience Branch, National Institute on Drug Abuse, Alcohol, Drug Abuse, Baltimore, Maryland 21224.

Paroxetine is a potent and selective inhibitor of serotonin uptake into neurons. Serotonin uptake sites have been identified, localized, and quantified in rat brain by autoradiography with 3H-paroxetine; 3H-paroxetine binding in slide-mounted sections of rat forebrain was of high affinity (KD = 10 pM) and the inhibition affinity constant (Ki) values of various drugs in competing 3H-paroxetine binding significantly correlated with their reported potencies in inhibiting synaptosomal serotonin uptake. Serotonin uptake sites labeled by 3H-paroxetine were highly concentrated in the dorsal and median raphe nuclei, central gray, superficial layer of the superior colliculus, lateral septal nucleus, paraventricular nucleus of the thalamus, and the islands of Calleja. High concentrations of 3H-paroxetine binding sites were found in brainstem areas containing dopamine (substantia nigra and ventral tegmental area) and norepinephrine (locus coeruleus) cell bodies. Moderate concentrations of 3H-paroxetine binding sites were present in laminae I and IV of the frontal parietal cortex, primary olfactory cortex, olfactory tubercle, regions of the basal ganglia, septum, amygdala, thalamus, hypothalamus, hippocampus, and some brainstem areas including the interpeduncular, trigeminal, and parabrachial nuclei. Lower densities of 3H-paroxetine binding sites were found in other regions of the neocortex and very low to nonsignificant levels of binding were present in white matter tracts and in the cerebellum. Lesioning of serotonin neurons with 3,4-methylenedioxyamphetamine caused large decreases in 3H-paroxetine binding. The autoradiographic distribution of 3H-paroxetine binding sites in rat brain corresponds extremely well to the distribution of serotonin terminals and cell bodies as well as with the pharmacological sites of action of serotonin.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2975068&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Autoradiography of antidepressant binding sites in the human brain: localization using [3H]imipramine and [3H]paroxetine.

Cortes R, Soriano E, Pazos A, Probst A, Palacios JM.

Department of Pathology, University of Basle, Switzerland.

[3H]Imipramine and [3H]paroxetine were used to label sites associated with serotonin uptake mechanisms in post-mortem brain tissue from control subjects. The anatomical localization of these sites was examined by autoradiography and densities measured by microdensitometry. We found [3H]imipramine binding to increase with age in the cortex and amygdala, but to be independent of gender and post-mortem delay. Preliminary results indicate that the binding of both [3H]imipramine and [3H]paroxetine is diminished in the brain of patients treated with imipramine. The distribution of [3H]imipramine and [3H]paroxetine high-affinity binding sites was very similar, and correlated well with the distribution of serotonergic presynaptic markers in the brain. The highest densities of binding sites were found in the raphe nuclei and the midline thalamic nuclei. Other structures presenting high levels of binding were the substantia nigra, nucleus interpeduncularis, locus coeruleus, nucleus nervi hypoglossi, nucleus nervi facialis, mammillary bodies and other parts of the hypothalamus. In contrast, regions such as the neocortex, hippocampus, amygdala and cerebellum showed low densities of [3H]imipramine and [3H]paroxetine binding sites. This distribution seems to indicate that the ascending serotonergic pathways are the main site of action of antidepressants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2975361&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
[Specific inhibitory action of a novel antidepressant paroxetine on 5-HT uptake]

[Article in Japanese]

Tanigaki N, Manno K, Sugihara K, Miki N, Ichida S, Yoshida H.

Effect of a novel antidepressant, paroxetine, on the uptake of serotonin (5-HT), noradrenaline (NA) and dopamine (DA) as well as on various neuro-receptors were investigated in comparison with those of the tricyclic antidepressants amitriptyline, chlorimipramine and imipramine. Paroxetine showed a potent 5-HT uptake inhibitory action, giving the NA/5-HT ratio of 886 in comparison with the ratios of 1.7, 15 and 1.5 for amitriptyline, chlorimipramine and imipramine, respectively. On the other hand, paroxetine showed almost no inhibitory action on the binding of the [3H]-labeled ligands examined in this study [( 3H]quinuclidinyl benzilate, [3H]5-HT, [3H]ketanserine, [3H]pyrilamine, [3H]dihydroalprenolol, [3H]prazosin, [3H]clonidine and [3H]spiroperidol). In contrast, the tricyclic antidepressants showed inhibitory action on a number of bindings and also revealed comparatively high affinities especially for muscarine, histamine-1 and alpha 1-adrenaline receptors responsible for the side effects. From the above findings, it can be concluded that paroxetine has only a weak affinity for various neuro-receptors and inhibits specifically 5-HT uptake.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3038714&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Association of [3H]-imipramine and [3H]-paroxetine binding with the 5HT transporter in brain and platelets: relevance to studies in depression.

Langer SZ, Galzin AM, Poirier MF, Loo H, Sechter D, Zarifian E.

[3H]-Imipramine and [3H]-paroxetine label with high affinity a site which is associated with the serotonergic transporter in brain and platelets. The pharmacological profile of inhibition by drugs of [3H]-imipramine and [3H]-paroxetine binding is highly correlated with the potency of the drugs to inhibit the uptake of 5HT. Denervation of serotonergic neurons by electrolytic lesions or with 5,7-dihydroxytryptamine produces marked decreases in the density of [3H]-imipramine as well as [3H]-paroxetine binding. Dissociation kinetic experiments support the view that the substrate recognition site for 5HT is different from the modulatory site which is labelled by [3H]-imipramine or [3H]-paroxetine. The existence of an endogenous ligand acting on the [3H]-imipramine recognition site to modulate the 5HT transporter was proposed by several laboratories. [3H]-Imipramine binding in platelets appears to be a biological marker in depression. Studies carried out in several laboratories report a significant decrease in the Bmax of platelet [3H]-imipramine binding without changes in Kd, when severely depressed untreated patients are compared with healthy volunteers matched for age and sex. The Bmax of platelet [3H]-imipramine binding appears to be a state-dependent biological marker in depression. It is tempting to speculate that the endocoid of the [3H]-imipramine recognition site may play a role in the pathogenesis of depression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3040983&dopt=Abstract paroxetine, Paxil, Paxil CR